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• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
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  • A61P9/08—Vasodilators for multiple indications

Definitions

• mTOR The mammalian target of rapamycin (mTOR) is a serine- threonine kinase related to the lipid kinases of the phosphoinositide 3-kinase (PI3K) family.
• PI3K phosphoinositide 3-kinase
• mTOR exists in two complexes, mTORCl 1 2 and mTORC2 3 4 , which are differentially regulated, have distinct substrate specificities, and are differentially sensitive to rapamycin.
• mTORCl integrates signals from growth factor receptors with cellular nutritional status and controls the level of cap-dependent mRNA translation by modulating the activity of key translational components such as the cap- binding protein and oncogene eIF4E 5 .
• Rapamycin is a selective mTORCl inhibitor through the binding to the FK506 Rapamycin Binding (FRB) domain of mTOR kinase with the aid of FK506 binding protein 12 (FKBP12).
• FRB domain of mTOR is accessible in the mTORC 1 complex, but less so in the mTORC2 complex.
• the potency of inhibitory activities against downstream substrates of mTORCl by the treatment of Rapamycin is known to be diverse among the mTORCl substrates.
• Rapamycin strongly inhibits phosphorylation of S6K and phosphorylation of the downstream ribosomal protein S6 which control ribosomal biogenesis.
• Rapamycin shows only partial inhibitory activity against phosphorylation of 4E-BP1, a major regulator of eIF4E which controls the initiation of CAP-dependent translation.
• more complete inhibitors of mTORCl signaling are of interest 1 .
• the asTORi also inhibit mTORC2, which is not inhibited by Rapamycin, since the former do not require the FRB domain to bind and inhibit mTORC2.
• the compound ⁇ 128 (now termed MLN0128) is related to PP242 6 ' u and is in numerous anti-cancer Phase I and Phase II clinical trials.
• MLN0128 has the effect of blocking 4E-BP1 phosphorylation.
• asTORi may have the effect of blocking 4E-BP 1 phosphorylation, these agents may also inhibit mTORC2, which leads to a block of Akt activation due to
• a compound including a monovalent active site mTOR inhibitor covalently bound to a monovalent rapamycin or a monovalent rapamycin analog.
• composition including a
• a method of treating a disease associated with an aberrant level of mTORCl activity in a subject in need of such treatment is provided.
• a method of treating an mTORCl activity-associated disease in a subject in need of such treatment including administering a compound, or a pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. a claim, embodiment, example, table, figure, or claim).
• FIGS. 2A-2B Design concept.
• FIG. 2A Overlap modeling of cocrystal structure of mTOR catalytic domain with PP242 (MLN0128 has not been crystalized in mTOR, but PP242 was the prototype for MLN0128 and thus served as a model) with mTOR FRB domain with Rapamycin. Dotted lines represent the distance between isopropyl group of PP242 and C40- hydroxy group of Rapamycin.
• FIG. 2B General structure of Rapamycin derivative conjugated with asTORi.
• FIGS. 3A-3B Model of mTOR signaling inhibition.
• FIG. 3 A Known inhibitors such as Rapalog and mTOR catalytic inhibitor (asTORi).
• FIG. 3B Novel Rapamycin derivatives conjugated with asTORi.
• FIGS. 4A-4B Design concept.
• FIGS. 4A-4B Design concept.
• FIG. 4A Overlap modeling of co-crystal structure of mTOR catalytic domain bearing active site inhibitor PP242 (4JT5) with mTOR FRB
• FIGS. 5A-5B Cell viability assays of SNU-449 Cells treated with (FIG. 5A) M-1 115, Rapamycin, M-1071, M-1 11 1, and MLN0128. or (FIG. 5B) MLN0128, M-1071, or a combination of Rapamycin+ MLN0128.
• FIG. 5A M-11 15 (squares); Rapamycin (circles); M-1071 (triangles); M-l l l l (squares); MLN0128 (circles);
• FIGS. 6A-6B Cell viability assays of 786-0 Cells treated with (FIG. 6A) M-11 15, Rapamycin, M-1071, M-1 11 1, and MLN0128. or (FIG. 6B) HCT-15 Cells treated with M-11 15, Rapamycin, M-1071, M-1 11 1, and MLN0128.
• FIG. 6A M-11 15 (squares); Rapamycin (circles); M-1071 (triangles); M-l l l l (squares); MLN0128 (circles).
• FIG. 6B Rapamycin (circles); M-11 15 (squares); M-1071 (triangles); M-l l l l (squares); MLN0128 (circles).
• FIG. 7. Dose dependent effects on TORC1 and TORC2 outputs for (left) M-1071, (center) M-l 1 11, and (right) M-l 115 in HCT-15 Cells.
• FIGS. 8A-8B Dose dependent effects on TORC1 and TORC2 (FIG. 8A) outputs for MLN0128, Rapamycin, M-1071, M-l 11 1, and M-l 1 15 in SNU-449 Cells. (FIG. 8B) Time dependent signaling effects of MLN0128 (dose), M-1071(dose), and Rapamycin (dose), in SNU- 449 Cells.
• FIG. 9 In vivo effects of M-1071 on 786-0 tumor bearing mice following single or multiple day dosing.
• M- 1077 1 mg/kg (triangle in dotted line); M-1071 3 mg/kg (circle in dashed line); M-1071 5 mg/kg (square in solid line); Rapamycin 5 mg/kg (cross in solid line); MLN0128 1 mg/kg (triangle in dotted line); MLN0128 3 mg/kg (circle in dashed line); MLN0128 5 mg/kg (square in solid line); Vehicle (diamond in solid line).
• FIG. 1 TORC 1 and TORC2 outputs at times after washout for (left) M- 1071 , (center) MLN0128, and (right) Rapamycin in SNU-449 cells.
• FIG. 12 Chemical drawings depicting the Rapa-LINK inhibitor Ml 071 combining the allosteric inhibitor, rapamycin, with the ASi, MLN-0128. Compounds E1035 and E1010 combined rapamycin with the known ASi, PP242, and a PP242 derivative, MeO-PP242, respectively, as depicted.
• FIGS 13A-13B FIG. 13A: MCF-7 cells were treated for 4 hours with E1035 and M1071 before harvesting.
• FIG. 13B SNU-449 cells were treated with 3 hours with E1010 before harvesting. Cells were lysed and blotted for the indicated proteins.
• Ml 071 has the narrowest concentration range between mTORCl and mTORC2 inhibition.
• concentration range between mTORCl and mTORC2 inhibition widens for El 035.
• El 010 which contains an extremely weak ASi, only partially inhibits mTORC 1.
• FIGS. 14A-14B FIG. 14A: 786-0 cells were treated for 72 hours with the indicated drugs before cell viability was measured. Legend: E1010 (squares); MLN0128 (circles);
• FIG. 14B MCF-7 cells were treated for 72 hours with the indicated drugs before cell viability was measured. Legend: E1035 (circles); M1071 (squares);
• substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 0- is equivalent to -OCH 2 -.
• alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched non-cyclic carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbons).
• saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec -butyl,
• an unsaturated alkyl group is one having one or more double bonds or triple bonds.
• unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers.
• An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-).
• An alkyl moiety may be an alkenyl moiety.
• An alkyl moiety may be an alkynyl moiety.
• An alkyl moiety may be fully saturated.
• alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited
• alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
• a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
• alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
• heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched non-cyclic chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
• the heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
• a heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P).
• a heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P).
• a heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P).
• a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
• a heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P).
• a heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).
• heteroalkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
• heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy,
• heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R', -C(0)NR, -NR'R", -OR', -SR', and/or -S0 2 R.
• heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive.
• heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.
• cycloalkyl and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, non-aromatic cyclic versions of “alkyl” and
• heteroalkyl respectively, wherein the carbons making up the ring or rings do not necessarily need to be bonded to a hydrogen due to all carbon valencies participating in bonds with non- hydrogen atoms. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
• cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3 -cyclohexenyl, cycloheptyl, 3-hydroxy-cyclobut-3-enyl-l,2, dione, lH-l,2,4-triazolyl-5(4H)- one, 4H-l,2,4-triazolyl, and the like.
• heterocycloalkyl examples include, but are not limited to, l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3- yl, 1-piperazinyl, 2-piperazinyl, and the like.
• a heterocycloalkyl moiety may include one ring heteroatom (e.g., O, N, S, Si, or P).
• a heterocycloalkyl moiety may include two optionally different ring heteroatoms (e.g., O, N, S, Si, or P).
• a heterocycloalkyl moiety may include three optionally different ring heteroatoms (e.g., O, N, S, Si, or P).
• a heterocycloalkyl moiety may include four optionally different ring heteroatoms (e.g., O, N, S, Si, or P).
• a heterocycloalkyl moiety may include five optionally different ring heteroatoms (e.g., O, N, S, Si, or P).
• a heterocycloalkyl moiety may include up to 8 optionally different ring heteroatoms (e.g., O, N, S, Si, or P).
• halo or halogen
• haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
• terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
• halo(Ci-C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
• acyl means, unless otherwise stated, -C(0)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
• a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
• the term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
• heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
• a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
• a 6,6- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
• a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
• a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
• Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1- pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- is
• aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
• Non-limiting examples of aryl and heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl,
• a heteroaryl moiety may include one ring heteroatom (e.g., O, N, or S).
• a heteroaryl moiety may include two optionally different ring heteroatoms (e.g., O, N, or S).
• a heteroaryl moiety may include three optionally different ring heteroatoms (e.g., O, N, or S).
• a heteroaryl moiety may include four optionally different ring heteroatoms (e.g., O, N, or S).
• a heteroaryl moiety may include five optionally different ring heteroatoms (e.g., O, N, or S).
• An aryl moiety may have a single ring.
• An aryl moiety may have two optionally different rings.
• An aryl moiety may have three optionally different rings.
• An aryl moiety may have four optionally different rings.
• a heteroaryl moiety may have one ring.
• a heteroaryl moiety may have two optionally different rings.
• a heteroaryl moiety may have three optionally different rings.
• a heteroaryl moiety may have four optionally different rings.
• a heteroaryl moiety may have five optionally different rings.
• a fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl.
• a fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl.
• heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.
• a fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl.
• Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substitutents described herein.
• oxo as used herein, means an oxygen that is double bonded to a carbon atom.
• alkylsulfonyl means a moiety having the formula -S(02)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R may have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").
• -NRC (0)NR"NR"R"", -CN, -N0 2 , in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical.
• R, R, R", R'", and R"" each preferably
• each of the R groups is independently selected as are each R, R", R'", and R"" group when more than one of these groups is present.
• R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring.
• -NR'R includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
• alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like).
• substituents for the aryl and heteroaryl groups are varied and are selected from, for
• R, R", R', and R" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
• R groups are independently selected as are each R', R", R", and R"” groups when more than one of these groups
• Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
• Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
• the ring- forming substituents are attached to adjacent members of the base structure.
• two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
• the ring-forming substituents are attached to a single member of the base structure.
• two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
• the ring- forming substituents are attached to non-adjacent members of the base structure.
• Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR') q -U-, wherein T and U are
• q is an integer of from 0 to 3.
• two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR-, -0-, -NR-, -S-, -S(O) -, -S(0) 2 -, -S(0) 2 NR-, or a single bond, and r is an integer of from 1 to 4.
• One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
• two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the
• R, R, R", and R' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
• heteroatom or "ring heteroatom” are meant to include, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
• a substituent group as used herein, may be a group selected from the following moieties:
• heterocycloalkyl unsubstituted aryl, unsubstituted heteroaryl, and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo,
• a "size-limited substituent” or " size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a "substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C2 0 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C1 0 aryl, and each substituted or unsubstituted hetero
• a "lower substituent” or " lower substituent group,” as used herein, means a group selected from all of the substituents described above for a "substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C1 0 aryl, and each substituted or unsubstituted heteroaryl is a substituted or un
• each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.
• each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C2 0 alkyl
• each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
• each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl
• each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl
• each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C1 0 aryl
• each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.
• each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C2 0 alkylene
• each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene
• each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene
• each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene
• each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C1 0 arylene
• each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
• each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl
• each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
• each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl
• each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl
• each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C1 0 aryl
• each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
• each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-Cs alkylene
• each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene
• each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene
• each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene
• each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C1 0 arylene
• each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
• the compound is a chemical species set forth in the Examples section, figures, or tables below.
• pharmaceutically acceptable salts is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
• base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
• pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
• acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
• suitable inert solvent examples include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
• salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et ah, Journal of Pharmaceutical Science 66: 1-19 (1977)).
• Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
• Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
• the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.
• the compounds of the present invention may exist as salts, such as with
• the present invention includes such salts.
• salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid.
• These salts may be prepared by methods known to those skilled in the art.
• the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
• the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
• agents e.g. compounds, drugs, therapeutic agents
• Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under select physiological conditions to provide the final agents (e.g. compounds, drugs, therapeutic agents). Additionally, prodrugs can be converted to agents (e.g. compounds, drugs, therapeutic agents) by chemical or biochemical methods in an ex vivo environment.
• Prodrugs described herein include compounds that readily undergo chemical changes under select physiological conditions to provide agents (e.g. compounds, drugs, therapeutic agents) to a biological system (e.g. in a subject, in a cell, in the extracellular space near a cell).
• Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
• salt refers to acid or base salts of the compounds used in the methods of the present invention.
• acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.
• Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention.
• the compounds of the present invention do not include those which are known in art to be too unstable to synthesize and/or isolate.
• the present invention is meant to include compounds in racemic and optically pure forms.
• Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
• the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
• isomers refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
• tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.
• structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
• structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this invention.
• the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
• the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
• the symbol denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.
• a or “an,” as used in herein means one or more.
• substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
• a group such as an alkyl or heteroaryl group
• the group may contain one or more unsubstituted C1-C2 0 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
• R-substituted where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.
• Descriptions of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.
• treating refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.
• the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. For example, certain methods herein treat diseases associated with mTORCl activity.
• Certain methods described herein may treat diseases associated with mTORCl activity by inhibiting mTORCl activity. Certain methods described herein may treat diseases associated with mTORCl by inhibiting mTORCl activity to a greater degree than inhibiting mTORC2 activity. For example, certain methods herein treat cancer. For example certain methods herein treat cancer by decreasing a symptom of cancer. Symptoms of cancer would be known or may be determined by a person of ordinary skill in the art. For example, certain methods herein treat an autoimmune disease. For example certain methods herein treat an autoimmune disease by decreasing a symptom of the autoimmune disease. Symptoms of an autoimmune disease would be known or may be determined by a person of ordinary skill in the art. For example, certain methods herein treat an inflammatory disease.
• certain methods herein treat an inflammatory disease by decreasing a symptom of the inflammatory disease. Symptoms of an inflammatory disease would be known or may be determined by a person of ordinary skill in the art. For example, certain methods herein treat a neurodegenerative disease. For example certain methods herein treat a neurodegenerative disease by decreasing a symptom of the neurodegenerative disease. Symptoms of a neurodegenerative disease would be known or may be determined by a person of ordinary skill in the art. For example, certain methods herein treat a metabolic disease. For example certain methods herein treat a metabolic disease by decreasing a symptom of the metabolic disease. Symptoms of a metabolic disease would be known or may be determined by a person of ordinary skill in the art. For example, certain methods herein treat transplant rejection.
• certain methods herein treat transplant rejection by decreasing a symptom of transplant rejection. Symptoms of transplant rejection would be known or may be determined by a person of ordinary skill in the art.
• certain methods herein treat fungal infection.
• certain methods herein treat fungal infection by decreasing a symptom of fungal infection.
• Symptoms of fungal infection would be known or may be determined by a person of ordinary skill in the art.
• certain methods herein treat a cardiovascular disease.
• certain methods herein treat a cardiovascular disease by decreasing a symptom of the cardiovascular disease. Symptoms of a cardiovascular disease would be known or may be determined by a person of ordinary skill in the art.
• the term "treating" and conjugations thereof, include prevention of an injury, pathology, condition, or disease.
• an "effective amount” is an amount sufficient to accomplish a stated purpose (e.g.
• an "effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a "therapeutically effective amount.”
• a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
• a “prophylactically effective amount" of a drug or prodrug is an amount of a drug or prodrug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
• the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
• a prophylactically effective amount may be administered in one or more administrations.
• cancer autoimmune disease, inflammatory disease, metabolic disease, neurodegenerative disease, fungal infection, cardiovascular disease, or transplant rejection
• a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function.
• an agent e.g. compound as described herein
• Control or "control experiment” or “standard control” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects.
• Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including
• contacting may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme.
• inhibition means negatively affecting (e.g. decreasing) the level of activity or function of the protein relative to the level of activity or function of the protein in the absence of the inhibitor.
• inhibition refers to reduction of a disease or symptoms of disease.
• inhibition may include, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating,
• activation means positively affecting (e.g.
• activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.
• activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up- regulating signal transduction or enzymatic activity or the amount of a protein.
• modulator refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule.
• a modulator is an anti- cancer agent.
• a modulator is an anti-autoimmune disease agent.
• a modulator is an anti-inflammatory disease agent. In embodiments, a modulator is an anti-neurodegenerative disease agent. In embodiments, a modulator is an anti-metabolic disease agent. In embodiments, a modulator is an anti-transplant rejection agent. In
• a modulator is an anti-fungal infection agent. In embodiments, a modulator is an anti-cardiovascular disease agent. In embodiments, a modulator is a longevity agent. In embodiments, a modulator is a modulator of mTORCl activity. In embodiments, a modulator is an mTORCl activity inhibitor. In embodiments, a modulator is an mTORCl activity activator. In embodiments, a modulator is a modulator of a signaling pathway including mTORCl .
• Anti-cancer agent or "anti-cancer drug” is used in accordance with its plain ordinary meaning and refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.
• an anti-cancer agent is a chemotherapeutic.
• an anticancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer.
• anti-cancer agents include, but are not limited to, rapamycin, rapamycin analog, bevacizumab, PP242, ⁇ 128, MLN0128, anti-androgens (e.g., Casodex, Flutamide, MDV3100, or ARN-509), MEK (e.g. MEKl, MEK2, or MEKl and MEK2) inhibitors (e.g.
• alkylating agents e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates
• alkylating agents e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambuci
• anti-metabolites e.g., 5- azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP 16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.
• fluorodaunorunicin hydrochloride gadolinium texaphyrin; gallium nitrate; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; matrilysin inhibitors; matrix metalloproteinase inhibitors; MIF inhibitor; mifepristone;
• mismatched double stranded RNA monoclonal antibody,; mycobacterial cell wall extract; nitric oxide modulators; oxaliplatin; panomifene; pentrozole; phosphatase inhibitors; plasminogen activator inhibitor; platinum complex; platinum compounds; prednisone; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; ribozymes; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; stem cell inhibitor; stem-cell division inhibitors; stromelysin inhibitors; synthetic glycosaminoglycans; tamoxifen methiodide;
• telomerase inhibitors thyroid stimulating hormone; translation inhibitors; tyrosine kinase inhibitors; urokinase receptor antagonists; steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate,
• GnRH gonadotropin-releasing hormone agonists
• adrenocorticosteroids e.g., prednisone
• fluoxymesterone e.g., flutamide
• immunostimulants e.g., Bacillus Calmette- Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.
• monoclonal antibodies e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies
• immunotoxins e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.
• radioimmunotherapy e.g., anti- CD20 monoclonal antibody conjugated to U 1 ln, 90 Y, or 131 I, etc.
• triptolide homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vin
• gefitinib IressaTM
• erlotinib TarcevaTM
• cetuximab ErbituxTM
• lapatinib TykerbTM
• panitumumab VectibixTM
• vandetanib CaprelsaTM
• afatinib/BIBW2992 CI-1033/canertinib, neratinib/HKI-272, CP- 724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasat
• tomaymycin carboplatin
• CC-1065 and CC-1065 analogs including amino-CBIs, nitrogen mustards (such as chlorambucil and melphalan), dolastatin and dolastatin analogs (including auristatins: eg. monomethyl auristatin E), anthracycline antibiotics (such as doxorubicin, daunorubicin, etc.), duocarmycins and duocarmycin analogs, enediynes (such as neocarzinostatin and calicheamicins), leptomycin derivaties, maytansinoids and maytansinoid analogs (e.g.
• mertansine methotrexate, mitomycin C, taxoids, vinca alkaloids (such as vinblastine and vincristine), epothilones (e.g. epothilone B), camptothecin and its clinical analogs topotecan and irinotecan, ⁇ 128, PP242, PP121, MLN0128, AZD8055, AZD2014, VP-BEZ235, BGT226, SFl 126, Torin 1, Torin 2, WYE 687, WYE 687 salt (e.g., hydrochloride), PF04691502, PI- 103, CC-223, OSI-027, XL388, KU- 0063794, GDC-0349, PKI-587, rapamycin, deforolimus (AP23573, MK-8669, ridaforolimus), temsirolimus (CCI-779), ABT478, everolimus (RAD001) or the like.
• “Chemotherapeutic” or “chemotherapeutic agent” is used in accordance with its plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.
• Patient or “subject in need thereof or “subject” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a compound or pharmaceutical composition or by a method, as provided herein.
• Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.
• a patient is human.
• a subject is human.
• Disease or “condition” refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein.
• the disease is a disease having the symptom of cell
• the disease is a disease having the symptom of an aberrant level of mTORC 1 activity. In some embodiments, the disease is a disease having the symptom of an aberrant level of mTORC 1 pathway activity. In some embodiments, the disease is a disease associated with mTORC 1 activity. In some embodiments, the disease is a disease associated with mTORC 1 pathway activity. In some embodiments, the disease is a cancer. In some embodiments, the disease is an autoimmune disease. In some embodiments, the disease is a neurodegenerative disease. In some embodiments, the disease is a metabolic disease. In some embodiments, the disease is an inflammatory disease. In some embodiments, the disease is transplant rejection. In some embodiments, the disease is fungal infection. In some
• the disease is a cardiovascular disease.
• cancer refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g.
• a disease that may be treated with a compound, pharmaceutical composition, or method described herein is Organ or tissue transplant rejection (e.g.
• encephalomyelitis insulin-dependent diabetes mellitus, lupus, dermatomyositis, arthritis, rheumatic diseases, Steroid-resistant acute Lymphoblastic Leukemia, fibrosis, scleroderma, pulmonary fibrosis, renal fibrosis, cystic fibrosis, Pulmonary hypertension, Multiple sclerosis, VHL syndrome, Carney complex, Familial adenonamtous polyposis, Juvenile polyposis syndrome, Birt-Hogg-Duke syndrome, Familial hypertrophic cardiomyopathy, Wolf-Parkinson- White syndrome, Parkinson's disease, Huntingtin's disease, Alzheimer's disease, dementias caused by tau mutations, spinocerebellar ataxia type 3, motor neuron disease caused by SOD1 mutations, neuronal ceroid lipofucinoses/Batten disease (pediatric neurodegeneration), wet macular degeneration, dry macular degeneration, muscle wasting (atrophy, cachexia), myopathies (e
• cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, carcinomas and sarcomas.
• Exemplary cancers that may be treated with a compound or method provided herein include cancer of the prostate, thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, pancreatic cancer.
• Additional examples may include, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.
• leukemia refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number of aberrant cells in the blood-leukemic or aleukemic (subleukemic).
• Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,
• hemocytoblastic leukemia histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblasts leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia,
• sarcoma generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
• Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sar
• melanoma is taken to mean a tumor arising from the melanocyte system of the skin and other organs.
• Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
• carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
• exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid
• autoimmune disease refers to a disease or condition in which a subject's immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy subject.
• autoimmune diseases include Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia,
• ADAM Acute Disseminated Encephalomyelitis
• Alopecia areata
• Amyloidosis Ankylosing spondylitis
• Anti-GBM/Anti-TBM nephritis Antiphospholipid syndrome (APS), Autoimmune angioe
• Autoimmune inner ear disease AIED
• Autoimmune myocarditis Autoimmune myocarditis
• Autoimmune oophoritis Autoimmune pancreatitis
• Autoimmune retinopathy Autoimmune thrombocytopenic purpura (ATP)
• Autoimmune thyroid disease Autoimmune urticaria, Axonal or neuronal neuropathies, Balo disease, Behcet's disease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricial pemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogans syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST
• Hashimoto's thyroiditis Hemolytic anemia, Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4- related sclerosing disease, Immunoregulatory lipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere's disease, Microscopic polyangiitis, Mixed connective tissue disease (MCTD),
• Pernicious anemia POEMS syndrome, Polyarteritis nodosa, Type I, II, & III autoimmune polyglandular syndromes, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia, Raynauds phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Reiter's syndrome, Relapsing polychondritis, Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity,
• Tolosa-Hunt syndrome Transverse myelitis, Type 1 diabetes, Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, Vitiligo, or Wegener's granulomatosis (i.e., Granulomatosis with Polyangiitis (GPA).
• neurodegenerative disease refers to a disease or condition in which the function of a subject's nervous system becomes impaired. Examples of
• neurodegenerative diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer- Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt- Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HlV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado- Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy,
• Narcolepsy Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick's disease, Primary lateral sclerosis, Prion diseases, Refsum's disease, Sandhoff s disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia,
• the term "metabolic disease” refers to a disease or condition in which a subject's metabolism or metabolic system (e.g., function of storing or utilizing energy) becomes impaired.
• metabolic diseases include diabetes (e.g., type I or type II), obesity, metabolic syndrome, or a mitochondrial disease (e.g., dysfunction of mitochondria or aberrant mitochondrial function).
• fungal disease refers to a disease or condition associated with a fungus infection of the subject.
• fungal diseases that may be treated with a compound, pharmaceutical composition, or method described herein include infection with Mucor circinelloides, zygomycetes, Cryptococcus neoformans, Candida albicans, yeast, and Saccharomyces cerevisiae among others.
• inflammatory disease refers to a disease or condition characterized by aberrant inflammation (e.g. an increased level of inflammation compared to a control such as a healthy person not suffering from a disease).
• inflammatory diseases include traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's
• vasculitis vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.
• cardiovascular disease refers to a disease or condition in which the function of a subject's cardiovascular system becomes impaired.
• cardiovascular diseases include congestive heart failure; arrhythmogenic syndromes (e.g., paroxysomal tachycardia, delayed after depolarizations, ventricular tachycardia, sudden tachycardia, exercise-induced arrhythmias, long QT syndromes, or bidirectional tachycardia); thromboembolic disorders (e.g., arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, or thromboembolic disorders in the chambers of the heart); atherosclerosis; restenosis; peripheral arterial disease; coronary bypass grafting surgery; carotid artery disease; arteritis; myocarditis; cardiovascular inflammation; vascular
• coronary heart disease (CHD); unstable angina (UA); unstable refractory angina; stable angina (SA); chronic stable angina; acute coronary syndrome (ACS); myocardial infarction (first or recurrent); acute myocardial infarction (AMI); myocardial infarction; non-Q wave myocardial infarction; non-STE myocardial infarction; coronary artery disease; ischemic heart disease; cardiac ischemia; ischemia; ischemic sudden death; transient ischemic attack; stroke; peripheral occlusive arterial disease; venous thrombosis; deep vein thrombosis;
• thrombophlebitis arterial embolism; coronary arterial thrombosis; cerebral arterial thrombosis, cerebral embolism; kidney embolism; pulmonary embolism; thrombosis (e.g., associated with prosthetic valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis); thrombosis (e.g., associated with atherosclerosis, surgery, prolonged
• signaling pathway refers to a series of interactions between cellular and optionally extra-cellular components (e.g. proteins, nucleic acids, small molecules, ions, lipids) that conveys a change in one component to one or more other components, which in turn may convey a change to additional components, which is optionally propagated to other signaling pathway components.
• extra-cellular components e.g. proteins, nucleic acids, small molecules, ions, lipids
• aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples.
• Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non- disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
• amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
• Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ⁇ -carboxyglutamate, and O-phosphoserine.
• Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
• Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.
• non-naturally occurring amino acid and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.
• amino acid mimetics and polypeptide mimetics include peptoids, D-peptides, and ⁇ -peptides.
• Amino acids may be modified amino acids (natural or mimetics) including additional moieties, for example function, therapeutic, or detectable moieties. Modified amino acids may be modified in the side chain by the addition of additional moieties.
• Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical
• nucleotides likewise, may be referred to by their commonly accepted single-letter codes.
• Twenty amino acids are commonly found in proteins. Those amino acids can be grouped into nine classes or groups based on the chemical properties of their side chains. Substitution of one amino acid residue for another within the same class or group is referred to herein as a "conservative" substitution. Conservative amino acid substitutions can frequently be made in a protein without significantly altering the conformation or function of the protein. Substitution of one amino acid residue for another from a different class or group is referred to herein as a "non- conservative" substitution. In contrast, non-conservative amino acid substitutions tend to modify conformation and function of a protein.
• the conservative amino acid substitution comprises substituting any of glycine (G), alanine (A), isoleucine (I), valine (V), and leucine (L) for any other of these aliphatic amino acids; serine (S) for threonine (T) and vice versa; aspartic acid (D) for glutamic acid (E) and vice versa; glutamine (Q) for asparagine (N) and vice versa; lysine (K) for arginine (R) and vice versa; phenylalanine (F), tyrosine (Y) and tryptophan (W) for any other of these aromatic amino acids; and methionine (M) for cysteine (C) and vice versa.
• substitutions can also be considered conservative, depending on the environment of the particular amino acid and its role in the three- dimensional structure of the protein.
• G glycine
• A alanine
• V valine
• Methionine (M) which is relatively hydrophobic, can frequently be interchanged with leucine and isoleucine, and sometimes with valine.
• Lysine (K) and arginine (R) are frequently
• Polypeptide “peptide,” and “protein” are used herein interchangeably and mean any pepti de-linked chain of amino acids, regardless of length or post-translational modification.
• the polypeptides described herein can be, e.g., wild-type proteins, biologically- active fragments of the wild-type proteins, or variants of the wild- type proteins or fragments.
• Variants, in accordance with the disclosure can contain amino acid substitutions, deletions, or insertions. The substitutions can be conservative or non-conservative.
• amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.
• a polypeptide includes amino acid mimetics or modified amino acids, the monomer may be connected through bonds that are different from or derivatives of peptide links.
• proteins can be isolated.
• purified or “isolated” as applied to any of the proteins described herein refers to a polypeptide that has been separated or purified from components (e.g., proteins or other naturally-occurring biological or organic molecules) which naturally accompany it (e.g., other proteins, lipids, and nucleic acid in a cell expressing the proteins).
• a polypeptide is purified when it constitutes at least 60 (e.g., at least 65, 70, 75, 80, 85, 90, 92, 95, 97, or 99) %, by weight, of the total protein in a sample.
• amino acid residue in a protein "corresponds" to a given residue when it occupies the same essential structural position within the protein as the given residue.
• a selected residue in a selected protein corresponds to a residue when the selected residue occupies the same essential spatial or other structural relationship as a specified residue relative to the rest of the protein.
• “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
• Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
• Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
• auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
• auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
• auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents
• preparation is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
• cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
• administering means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow- release device, e.g., a mini-osmotic pump, to a subject.
• Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
• Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
• co-administer it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g. anti-cancer agent, anti-autoimmune disease agent, anti-inflammatory disease agent, anti-neurodegenerative disease agent, anti-metabolic disease agent, anti-transplant rejection agent, anti-fungal infection agent, or longevity agent).
• additional therapies e.g. anti-cancer agent, anti-autoimmune disease agent, anti-inflammatory disease agent, anti-neurodegenerative disease agent, anti-metabolic disease agent, anti-transplant rejection agent, anti-fungal infection agent, or longevity agent.
• the compound of the invention can be administered alone or can be coa
• compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
• Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient.
• Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
• Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
• the compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,91 1,920; 5,403,841 ; 5,212, 162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.
• compositions of the present invention can also be delivered as microspheres for slow release in the body.
• microspheres can be administered via intradermal injection of drug- containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Set Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997).
• the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis.
• liposomes particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo.
• the compositions of the present invention can also be delivered as nanoparticles.
• compositions provided by the present invention include compositions wherein the active ingredient (e.g. compounds described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose.
• the actual amount effective for a particular application will depend, inter alia, on the condition being treated.
• such compositions When administered in methods to treat a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., reducing, eliminating, or slowing the progression of disease symptoms (e.g. symptoms of cancer, autoimmune disease, inflammatory disease, metabolic disease,
• the dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g. symptoms of cancer or neurodegenerative disease), kind of concurrent treatment, complications from the disease being treated or other health-related problems.
• Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of Applicants' invention. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art.
• the therapeutically effective amount can be initially determined from cell culture assays.
• Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
• therapeutically effective amounts for use in humans can also be determined from animal models.
• a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.
• the dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
• Dosages may be varied depending upon the requirements of the patient and the compound being employed.
• the dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time.
• the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
• Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
• an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.
• the compounds described herein can be used in combination with one another, with other active agents known to be useful in treating cancer, autoimmune disease, inflammatory disease, metabolic disease, neurodegenerative disease, fungal infection, or transplant rejection, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
• the compounds described herein can be used in combination with other active agents known to be longevity agents or anti-aging agents.
• co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent.
• Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order.
• co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents.
• the active agents can be formulated separately.
• the active and/or adjunctive agents may be linked or conjugated to one another.
• the compounds described herein may be combined with treatments for cancer such as radiation or surgery.
• mTORCl binds to a protein or complex
• mTORCl binds to a binding reaction which is determinative of the presence of the protein or complex in the presence of a heterogeneous population of proteins and other biologies.
• the specified compound binds to a particular protein (mTOR) or complex (e.g., mTORCl) and does not bind in a significant amount to other proteins or complexes present in the sample (e.g., mTORC2).
• Specific or significant or selective binding of a compound to mTORCl and not mTORC2 may be binding to mTORCl with at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 100000, 200000, 300000, 400000, 500000, 600000, 700000, 800000, 900000, or 1000000 fold greater affinity than binding of the identical compound to mTORC2 under identical assay conditions.
• mTOR refers to the protein "mechanistic target of rapamycin
• mTOR may refer to the nucleotide sequence or protein sequence of human mTOR (e.g., Entrez 2475, Uniprot P42345, RefSeq NM_004958, or RefSeq NP_004949) (SEQ ID NO: 1).
• mTOR includes both the wild-type form of the nucleotide sequences or proteins as well as any mutants thereof.
• “mTOR” is wild-type mTOR.
• mTOR is one or more mutant forms.
• mTOR XYZ refers to a nucleotide sequence or protein of a mutant mTOR wherein the Y numbered amino acid of mTOR that normally has an X amino acid in the wildtype, instead has a Z amino acid in the mutant.
• an mTOR is the human mTOR.
• the mTOR has the nucleotide sequence corresponding to reference number GL206725550 (SEQ ID NO:2).
• the mTOR has the nucleotide sequence corresponding to RefSeq NM_004958.3 (SEQ ID NO:2).
• the mTOR has the protein sequence corresponding to reference number GL4826730 (SEQ ID NO: 1).
• the mTOR has the protein sequence corresponding to RefSeq
• the mTOR has the following amino acid sequence:
• the mTOR is a mutant mTOR.
• the mutant mTOR is associated with a disease that is not associated with wildtype mTOR.
• the mTOR includes at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared to the sequence above.
• mTORCl refers to the protein complex including mTOR and Raptor (regulatory-associated protein of mTOR). mTORCl may also include MLST8 (mammalian lethal with SEC 13 protein 8), PRAS40, and/or DEPTOR. mTORCl may function as a nutrient/energy/redox sensor and regulator of protein synthesis.
• mTORCl pathway or "mTORCl signal transduction pathway” refers to a cellular pathway including mTORCl. An mTORCl pathway includes the pathway components upstream and downstream from mTORCl. An mTORCl pathway is a signaling pathway that is modulated by modulation of mTORCl activity.
• an mTORC 1 pathway is a signaling pathway that is modulated by modulation of mTORCl activity but not by modulation of mTORC2 activity.
• an mTORCl pathway is a signaling pathway that is modulated to a greater extent by modulation of mTORC 1 activity than by modulation of mTORC2 activity.
• mTORC2 refers to the protein complex including mTOR and RICTOR (rapamycin-insensitive companion of mTOR). mTORC2 may also include G L, mSINl (mammalian stress-activated protein kinase interacting protein 1), Protor 1/2, DEPTOR, TTI1, and/or TEL2. mTORC2 may regulate cellular metabolism and the cytoskeleton.
• mTORC2 pathway or “mTORC2 signal transduction pathway” refers to a cellular pathway including mTORC2.
• An mTORC2 pathway includes the pathway components upstream and downstream from mTORC2.
• An mTORC2 pathway is a signaling pathway that is modulated by modulation of mTORC2 activity.
• an mTORC2 pathway is a signaling pathway that is modulated by modulation of mTORC2 activity but not by modulation of mTORCl activity.
• an mTORC2 pathway is a signaling pathway that is modulated to a greater extent by modulation of mTORC2 activity than by modulation of mTORC 1 activity.
• Rapamycin refers to a macrolide produced by the bacteria Streptomyces hygroscopicus. Rapamycin may prevent the activation of T cells and B cells. Rapamycin has the IUPAC name
• Rapamycin has the CAS number 53123-88-9. Rapamycin may be produced synthetically (e.g., by chemical synthesis) or through use of a production method that does not include use of Streptomyces hygroscopicus.
• Analog is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound, including isomers thereof. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.
• rapaymcin analog refers to analogs or derivatives (e.g., prodrugs) of rapamycin.
• examples of rapamycin analogs include, but are not limited to, deforolimus (AP23573, MK-8669, ridaforolimus), temsirolimus (CCI-779), ABT478, and everolimus (RAD001).
• rapamycin analogs include esters, ethers, amides, carbonates, carbamates, sulfonates, oximes, hydrazones, or hydroxyamines of rapamycin.
• rapamycin analogs include rapamycins in which functional groups on rapamycin have been modified, (e.g., through reduction or oxidation, replacement with a nucleophile).
• rapamycin analogs include a metabolite of rapamycin (e.g., a desmethylrapamycin derivative or a linear rapamycin (e.g., secorapamycin, as described in U.S. Pat. No. 5,252,579).
• rapamycin analogs include O-desmethylrapamycin, desmethylrapamycin, or desmethoxyrapamycin (for example, as described in WO 2006/095185, U.S. Pat. No. 6,358,969).
• rapamycin analogs include ester derivatives or ether derivatives of rapamycin, including alkyl esters (U.S. Pat. No. 4,316,885); aminoalkyl esters (U.S. Pat. No. 4,650,803); fluorinated esters (U.S. Pat. No. 5, 100,883); amide esters (U.S. Pat. No. 5, 118,677); carbamate esters (U.S. Pat. Nos. 5, 118,678; 5,411,967; 5,480,989; 5,480,988; 5,489,680); amino carbamate esters (U.S. Pat. No. 5,463,048); silyl ethers (U.S. Pat. No.
• rapamycin analogs include ester, oxime, hydrazone, ether, or hydroxylamine derivatives of rapamycin, including those described in .U.S. Pat. Nos. 5,256,790, 5,373,014, 5,378,836, 5,023,264, 5,563, 145, and 5,023,263.
• rapamycin analogs include rapamycin 42-ester with 3-hydroxy-2- (hydroxymethyl)-2-methylpropionic acid (U.S. Pat. No. 5,362,718), 42-Q-(2-hydroxy)ethyl rapamycin (U.S. Pat. No.
• rapamycin analogs include a substituted rapamycin e.g. a 40-O-substituted rapamycin e.g.
• rapamycin analogs include a 16-O-substituted rapamycin e.g. as disclosed in WO 94/02136, WO 95/16691 or WO 96/41807.
• rapamycin analogs include a 32-hydrogenated rapamycin e.g.
• rapamycin analogs include 32- deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy- 32(S)-dihydro- rapamycin, 16-pent-2-ynyloxy-32(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin or 40-0-(2- hydroxyethyl)-rapamycin.
• rapamycin analogs include 40-O-(2-hydroxyethyl)- rapamycin, 40-[3-hydroxy-2- (hydroxymethyl)-2-methylpropanoate]-rapamycin (also called CCI779), 40-epi-(tetrazolyl)-rapamycin (also called ABT578), 32-deoxorapamycin, 16-pent-2- ynyloxy-32(S)-dihydro rapamycin, or TAFA- 93.
• the publications, patents, and applications described above are incorporated by reference in their entireties for all purposes.
• active site mTOR inhibitor refers to a compound that inhibits the activity of mTOR (e.g., kinase activity) and binds to the the active site of mTOR (e.g., the ATP binding site, overlapping with the ATP binding site, blocking access by ATP to the ATP binding site of mTOR).
• active site mTOR inhibitors include, but are not limited to, ⁇ 128, PP242, PP121, MLN0128, AZD8055, AZD2014, NVP-BEZ235, BGT226, SF1126, Torin 1, Torin 2, WYE 687, WYE 687 salt (e.g., hydrochloride), PF04691502, PI-103, CC-223, OSI-027, XL388, KU-0063794, GDC-0349, and PKI-587.
• an active site mTOR inhibitor is an asTORi.
• FKBP refers to the protein Peptidyl-prolyl cis-trans isomerase.
• FKBP refers to “FKBP- 12" or “FKBP 12" or “FKBP 1 A”.
• FKBP refers to the human protein. Included in the term “FKBP” is the wildtype and mutant forms of the protein.
• FKBP refers to the wildtype human protein.
• FKBP refers to the wildtype human nucleic acid.
• the FKBP is a mutant FKBP.
• the mutant FKBP is associated with a disease that is not associated with wildtype FKBP.
• the FKBP includes at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared to wildtype FKBP.
• the term "FKBP-12” or “FKBP 12" or “FKBP1A” refers to the protein "Peptidyl- prolyl cis-trans isomerase FKBP 1 A". In embodiments, ""FKBP-12" or "FKBP 12" or
• FKBP 1 A refers to the human protein. Included in the term “FKBP-12” or “FKBP 12” or “FKBP 1 A” are the wildtype and mutant forms of the protein. In embodiments, “FKBP-12” or “FKBP 12” or “FKBP 1 A” refers to the protein associated with Entrez Gene 2280, OMIM 186945, UniProt P62942, and/or RefSeq (protein) NP_000792 (SEQ ID NO:3). In
• the reference numbers immediately above refer to the protein, and associated nucleic acids, known as of the date of filing of this application.
• FKBP-12 or “FKBP 12” or “FKBP 1 A” refers to the wildtype human protein.
• FKBP-12 or “FKBP 12” or “FKBP1A” refers to the wildtype human nucleic acid.
• the FKBP-12 is a mutant FKBP-12.
• the mutant FKBP-12 is associated with a disease that is not associated with wildtype FKBP-12.
• the FKBP-12 includes at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared to wildtype FKBP-12.
• the FKBP-12 has the protein sequence corresponding to reference number GI:206725550.
• the FKBP-12 has the protein sequence corresponding to RefSeq NP_000792.1 (SEQ ID NO:3).
• 4E-BP1 or “4EBP1” or “EIF4EBP1” refers to the protein "Eukaryotic translation initiation factor 4E-binding protein 1".
• 4E-BP1 or “4EBP1” or “EIF4EBP 1” refers to the human protein. Included in the term “4E-BP 1 " or "4EBP 1 " or
• EIF4EBP1 are the wildtype and mutant forms of the protein.
• 4E-BP1 or “4EBP1” or “EIF4EBP1” refers to the protein associated with Entrez Gene 1978, OMIM
• the reference numbers immediately above refer to the protein, and associated nucleic acids, known as of the date of filing of this application.
• ""4E-BP 1 " or “4EBP1” or “EIF4EBP1” refers to the wildtype human protein.
• “4E-BP1” or “4EBP1” or “EIF4EBP1” refers to the wildtype human nucleic acid.
• the 4EBP1 is a mutant 4EBP1.
• the mutant 4EBP1 is associated with a disease that is not associated with wildtype 4EBP1.
• the 4EBP1 includes at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared to wildtype 4EBP1.
• the 4EBP1 has the protein sequence corresponding to reference number GL4758258.
• the 4EBP1 has the protein sequence corresponding to RefSeq NP_004086.1 (SEQ ID NO:4).
• Akt refers to the serine/threonine specific protein kinase involved in cellular processes such as glucose metabolism, apoptosis, proliferation, and other functions, also known as “protein kinase B” (PKB) or "Aktl".
• PKA protein kinase B
• Akt protein kinase B
• Akt protein kinase B
• Akt or AM” or “PKB” refers to the human protein. Included in the term “Akt” or “Aktl” or “PKB” are the wildtype and mutant forms of the protein.
• Akt or “Aktl” or “PKB” refers to the protein associated with Entrez Gene 207, OMIM 164730, UniProt P31749, and/or RefSeq (protein) NP_005154 (SEQ ID NO:5).
• the reference numbers immediately above refer to the protein, and associated nucleic acids, known as of the date of filing of this application.
• Akt or “Aktl” or “PKB” refers to the wildtype human protein.
• Akt or “Aktl” or “PKB” refers to the wildtype human nucleic acid.
• the Akt is a mutant Akt.
• the mutant Akt is associated with a disease that is not associated with wildtype Akt.
• the Akt includes at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared to wildtype Akt.
• the Akt has the protein sequence corresponding to reference number GI: 62241011.
• the Akt has the protein sequence corresponding to RefSeq NP_005154.2 (SEQ ID NO:5).
• longevity agent is an agent (e.g., composition as described herein) capable of extending the life expectancy of a subjct in comparison to the life expectancy of the subject in the absence of the agent (Lamming, D. W., et al. (2012). Science (New York, NY), 335(6076), 1638-1643., McCormick, M. A., et al. (201 1). Philosophical Transactions of the Royal Society B: Biological Sciences, 366(1561)).
• a longevity agent may be capable of inducing one or more anti-aging effects in a subject wherein an aging effect is a condition or symptom of aging normally found in a similar subject.
• the term "about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about means the specified value.
• a compound including a monovalent active site mTOR inhibitor covalently bound to a monovalent rapamycin or a monovalent rapamycin analog.
• a divalent linker binds the monovalent active site mTOR inhibitor (active site mTOR inhibitor moiety) to the monovalent rapamycin (rapamycin moiety) or the monovalent rapamycin analog (rapamycin analog moiety).
• the divalent linker may be bonded to rapamycin or a rapamycin analog at a position capable of being modified to include a linker.
• a linker may be bonded to rapamycin or a rapamycin analog at position 10, 16, 27, 28, 39, or 40, among others (as indicated in figure immediately below).
• a linker is bonded to position 10 of rapamycin or a rapamycin analog.
• a linker is bonded to position 16 of rapamycin or a rapamycin analog.
• a linker is bonded to position 27 of rapamycin or a rapamycin analog.
• a linker is bonded to position 28 of rapamycin or a rapamycin analog.
• a linker is bonded to position 39 of rapamycin or a rapamycin analog.
• a linker is bonded to position 40 of
• the divalent linker is at least about or about 5 A in length (e.g., at least about or about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,
• the divalent linker is at least about or about the length of 5 methylene groups (e.g., 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 methylene groups).
• 5 methylene groups e.g., 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 methylene groups.
• the divalent linker is at least about or about the length of 11 methylene groups (e.g., at least about or about 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 methylene groups).
• the divalent linker is at least about or about the length of 27 methylene groups (e.g., 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 methylene groups).
• the divalent linker is from about 5 to 54 A in length. In embodiments, the divalent linker is from about 6 to 54 A in length. In embodiments, the divalent linker is from about 7 to 54 A in length. In embodiments, the divalent linker is from about 9 to 54 A in length. In embodiments, the divalent linker is from about 11 to 54 A in length. In embodiments, the divalent linker is from about 13 to 54 A in length. In embodiments, the divalent linker is from about 15 to 54 A in length. In embodiments, the divalent linker is from about 20 to 54 A in length. In embodiments, the divalent linker is from about 24 to 54 A in length. In embodiments, the divalent linker is from about 28 to 54 A in length.
• the divalent linker is from about 5 to 50 A in length. In embodiments, the divalent linker is from about 5 to 46 A in length. In embodiments, the divalent linker is from about 5 to 42 A in length. In embodiments, the divalent linker is from about 5 to 38 A in length. In embodiments, the divalent linker is from about 5 to 34 A in length. In embodiments, the divalent linker is from about 5 to 30 A in length. In embodiments, the divalent linker is from about 5 to 26 A in length. In embodiments, the divalent linker is from about 5 to 22 A in length. In embodiments, the divalent linker is from about 5 to 39 A in length. In embodiments, the divalent linker is from about 7 to 37 A in length.
• the divalent linker is from about 9 to 35 A in length. In embodiments, the divalent linker is from about 11 to 33 A in length. In embodiments, the divalent linker is from about 13 to 31 A in length. In embodiments, the divalent linker is from about 15 to 29 A in length. In embodiments, the divalent linker is from about 15 to 25 A in length. In embodiments, the divalent linker is from about 15 to 23 A in length.
• the divalent linker is at least about or about 32 A in length (e.g., at least about or about 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 A in length).
• the divalent linker is at least about or about the length of 27 methylene groups. In embodiments, the divalent linker is from about 32 to 54 A in length. In embodiments, the divalent linker is from about 33 to 53 A in length. In embodiments, the divalent linker is from about 34 to 52 A in length. In embodiments, the divalent linker is from about 35 to 51 A in length. In embodiments, the divalent linker is from about 36 to 50 A in length. In embodiments, the divalent linker is from about 37 to 49 A in length. In embodiments, the divalent linker is from about 38 to 48 A in length. In embodiments, the divalent linker is from about 39 to 47 A in length.
• the divalent linker is from about 40 to 46 A in length. In embodiments, the divalent linker is from about 41 to 45 A in length. In embodiments, the divalent linker is from about 42 to 44 A in length. In embodiments, the divalent linker is from about 32 to 52 A in length. In embodiments, the divalent linker is from about 32 to 50 A in length. In embodiments, the divalent linker is from about 32 to 48 A in length. In embodiments, the divalent linker is from about 32 to 46 A in length. In embodiments, the divalent linker is from about 32 to 44 A in length. In embodiments, the divalent linker is from about 32 to 42 A in length. In embodiments, the divalent linker is from about 32 to 40 A in length.
• the divalent linker is from about 32 to 38 A in length. In embodiments, the divalent linker is from about 32 to 36 A in length. In embodiments, the divalent linker is from about 34 to 54 A in length. In embodiments, the divalent linker is from about 36 to 54 A in length. In embodiments, the divalent linker is from about 38 to 54 A in length. In embodiments, the divalent linker is from about 40 to 54 A in length. In embodiments, the divalent linker is from about 42 to 54 A in length. In embodiments, the divalent linker is from about 44 to 54 A in length. In embodiments, the divalent linker is from about 46 to 54 A in length. In embodiments, the divalent linker is from about 48 to 54 A in length. In embodiments, the divalent linker is from about 50 to 54 A in length.
• the specified length of a linker is the through space distance between the ends of the linker (i.e., the ends or termini that are connected to the two parts of the molecule connected by the linker) wherein the length of the linker is measured when the linker is fully extended and wherein the linker termini are the furthest apart they may naturally exist in solution (i.e., the longest distance between the ends of the linker wherein the linker adopts allowable
• the linker length is measured when included in a compound as described herein (e.g., aspect, embodiment, example, figures, table, claim). It will be understood that a linker may adopt a through space distance (e.g., in solution, when bound to mTORCl, when bound to mTOR) that is less than the fully extended conformation used to define the linker length.
• the linker is a hydrolysable linker (e.g., in solution). In embodiments, the linker is a non-hydrolysable linker (e.g., in solution). In embodiments, the linker may be cleaved by an enzyme (e.g., hydrolase, protease, cytochrome). In embodiments, the linker is not cleavable by an enzyme (e.g., under normal cellular conditions). In embodiments, the linker is a polyethylene glycol linker. In embodiments, the linker is hydrophilic. In embodiments, the linker is hydrophobic. In embodiments, the linker includes a disulfide bond.
• an enzyme e.g., hydrolase, protease, cytochrome
• the linker is not cleavable by an enzyme (e.g., under normal cellular conditions).
• the linker is a polyethylene glycol linker.
• the linker is hydrophilic. In embodiments, the linker is hydro
• the linker includes a hydrazone bond. In embodiments, the linker includes an ester. In embodiments, the linker includes a sulfonyl. In embodiments, the linker includes a thioether. In embodiments, the linker includes a phosphinate. In embodiments, the linker includes an alkyloxime bond. In embodiments, the linker includes one or more amino acids. In
• the linker consists of amino acids. In embodiments, the linker includes an amino acid analog. In embodiments, the linker includes an amino acid mimetic. In embodiments, the linker is a linker known in the art for use in linking antibodies to agents (e.g., antibody drug conjugates). In embodiments, the linker is a linker as described in Bioconjugate Techniques (Second Edition) by Greg T. Hermanson (2008), which is herein incorporated by referenced in its entirety for all purposes. In embodiments, the linker is a linker as described in Flygare JA, Pillow TH, Aristoff P., Antibody-drug conjugates for the treatment of cancer. Chemical Biology and Drug Design.
• the linker is a linker as described in Drachman JG, Senter PD., Antibody-drug conjugates: the chemistry behind empowering antibodies to fight cancer. Hematology Am Soc Hematol Educ Program. 2013; 2013:306-10, which is herein incorporated by referenced in its entirety for all purposes.
• the compound includes a divalent linker covalently bound to the monovalent active site mTOR inhibitor and the monovalent rapamycin or monovalent rapamycin analog. In embodiments, the compound includes a divalent linker covalently bound directly to the monovalent active site mTOR inhibitor and directly to the monovalent rapamycin or monovalent rapamycin analog.
• the active site mTOR inhibitor is an asTORi. In embodiments, the active site mTOR inhibitor is ⁇ 128. In embodiments, the active site mTOR inhibitor is PP242. In embodiments, the active site mTOR inhibitor is PP121. In embodiments, the active site mTOR inhibitor is MLN0128. In embodiments, the active site mTOR inhibitor is AZD8055. In embodiments, the active site mTOR inhibitor is AZD2014. In embodiments, the active site mTOR inhibitor is NVP-BEZ235. In embodiments, the active site mTOR inhibitor is BGT226. In embodiments, the active site mTOR inhibitor is SF1 126. In embodiments, the active site mTOR inhibitor is Torin 1.
• the active site mTOR inhibitor is Torin 2. In embodiments, the active site mTOR inhibitor is WYE 687. In embodiments, the active site mTOR inhibitor is WYE 687 salt (e.g., hydrochloride). In embodiments, the active site mTOR inhibitor is PF04691502. In embodiments, the active site mTOR inhibitor is PI-103, CC-223. In embodiments, the active site mTOR inhibitor is OSI-027, XL388. In embodiments, the active site mTOR inhibitor is KU-0063794. In embodiments, the active site mTOR inhibitor is GDC- 0349. In embodiments, the active site mTOR inhibitor is PKI-587. When included in the compounds described herein, an active site mTOR inhibitor described above and elsewhere herein will be understood to be a monovalent form of the described active site mTOR inhibitor.
• the compound has the formula:
• L 1 is a floating substituent
• R is a monovalent active site mTOR inhibitor
• the compound has the formula:
• L is as described herein and may be bonded to any atom in the ring (L 1 is a floating substituent) and R 100 is a monovalent active site mTOR inhibitor.
• R 100 is a monovalent active site mTOR inhibitor.
• L 1 is as described herein and may be bonded to any atom in the ring (L 1 is a floating substituent) and R 100 is a monovalent active site mTOR inhibitor.
• the compound has the formula:
• L is as described herein and may be bonded to any atom in the ring (L 1 is a floating substituent) and R 100 is a monovalent active site mTOR inhibitor.
• R 100 is a monovalent active site mTOR inhibitor. In embodiments, R 100 is
• W 1 , W 2 , W 3 , W 4 , and R 3 are as described herein.
• R are as described herein.
• R and R are as described herein.
• R 3 is as described herein.
• R is wherein R 3 and R 11 are as described herein.
• R 100 is
• R 3 , R 11 , and R 12 are as described herein.
• R 1
• R 3 and R 12 are as described herein.
• the compound has the formula:
• W 3 , W 4 , L 1 , Y, and R 3 are as described herein.
• the compound has the formula:
• the compound has the formula:
• the compound has the formula:
• R are as described herein.
• the compound has the formula:
• L 1 is a divalent linker as described herein.
• W 1 is N or CR 11 .
• W 2 is N and W 3 is C or, alternatively, W 2 is C and W 3 is N.
• W 4 is N or CR 12 .
• Y is O or NR 13 .
• R 7 and R 8 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
• the variables m and v are independently 1 or 2.
• the variable n is independently an integer from 0 to 4.
• the variable X is independently -CI, -Br, -I, or -F.
• L 1 is a divalent linker including one or more amino acids.
• L 1 is a divalent linker consisting of amino acids (i.e. a peptidyl linker).
• L 1 is a divalent linker (e.g. a peptidyl linker) including an amino acid analog.
• L 1 is a divalent linker (e.g. a peptidyl linker) including an amino acid mimetic. In embodiments, L 1 is a divalent linker consisting of amino acid analogs (also referred to herein as a peptidyl analog linker). In embodiments, L 1 is a divalent linker consisting of amino acid mimetics (also referred to herein as a peptidyl mimetic linker). [0143] In embodiments, W 1 is N. In embodiments, W 1 is CR 11 . In embodiments, W 2 is N and W 3 is C. In embodiments, W 2 is C and W 3 is N. In embodiments, W 4 is N. In embodiments, W 4 is CR 12 . In embodiments, Y is O. In embodiments, Y is NR 13 . In embodiments, W 1 is CH. In embodiments, W 4 is CH. In embodiments, Y is NH.
• the compound has the formula:
• the compound has the formula:
• R 3 is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• R 3 is independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• R 3 is independently substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R 3 is independently substituted or unsubstituted fused ring aryl, or substituted or unsubstituted fused ring heteroaryl. In embodiments, R 3 is independently substituted or unsubstituted fused ring heteroaryl. In embodiments, R 3 is independently substituted fused ring heteroaryl.
• R is as described herein.
• Ring A is an aryl (e.g., phenyl, diphenyl, or fused ring aryl) or a heteroaryl (e.g., monocyclic heteroaryl or fused ring heteroaryl). Ring A may be any of the aryl or heteroaryl rings in the embodiments of
• R 3 described herein e.g., benzoxazolyl, indolyl, phenyl, or naphthyl.
• the symbol z3 is an integer from 0 to 7. In embodiments, z3 is 0. In embodiments, z3 is 1. In embodiments, z3 is 2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3 is 5. In embodiments, z3 is 6. In embodiments, z3 is 7.
• R 3 is independently substituted benzoxazolyl, substituted pyrimidinyl, substituted thiophenyl, substituted furanyl, substituted indolyl, substituted benzoxadiazolyl, substituted benzodioxolyl, substituted benzodioxanyl, substituted thianaphthanyl, substituted pyrrolopyridinyl, substituted indazolyl, substituted quinolinyl, substituted quinoxalinyl, substituted pyridopyrazinyl, substituted quinazolinonyl, substituted benzoisoxazolyl, substituted imidazopyridinyl, substituted benzofuranyl, substituted benzothiophenyl, substituted phenyl, substituted naphthyl, substituted biphenyl, substituted pyrrolyl, substituted pyrazolyl, substituted imidazolyl, substituted pyrazinyl, substituted substituted
• R 3 is independently substituted benzoxazolyl. In embodiments, R 3 is substituted pyrimidinyl. In embodiments, R 3 is substituted thiophenyl. In embodiments, R 3 is substituted furanyl. In embodiments, R 3 is substituted indolyl. In embodiments, R 3 is substituted benzoxadiazolyl. In embodiments, R 3 is substituted benzodioxolyl. In embodiments, R 3 is substituted benzodioxanyl. In embodiments, R 3 is substituted thianaphthanyl. In embodiments, R 3 is substituted pyrrolopyridinyl. In embodiments, R 3 is substituted indazolyl.
• R 3 is substituted quinolinyl. In embodiments, R 3 is substituted quinoxalinyl. In embodiments, R 3 is substituted pyridopyrazinyl. In embodiments, R 3 is substituted quinazolinonyl. In
• R 3 is substituted benzoisoxazolyl. In embodiments, R 3 is substituted
• R 3 is substituted benzofuranyl. In embodiments, R 3 is substituted benzothiophenyl. In embodiments, R 3 is substituted phenyl. In embodiments, R 3 is substituted naphthyl. In embodiments, R 3 is substituted biphenyl. In embodiments, R 3 is substituted pyrrolyl. In embodiments, R 3 is substituted pyrazolyl. In embodiments, R 3 is substituted imidazolyl. In embodiments, R 3 is substituted pyrazinyl. In embodiments, R 3 is substituted oxazolyl. In embodiments, R 3 is substituted isoxazolyl. In embodiments, R 3 is substituted thiazolyl.
• R 3 is substituted furylthienyl. In embodiments, R 3 is substituted pyridyl. In embodiments, R 3 is substituted pyrimidyl. In embodiments, R 3 is substituted benzothiazolyl. In embodiments, R 3 is substituted purinyl. In embodiments, R 3 is substituted benzimidazolyl. In embodiments, R 3 is substituted isoquinolyl. In embodiments, R 3 is substituted thiadiazolyl. In embodiments, R 3 is substituted oxadiazolyl. In embodiments, R 3 is substituted pyrrolyl. In embodiments, R 3 is substituted diazolyl. In embodiments, R 3 is substituted triazolyl. In embodiments, R 3 is substituted tetrazolyl. In embodiments, R 3 is substituted benzothiadiazolyl. In embodiments, R 3 is substituted isothiazolyl. In embodiments,
• R 3 is substituted pyrazolopyrimidinyl. In embodiments, R 3 is substituted pyrrolopyrimidinyl. In embodiments, R 3 is substituted benzotriazolyl. In embodiments, R 3 is substituted quinolyl. In embodiments, R 3 is independently substituted benzoxazolyl.
• R 3 is independently unsubstituted benzoxazolyl. In embodiments, R 3 is unsubstituted pyrimidinyl. In embodiments, R 3 is unsubstituted thiophenyl. In embodiments, R 3 is unsubstituted furanyl. In embodiments, R 3 is unsubstituted indolyl. In embodiments, R 3 is unsubstituted benzoxadiazolyl. In embodiments, R 3 is unsubstituted benzodioxolyl. In embodiments, R 3 is unsubstituted benzodioxanyl. In embodiments, R 3 is unsubstituted thianaphthanyl.
• R 3 is unsubstituted pyrrolopyridinyl. In embodiments, R 3 is unsubstituted indazolyl. In embodiments, R 3 is unsubstituted quinolinyl. In embodiments, R 3 is unsubstituted quinoxalinyl. In embodiments, R 3 is unsubstituted pyridopyrazinyl. In
• R 3 is unsubstituted quinazolinonyl. In embodiments, R 3 is unsubstituted benzoisoxazolyl. In embodiments, R 3 is unsubstituted imidazopyridinyl. In embodiments, R 3 is unsubstituted benzofuranyl. In embodiments, R 3 is unsubstituted benzothiophenyl. In
• R 3 is unsubstituted phenyl. In embodiments, R 3 is unsubstituted naphthyl. In embodiments, R 3 is unsubstituted biphenyl. In embodiments, R 3 is unsubstituted pyrrolyl. In embodiments, R 3 is unsubstituted pyrazolyl. In embodiments, R 3 is unsubstituted imidazolyl. In embodiments, R 3 is unsubstituted pyrazinyl. In embodiments, R 3 is unsubstituted oxazolyl. In embodiments, R 3 is unsubstituted isoxazolyl. In embodiments, R 3 is unsubstituted thiazolyl.
• R 3 is unsubstituted furylthienyl. In embodiments, R 3 is unsubstituted pyridyl. In embodiments, R 3 is unsubstituted pyrimidyl. In embodiments, R 3 is unsubstituted benzothiazolyl. In embodiments, R 3 is unsubstituted purinyl. In embodiments, R 3 is unsubstituted
• R 3 is unsubstituted isoquinolyl. In embodiments, R 3 is unsubstituted thiadiazolyl. In embodiments, R 3 is unsubstituted oxadiazolyl. In embodiments, R 3 is unsubstituted pyrrolyl. In embodiments, R 3 is unsubstituted diazolyl. In embodiments, R 3 is unsubstituted triazolyl. In embodiments, R 3 is unsubstituted tetrazolyl. In embodiments, R 3 is unsubstituted benzothiadiazolyl. In embodiments, R 3 is unsubstituted isothiazolyl. In
• R 3 is unsubstituted pyrazolopyrimidinyl. In embodiments, R 3 is unsubstituted pyrrolopyrimidinyl. In embodiments, R 3 is unsubstituted benzotriazolyl. In embodiments, R 3 is unsubstituted quinolyl. In embodiments, R 3 is independently unsubstituted benzoxazolyl.
• R 3 is substituted with one or more substituents independently selected from halogen, -CF 3 , -OH, and -NH 2 .
• R 3 is substituted heteroaryl, such as benzoxazolyl or benzothiazolyl.
• R 3 is heteroaryl, such as benzoxazolyl or benzothiazolyl, substituted with one or more substituents independently selected from halogen, -CF 3 , -OH, and -NH 2 .
• R is independently R -substituted benzoxazolyl, R -substituted
• 20 20 20 20 20 isothiazolyl, R -substituted pyrazolopyrimidinyl, R -substituted pyrrolopyrimidinyl, R -
• R is independently R - substituted benzoxazolyl.
• R 3 is independently R 20 -substituted benzoxazolyl. In embodiments, R 3 is R -substituted pyrimidinyl. In embodiments, R is R -substituted thiophenyl. In
• R is R -substituted furanyl. In embodiments, R is R -substituted indolyl. In embodiments, R is R -substituted benzoxadiazolyl. In embodiments, R is R -substituted benzodioxolyl. In embodiments, R is R -substituted benzodioxanyl. In embodiments, R is R - substituted thianaphthanyl. In embodiments, R 3 is R 20 -substituted pyrrolopyridinyl. In embodiments, R is R -substituted indazolyl. In embodiments, R is R -substituted quinolinyl.
• R is R -substituted quinoxalinyl. In embodiments, R is R -substituted pyridopyrazinyl. In embodiments, R 3 is R 20 -substituted quinazolinonyl. In embodiments, R 3 is
• R is R -substituted benzoisoxazolyl.
• R is R -substituted imidazopyridinyl.
• R is R -substituted benzofuranyl.
• R is R -substituted
• R is R -substituted phenyl. In embodiments, R is R -
• R is R -substituted biphenyl. In embodiments, R is R -
• R 3 20 3 20 substituted pyrrolyl.
• R is R -substituted pyrazolyl.
• R is R - substituted imidazolyl.
• R 3 is R 20 -substituted pyrazinyl.
• R 3 is
• R -substituted oxazolyl In embodiments, R is R -substituted isoxazolyl. In embodiments, R
• R is R -substituted thiazolyl. In embodiments, R is R -substituted furylthienyl. In embodiments, R is R -substituted pyridyl. In embodiments, R is R -substituted pyrimidyl. In embodiments,
• R is R -substituted benzothiazolyl. In embodiments, R is R -substituted purinyl. In embodiments, R is R -substituted benzimidazolyl. In embodiments, R is R -substituted isoquinolyl. In embodiments, R is R -substituted thiadiazolyl. In embodiments, R is R - substituted oxadiazolyl. In embodiments, R 3 is R 20 -substituted pyrrolyl. In embodiments, R 3 is R -substituted diazolyl. In embodiments, R is R -substituted triazolyl. In embodiments, R is R -substituted tetrazolyl. In embodiments, R is R -substituted benzothiadiazolyl. In
• R is R -substituted isothiazolyl. In embodiments, R is R -substituted pyrazolopyrimidinyl. In embodiments, R 3 is R 20 -substituted pyrrolopyrimidinyl.
• R is R -substituted benzotriazolyl. In embodiments, R is R -substituted quinolyl. In embodiments, R 3 is independently R 20 -substituted benzoxazolyl.
• R 20 is independently oxo
• R 20 is independently -NH 2 . In embodiments, R 20 is independently - OH. In embodiments, R 20 is independently halogen. In embodiments, R 20 is independently - CN. In embodiments, R 20 is independently oxo. In embodiments, R 20 is independently -CF 3 . In embodiments, R 20 is independently -COOH. In embodiments, R 20 is independently -CONH 2 . In embodiments, R 20 is independently -N0 2 . In embodiments, R 20 is independently -SH. In embodiments, R 20 is independently -SO 3 H. In embodiments, R 20 is independently -S0 4 H. In embodiments, R is independently -SO2NH2. In embodiments, R is independently -NHNH 2 . In embodiments, R 20 is independently -ONH 2 . In embodiments, R 20 is independently
• R 20 is independently -NHS0 2 H.
• R 20 is independently -NHC(0)OH.
• R 20 is
• R 20 is independently -NHOH. In embodiments, R 20 is independently -OCF 3 . In embodiments, R 20 is independently -OCHF 2 . In embodiments, R 20 is independently a
• R 20 is independently a halogen, -CF 3 , -CN, -NH 2 , -OH, R 21 -substituted or unsubstituted C1-C4 alkyl, R 21 -substituted or unsubstituted 2 to 4 membered heteroalkyl, R 21 -substituted or unsubstituted C 3 -C6 cycloalkyl, R 21 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 21 -substituted or unsubstituted phenyl, or R 21 -substituted or unsubstituted 5 to 6 membered heteroaryl.
• R 20 is independently a halogen, -CF 3 , -CN, -NH 2 , -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.
• R 20 is independently a halogen, -CF 3 , unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, unsubstituted methoxy, or unsubstituted ethoxy.
• R 20 is independently unsubstituted methyl.
• R 20 is independently unsubstituted ethyl.
• R 20 is independently unsubstituted methoxy. In embodiments, R 20 is independently unsubstituted ethoxy. In embodiments, R 20 is independently -CCI 3 . In embodiments, R 20 is independently -CBr 3 . In embodiments, R 20 is independently -CI 3 . In embodiments, R 20 is independently -F. In embodiments, R 20 is independently -CI. In embodiments, R 20 is independently -Br. In embodiments, R 20 is independently -I.
• R 21 is independently oxo
• R 21 is independently -NH 2 . In embodiments, R 21 is independently - OH. In embodiments, R 21 is independently halogen. In embodiments, R 21 is independently - CN. In embodiments, R 21 is independently oxo. In embodiments, R 21 is independently -CF 3 . In embodiments, R 21 is independently -COOH. In embodiments, R 21 is independently -CONH 2 . In embodiments, R 21 is independently -NO2. In embodiments, R 21 is independently -SH. In embodiments, R 21 is independently -SO 3 H. In embodiments, R 21 is independently -SO4H. In embodiments, R 21 is independently -SO2NH2. In embodiments, R 21 is independently -NHNH 2 . In embodiments, R 21 is independently -ONH 2 . In embodiments, R 21 is independently
• R 21 is independently -NHS0 2 H.
• R 21 is independently -NHC(0)OH.
• R 21 is
• R 21 is independently -NHOH. In embodiments, R 21 is independently -OCF 3 . In embodiments, R 21 is independently -OCHF 2 . In embodiments, R 21 is independently a
• R 21 is independently a halogen, -CF 3 , -CN, -NH 2 , -OH, R 22 -substituted or unsubstituted C1-C4 alkyl, R 22 -substituted or unsubstituted 2 to 4 membered heteroalkyl, R 22 -substituted or unsubstituted C 3 -C6 cycloalkyl, R 22 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 22 -substituted or unsubstituted phenyl, or R 22 -substituted or unsubstituted 5 to 6 membered heteroaryl.
• R 21 is independently a halogen, -CF 3 , -CN, -NH 2 , -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.
• R 21 is independently a halogen, -CF 3 , unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, unsubstituted methoxy, or unsubstituted ethoxy.
• R 21 is independently unsubstituted methyl.
• R 21 is independently unsubstituted ethyl.
• R 21 is independently unsubstituted methoxy. In embodiments, R 21 is independently unsubstituted ethoxy. In embodiments, R 21 is independently -CCI 3 . In embodiments, R 21 is independently -CBr 3 . In embodiments, R 21 is independently -CI 3 . In embodiments, R 21 is independently -F. In embodiments, R 21 is independently -CI. In embodiments, R 21 is independently -Br. In embodiments, R 21 is independently -I.
• R 7 is independently hydrogen
• R 7 is independently hydrogen, -CF 3 , -CN, -COOH, -CONH 2 , R 38 - substituted or unsubstituted alkyl, R 38 -substituted or unsubstituted heteroalkyl, R 38 -substituted or unsubstituted cycloalkyl, R 38 -substituted or unsubstituted heterocycloalkyl, R 38 -substituted or unsubstituted aryl, or R 38 -substituted or unsubstituted heteroaryl.
• R 7 is independently an R 38 -substituted or unsubstituted C1-C4 alkyl, R 38 -substituted or unsubstituted 2 to 4 membered heteroalkyl, R 38 -substituted or unsubstituted C3-C6 cycloalkyl, R 38 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 38 -substituted or unsubstituted phenyl, or R 38 - substituted or unsubstituted 5 to 6 membered heteroaryl.
• R 7 is independently an unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl.
• R 7 is independently an unsubstituted C1-C4 alkyl.
• R 7 is independently an unsubstituted methyl.
• R 7 is independently an unsubstituted ethyl.
• R 7 is independently an unsubstituted isopropyl.
• R 7 is independently an unsubstituted tert-butyl.
• R 7 is independently hydrogen. [0161]
• R 38 is independently oxo,
• R is independently -NH 2 .
• R is independently - OH.
• R 38 is independently halogen.
• R 38 is independently - CN.
• R 38 is independently oxo.
• R 38 is independently -CF 3 . In embodiments, R 38 is independently -COOH. In embodiments, R 38 is independently -CONH 2 . In embodiments, R 38 is independently -NO 2 . In embodiments, R 38 is independently -SH. In embodiments, R 38 is independently -SO 3 H. In embodiments, R 38 is independently -SO 4 H. In embodiments, R 38 is independently -SO 2 NH 2 . In embodiments, R 38 is independently -NHNH 2 . In embodiments, R 38 is independently -ONH 2 . In embodiments, R 38 is independently
• R 38 is independently -NHS0 2 H.
• R 38 is independently -NHC(0)-OH.
• R 38 is
• R 38 is independently -NHOH. In embodiments, R 38 is independently -OCF 3 . In embodiments, R 38 is independently -OCHF 2 . In embodiments, R 38 is independently -CCI 3 . In embodiments, R 38 is independently -CBr 3 . In embodiments, R 38 is independently -CI 3 . In embodiments, R 38 is independently -F. In embodiments, R 38 is independently -CI. In embodiments, R 38 is independently -Br. In embodiments, R 38 is independently -I. In embodiments, R 38 is
• R 38 is independently R 39 -substituted phenyl.
• R 38 is independently R 39 -substituted 5 to 6 membered heteroaryl.
• R 38 is independently unsubstituted C1-C4 alkyl. In embodiments, R 38 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 38 is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R 38 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 38 is independently unsubstituted phenyl. In embodiments, R 38 is independently unsubstituted 5 to 6 membered heteroaryl.
• R 39 is independently oxo
• R is independently -NH 2 .
• R is independently - OH.
• R 39 is independently halogen.
• R 39 is independently - CN.
• R 39 is independently oxo.
• R 39 is independently -CF 3 . In embodiments, R 39 is independently -COOH. In embodiments, R 39 is independently -CONH 2 . In embodiments, R 39 is independently -NO 2 . In embodiments, R 39 is independently -SH. In embodiments, R 39 is independently -SO 3 H. In embodiments, R 39 is independently -SO 4 H. In embodiments, R 39 is independently -SO 2 NH 2 . In embodiments, R 39 is independently -NHNH 2 . In embodiments, R 39 is independently -ONH 2 . In embodiments, R 39 is independently
• R 39 is independently -NHS0 2 H.
• R 39 is independently -NHC(0)-OH.
• R 39 is
• R 39 is independently -NHOH. In embodiments, R 39 is independently -OCF 3 . In embodiments, R 39 is independently -OCHF 2 . In embodiments, R 39 is independently -CCI 3 . In embodiments, R 39 is independently -CBr 3 . In embodiments, R 39 is independently -CI 3 . In embodiments, R 39 is independently -F. In embodiments, R 39 is independently -CI. In embodiments, R 39 is independently -Br. In embodiments, R 39 is independently -I. In embodiments, R 39 is independently R 40 -substituted C1-C4 alkyl. In embodiments, R 39 is independently R 40 -substituted 2 to 4 membered heteroalkyl. In embodiments, R 39 is independently R 40 -substituted C3-C6 cycloalkyl. In embodiments, R 39 is independently R 40 -substituted 3 to 6 membered
• R 39 is independently R 40 -substituted phenyl.
• R 39 is independently R 40 -substituted 5 to 6 membered heteroaryl.
• R 39 is independently unsubstituted C1-C4 alkyl. In embodiments, R 39 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 39 is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R 39 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 39 is independently unsubstituted phenyl. In embodiments, R 39 is independently unsubstituted 5 to 6 membered heteroaryl.
• R 8 is independently hydrogen
• R 8 is independently hydrogen, -CF 3 , -CN, -COOH, -CONH 2 , R 41 - substituted or unsubstituted alkyl, R 41 -substituted or unsubstituted heteroalkyl, R 41 -substituted or unsubstituted cycloalkyl, R 41 -substituted or unsubstituted heterocycloalkyl, R 41 -substituted or unsubstituted aryl, or R 41 -substituted or unsubstituted heteroaryl.
• R 8 is independently an R 41 -substituted or unsubstituted C1-C4 alkyl, R 41 -substituted or unsubstituted 2 to 4 membered heteroalkyl, R 41 -substituted or unsubstituted C3-C6 cycloalkyl, R 41 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 41 -substituted or unsubstituted phenyl, or R 41 - substituted or unsubstituted 5 to 6 membered heteroaryl.
• R 8 is independently an unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl.
• R 8 is independently an unsubstituted C1-C4 alkyl.
• R 8 is independently an unsubstituted methyl.
• R 8 is independently an unsubstituted ethyl.
• R 8 is independently an unsubstituted isopropyl.
• R 8 is independently an unsubstituted tert-butyl.
• R 8 is independently hydrogen.
• R 41 is independently oxo
• R 42 unsubstituted alkyl, R 42 -substituted or unsubstituted heteroalkyl, R 42 -substituted or unsubstituted cycloalkyl, R 42 substituted or unsubstituted heterocycloalkyl, R 42 -substituted or unsubstituted aryl, or R 42 -substituted or unsubstituted heteroaryl.
• R 41 is independently -NH 2 . In embodiments, R 41 is independently - OH. In embodiments, R 41 is independently halogen. In embodiments, R 41 is independently - CN. In embodiments, R 41 is independently oxo. In embodiments, R 41 is independently -CF 3 . In embodiments, R 41 is independently -COOH. In embodiments, R 41 is independently -CONH 2 . In embodiments, R 41 is independently -N0 2 . In embodiments, R 41 is independently -SH. In embodiments, R 41 is independently -SO 3 H. In embodiments, R 41 is independently -SO 4 H. In embodiments, R 41 is independently -S0 2 NH 2 . In embodiments, R 41 is independently -NHNH 2 . In embodiments, R 41 is independently -ONH 2 . In embodiments, R 41 is independently
• R 41 is independently -NHS0 2 H.
• R 41 is independently -NHC(0)-OH.
• R 41 is independently -NHOH.
• R is independently -OCF 3 .
• R is independently -OCHF 2 .
• R 41 is independently -CCI 3 .
• R 41 is independently -CBr 3 .
• R 41 is independently -CI 3 .
• R 41 is independently -F.
• R 41 is independently -CI.
• R 41 is independently -Br. In embodiments, R 41 is independently -I. In embodiments, R 41 is independently R 42 -substituted C1-C4 alkyl. In embodiments, R 41 is independently R 42 -substituted 2 to 4 membered heteroalkyl. In embodiments, R 41 is independently R 42 -substituted C3-C6 cycloalkyl. In embodiments, R 41 is independently R 42 -substituted 3 to 6 membered
• R 41 is independently R 42 -substituted phenyl.
• R 41 is independently R 42 -substituted 5 to 6 membered heteroaryl.
• R 41 is independently unsubstituted C1-C4 alkyl. In embodiments, R 41 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 41 is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R 41 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 41 is independently unsubstituted phenyl. In embodiments, R 41 is independently unsubstituted 5 to 6 membered heteroaryl.
• R 42 is independently oxo
• R 43 -substituted or unsubstituted heteroalkyl R 43 -substituted or unsubstituted cycloalkyl, R 43 -substituted or unsubstituted heterocycloalkyl, R 43 -substituted or unsubstituted aryl, or R 43 -substituted or unsubstituted heteroaryl.
• R 42 is independently -NH 2 . In embodiments, R 42 is independently - OH. In embodiments, R 42 is independently halogen. In embodiments, R 42 is independently - CN. In embodiments, R 42 is independently oxo. In embodiments, R 42 is independently -CF 3 . In embodiments, R 42 is independently -COOH. In embodiments, R 42 is independently -CONH 2 . In embodiments, R 42 is independently -N0 2 . In embodiments, R 42 is independently -SH. In embodiments, R 42 is independently -SO 3 H. In embodiments, R 42 is independently -SO 4 H. In embodiments, R 42 is independently -S0 2 NH 2 . In embodiments, R 42 is independently -NHNH 2 . In embodiments, R 42 is independently -ONH 2 . In embodiments, R 42 is independently
• R 42 is independently -NHS0 2 H.
• R 42 is independently -NHC(0)-OH.
• R 42 is independently -NHOH.
• R is independently -OCF 3 .
• R is independently -OCHF 2 .
• R 42 is independently -CCI 3 .
• R 42 is independently -CBr 3 .
• R 42 is independently -CI 3 .
• R 42 is independently -F.
• R 42 is independently -CI.
• R 42 is independently -Br. In embodiments, R 42 is independently -I. In embodiments, R 42 is independently R 43 -substituted C1-C4 alkyl. In embodiments, R 42 is independently R 43 -substituted 2 to 4 membered heteroalkyl. In embodiments, R 42 is independently R 43 -substituted C 3 -C6 cycloalkyl. In embodiments, R 42 is independently R 43 -substituted 3 to 6 membered
• R 42 is independently R 43 -substituted phenyl.
• R 42 is independently R 43 -substituted 5 to 6 membered heteroaryl.
• R 42 is independently unsubstituted C1-C4 alkyl. In embodiments, R 42 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 42 is independently unsubstituted C 3 -C6 cycloalkyl. In embodiments, R 42 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 42 is independently unsubstituted phenyl. In embodiments, R 42 is independently unsubstituted 5 to 6 membered heteroaryl.
• R 9 is independently hydrogen
• R 9 is independently hydrogen, -CF 3 , -CN, -COOH, -CONH 2 , R 44 - substituted or unsubstituted alkyl, R 44 -substituted or unsubstituted heteroalkyl, R ⁇ -substituted or unsubstituted cycloalkyl, R ⁇ -substituted or unsubstituted heterocycloalkyl, R ⁇ -substituted or unsubstituted aryl, or R ⁇ -substituted or unsubstituted heteroaryl.
• R 9 is independently an R 44 -substituted or unsubstituted C1-C4 alkyl, R 44 -substituted or unsubstituted 2 to 4 membered heteroalkyl, R ⁇ -substituted or unsubstituted C 3 -C6 cycloalkyl, R ⁇ -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 44 -substituted or unsubstituted phenyl, or R 44 - substituted or unsubstituted 5 to 6 membered heteroaryl.
• R 9 is independently an unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C 3 -C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl.
• R 9 is independently an unsubstituted C1-C4 alkyl.
• R 9 is independently an unsubstituted methyl.
• R 9 is independently an unsubstituted ethyl.
• R 9 is independently an unsubstituted isopropyl.
• R 9 is independently an unsubstituted tert-butyl.
• R 9 is independently hydrogen. [0173]
• R 44 is independently oxo,
• R 44 is independently -NH 2 . In embodiments, R 44 is independently - OH. In embodiments, R 44 is independently halogen. In embodiments, R 44 is independently - CN. In embodiments, R 44 is independently oxo. In embodiments, R 44 is independently -CF 3 . In embodiments, R 44 is independently -COOH. In embodiments, R 44 is independently -CONH 2 . In embodiments, R 44 is independently -N0 2 . In embodiments, R 44 is independently -SH. In embodiments, R 44 is independently -SO 3 H. In embodiments, R 44 is independently -SO 4 H. In embodiments, R 44 is independently -S0 2 NH 2 . In embodiments, R 44 is independently -NHNH 2 . In embodiments, R 44 is independently -ONH 2 . In embodiments, R 44 is independently
• R 44 is independently -NHS0 2 H.
• R 44 is independently -NHC(0)-OH.
• R 44 is
• R 44 is independently -NHOH. In embodiments, R 44 is independently -OCF 3 . In embodiments, R 44 is independently -OCHF 2 . In embodiments, R 44 is independently -CCI3. In embodiments, R 44 is independently -CBr 3 . In embodiments, R 44 is independently -CI3. In embodiments, R 44 is independently -F. In embodiments, R 44 is independently -CI. In embodiments, R 44 is independently -Br. In embodiments, R 44 is independently -I. In embodiments, R 44 is independently R 45 -substituted C1-C4 alkyl. In embodiments, R 44 is independently R 45 -substituted 2 to 4 membered heteroalkyl. In embodiments, R 44 is independently R 45 -substituted C3-C6 cycloalkyl. In embodiments, R 44 is independently R 45 -substituted 3 to 6 membered
• R 44 is independently R 45 -substituted phenyl.
• R 44 is independently R 45 -substituted 5 to 6 membered heteroaryl.
• R 44 is independently unsubstituted C1-C4 alkyl. In embodiments, R 44 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R 44 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 44 is independently unsubstituted phenyl. In embodiments, R 44 is independently unsubstituted 5 to 6 membered heteroaryl. [0175] R 45 is independently oxo,
• R 45 is independently -NH 2 . In embodiments, R 45 is independently - OH. In embodiments, R 45 is independently halogen. In embodiments, R 45 is independently - CN. In embodiments, R 45 is independently oxo. In embodiments, R 45 is independently -CF 3 . In embodiments, R 45 is independently -COOH. In embodiments, R 45 is independently -CONH 2 . In embodiments, R 45 is independently -N0 2 . In embodiments, R 45 is independently -SH. In embodiments, R 45 is independently -SO 3 H. In embodiments, R 45 is independently -SO 4 H. In embodiments, R 45 is independently -S0 2 NH 2 . In embodiments, R 45 is independently -NHNH 2 . In embodiments, R 45 is independently -ONH 2 . In embodiments, R 45 is independently
• R 45 is independently -NHS0 2 H.
• R 45 is independently -NHC(0)-OH.
• R 45 is
• R 45 is independently -NHOH. In embodiments, R 45 is independently -OCF 3 . In embodiments, R 45 is independently -OCHF 2 . In embodiments, R 45 is independently -CCI 3 . In embodiments, R 45 is independently -CBr 3 . In embodiments, R 45 is independently -CI 3 . In embodiments, R 45 is independently -F. In embodiments, R 45 is independently -CI. In embodiments, R 45 is independently -Br. In embodiments, R 45 is independently -I. In embodiments, R 45 is independently R 46 -substituted C1-C4 alkyl. In embodiments, R 45 is independently R 46 -substituted 2 to 4 membered heteroalkyl. In embodiments, R 45 is independently R 46 -substituted C 3 -C6 cycloalkyl. In embodiments, R 45 is independently R 46 -substituted 3 to 6 membered
• R 45 is independently R 46 -substituted phenyl.
• R 45 is independently R 46 -substituted 5 to 6 membered heteroaryl.
• R 45 is independently unsubstituted C1-C4 alkyl. In embodiments, R 45 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R 45 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 45 is independently unsubstituted phenyl. In embodiments, R 45 is independently unsubstituted 5 to 6 membered heteroaryl. [0177] In embodiments, R 10 is independently hydrogen,
• R 10 is independently hydrogen, -CF 3 , -CN, -COOH, -CONH 2 , R 47 - substituted or unsubstituted alkyl, R 47 -substituted or unsubstituted heteroalkyl, R 47 -substituted or unsubstituted cycloalkyl, R 47 -substituted or unsubstituted heterocycloalkyl, R 47 -substituted or unsubstituted aryl, or R 47 -substituted or unsubstituted heteroaryl.
• R 10 is independently an R 47 -substituted or unsubstituted C1-C4 alkyl, R 47 -substituted or unsubstituted 2 to 4 membered heteroalkyl, R 47 -substituted or unsubstituted C3-C6 cycloalkyl, R 47 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 47 -substituted or unsubstituted phenyl, or R 47 - substituted or unsubstituted 5 to 6 membered heteroaryl.
• R 10 is independently an unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl.
• R 10 is independently an unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl.
• R 10 is independently an unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C3-
• R 10 is independently an unsubstituted C1-C 4 alkyl.
• R 10 is independently an unsubstituted methyl.
• R 10 is independently an unsubstituted ethyl.
• R 10 is independently an unsubstituted isopropyl.
• R 10 is independently an unsubstituted tert-butyl.
• R 10 is independently hydrogen.
• R 47 is independently oxo
• R is independently -NH 2 . In embodiments, R is independently - OH. In embodiments, R 47 is independently halogen. In embodiments, R 47 is independently - CN. In embodiments, R 47 is independently oxo. In embodiments, R 47 is independently -CF 3 . In embodiments, R 47 is independently -COOH. In embodiments, R 47 is independently -CONH 2 . In embodiments, R 47 is independently -NO 2 . In embodiments, R 47 is independently -SH. In embodiments, R 47 is independently -SO 3 H. In embodiments, R 47 is independently -SO 4 H. In embodiments, R 47 is independently -SO 2 NH 2 . In embodiments, R 47 is independently -NHNH 2 . In embodiments, R 47 is independently -ONH 2 . In embodiments, R 47 is independently
• R 47 is independently -NHS0 2 H.
• R 47 is independently -NHC(0)-OH.
• R 47 is
• R 47 is independently -NHOH. In embodiments, R 47 is independently -OCF 3 . In embodiments, R 47 is independently -OCHF 2 . In embodiments, R 47 is independently -CCI 3 . In embodiments, R 47 is independently -CBr 3 . In embodiments, R 47 is independently -CI 3 . In embodiments, R 47 is independently -F. In embodiments, R 47 is independently -CI. In embodiments, R 47 is independently -Br. In embodiments, R 47 is independently -I. In embodiments, R 47 is independently R 48 -substituted C1-C4 alkyl. In embodiments, R 47 is independently R 48 -substituted 2 to 4 membered heteroalkyl. In embodiments, R 47 is independently R 48 -substituted C3-C6 cycloalkyl. In embodiments, R 47 is independently R 48 -substituted 3 to 6 membered
• R 47 is independently R 48 -substituted phenyl.
• R 47 is independently R 48 -substituted 5 to 6 membered heteroaryl.
• R 47 is independently unsubstituted C1-C4 alkyl. In embodiments, R 47 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 47 is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R 47 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 47 is independently unsubstituted phenyl. In embodiments, R 47 is independently unsubstituted 5 to 6 membered heteroaryl.
• R 48 is independently oxo
• R is independently -NH 2 . In embodiments, R is independently - OH. In embodiments, R 48 is independently halogen. In embodiments, R 48 is independently - CN. In embodiments, R 48 is independently oxo. In embodiments, R 48 is independently -CF 3 . In embodiments, R 48 is independently -COOH. In embodiments, R 48 is independently -CONH 2 . In embodiments, R 48 is independently -NO 2 . In embodiments, R 48 is independently -SH. In embodiments, R 48 is independently -SO 3 H. In embodiments, R 48 is independently -SO 4 H. In embodiments, R 48 is independently -SO 2 NH 2 . In embodiments, R 48 is independently -NHNH 2 . In embodiments, R 48 is independently -ONH 2 . In embodiments, R 48 is independently
• R 48 is independently -NHS0 2 H.
• R 48 is independently -NHC(0)-OH.
• R 48 is
• R 48 is independently -NHOH. In embodiments, R 48 is independently -OCF 3 . In embodiments, R 48 is independently -OCHF 2 . In embodiments, R 48 is independently -CCI 3 . In embodiments, R 48 is independently -CBr 3 . In embodiments, R 48 is independently -CI 3 . In embodiments, R 48 is independently -F. In embodiments, R 48 is independently -CI. In embodiments, R 48 is independently -Br. In embodiments, R 48 is independently -I. In embodiments, R 48 is independently R 49 -substituted C1-C4 alkyl. In embodiments, R 48 is independently R 49 -substituted 2 to 4 membered heteroalkyl. In embodiments, R 48 is independently R 49 -substituted C3-C6 cycloalkyl. In embodiments, R 48 is independently R 49 -substituted 3 to 6 membered
• R 48 is independently R 49 -substituted phenyl.
• R 48 is independently R 49 -substituted 5 to 6 membered heteroaryl.
• R 48 is independently unsubstituted C1-C4 alkyl. In embodiments, R 48 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 48 is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R 48 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 48 is independently unsubstituted phenyl. In embodiments, R 48 is independently unsubstituted 5 to 6 membered heteroaryl.
• R 11 is independently hydrogen
• R 11 is independently hydrogen, -CF 3 , -CN, -COOH, -CONH 2 , R 50 - substituted or unsubstituted alkyl, R 50 -substituted or unsubstituted heteroalkyl, R 50 -substituted or unsubstituted cycloalkyl, R 50 -substituted or unsubstituted heterocycloalkyl, R 50 -substituted or unsubstituted aryl, or R 50 -substituted or unsubstituted heteroaryl.
• R 11 is independently an R 50 -substituted or unsubstituted C1-C4 alkyl, R 50 -substituted or unsubstituted 2 to 4 membered heteroalkyl, R 50 -substituted or unsubstituted C3-C6 cycloalkyl, R 50 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 50 -substituted or unsubstituted phenyl, or R 50 - substituted or unsubstituted 5 to 6 membered heteroaryl.
• R 11 is independently an unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl.
• R 11 is independently an unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl.
• R 11 is independently an unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C3-
• R 11 is independently an unsubstituted C1-C4 alkyl.
• R 11 is independently an unsubstituted methyl.
• R 11 is independently an unsubstituted ethyl.
• R 11 is independently an unsubstituted isopropyl.
• R 11 is independently an unsubstituted tert-butyl.
• R 11 is independently hydrogen.
• R 11 is independently an R 50 - substituted or unsubstituted C1-C4 alkyl.
• R 11 is independently an R 50 - substituted or unsubstituted 2 to 4 membered heteroalkyl.
• R 11 is independently an R 50 -substituted or unsubstituted C3-C6 cycloalkyl. In embodiments, R 11 is independently an R 50 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 11 is independently an R 50 -substituted or unsubstituted phenyl. In embodiments, R 11 is independently an R 50 -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 11 is independently an unsubstituted C1-C4 alkyl. In embodiments, R 11 is independently an unsubstituted 2 to 4 membered heteroalkyl.
• R 11 is independently an unsubstituted C3-C6 cycloalkyl. In embodiments, R 11 is independently an unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 11 is independently an unsubstituted phenyl. In embodiments, R 11 is independently an unsubstituted 5 to 6 membered heteroaryl.
• R 50 is independently oxo
• R 12 is independently hydrogen
• R 12 is independently hydrogen, -CF 3 , -CN, -COOH, -CONH 2 , R 53 - substituted or unsubstituted alkyl, R 53 -substituted or unsubstituted heteroalkyl, R 53 -substituted or unsubstituted cycloalkyl, R 53 -substituted or unsubstituted heterocycloalkyl, R 53 -substituted or unsubstituted aryl, or R 53 -substituted or unsubstituted heteroaryl.
• R 12 is independently an R 53 -substituted or unsubstituted C1-C4 alkyl, R 53 -substituted or unsubstituted 2 to 4 membered heteroalkyl, R 53 -substituted or unsubstituted C3-C6 cycloalkyl, R 53 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 53 -substituted or unsubstituted phenyl, or R 53 - substituted or unsubstituted 5 to 6 membered heteroaryl.
• R 12 is independently an unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C 3 -C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl.
• R 12 is independently an unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C 3 -C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl.
• R 12 is independently an unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C
• R 12 is independently an unsubstituted C1-C4 alkyl.
• R 12 is independently an unsubstituted methyl.
• R 12 is independently an unsubstituted ethyl.
• R 12 is independently an unsubstituted isopropyl.
• R 12 is independently an unsubstituted tert-butyl.
• R 12 is independently hydrogen.
• R 12 is independently an R 53 - substituted or unsubstituted C1-C4 alkyl.
• R 12 is independently an R 53 - substituted or unsubstituted 2 to 4 membered heteroalkyl.
• R 12 is independently an R 53 -substituted or unsubstituted C 3 -C6 cycloalkyl. In embodiments, R 12 is independently an R 53 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 12 is independently an R -substituted or unsubstituted phenyl. In embodiments, R is independently an R 53 -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 12 is independently an unsubstituted C1-C4 alkyl. In embodiments, R 12 is independently an unsubstituted 2 to 4 membered heteroalkyl.
• R 12 is independently an unsubstituted C3-C6 cycloalkyl. In embodiments, R 12 is independently an unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 12 is independently an unsubstituted phenyl. In embodiments, R 12 is independently an unsubstituted 5 to 6 membered heteroaryl.
• R 53 is independently oxo
• R 13 is independently hydrogen
• R 13 is independently hydrogen, -CF 3 , -CN, -COOH, -CONH 2 , R 56 - substituted or unsubstituted alkyl, R 56 -substituted or unsubstituted heteroalkyl, R 56 -substituted or unsubstituted cycloalkyl, R 56 -substituted or unsubstituted heterocycloalkyl, R 56 -substituted or unsubstituted aryl, or R 56 -substituted or unsubstituted heteroaryl.
• R 13 is independently an R -substituted or unsubstituted C1-C4 alkyl, R -substituted or unsubstituted 2 to 4 membered heteroalkyl, R 56 -substituted or unsubstituted C3-C6 cycloalkyl, R 56 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 56 -substituted or unsubstituted phenyl, or R 56 - substituted or unsubstituted 5 to 6 membered heteroaryl.
• R 13 is independently an unsubstituted C1-C4 alkyl, unsubstituted 2 to 4 membered heteroalkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 13 is independently an
• R 13 is independently an unsubstituted C1-C4 alkyl.
• R 13 is independently an unsubstituted methyl.
• R 13 is independently an unsubstituted ethyl.
• R 13 is independently an unsubstituted isopropyl.
• R 13 is independently an unsubstituted tert-butyl.
• R 13 is independently hydrogen.
• R 13 is independently an R 56 - substituted or unsubstituted C1-C4 alkyl.
• R 13 is independently an R 56 - substituted or unsubstituted 2 to 4 membered heteroalkyl.
• R 13 is independently an R 56 -substituted or unsubstituted C3-C6 cycloalkyl. In embodiments, R 13 is independently an R 56 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 13 is independently an R 56 -substituted or unsubstituted phenyl. In embodiments, R 13 is independently an R 56 -substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 13 is independently an unsubstituted C1-C4 alkyl. In embodiments, R 13 is independently an unsubstituted 2 to 4 membered heteroalkyl.
• R 13 is independently an unsubstituted C3-C6 cycloalkyl. In embodiments, R 13 is independently an unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 13 is independently an unsubstituted phenyl. In embodiments, R 13 is independently an unsubstituted 5 to 6 membered heteroaryl.
• R 56 is independently oxo
• R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 are independently hydrogen. In embodiments, R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 are independently hydrogen,
• R', R°, R", R , R , R , and R 1J are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 are independently hydrogen,
• R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 are independently hydrogen
• R 11 , R 12 , and R 13 are independently hydrogen.
• R 11 , R 12 , and R 13 are independently hydrogen, substituted or unsubstituted Ci-C 8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C 3 - C 7 cycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 9 membered heteroaryl.
• R 11 , R 12 , and R 13 are independently hydrogen, unsubstituted Ci-Cs alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C3-C7 cycloalkyl, unsubstituted 3 to 7 membered heterocycloalkyl, unsubstituted C6-C10 aryl, or unsubstituted 5 to 9 membered heteroaryl.
• L 1 is a bond, -NH-, -NR 23 -, -S-, -0-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
• L 1 is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
• L 1 is L 2 -L 3 -L 4 -lA L 2 is connected directly to a monovalent rapamycin or a monovalent rapamycin analog.
• L 2 is a
• L 3 is a bond, -NH-, -NR 29 -, -S-, -0-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
• L 4 is a bond, -NH-, -NR 32 -, -S-, -0-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
• L is a bond, -NH-, -NR 35 -, -S-, -0-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
• L 2 is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
• L 3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
• L 4 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
• L 5 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
• L 1 is a divalent linker including one or more amino acids. In embodiments, L 1 is a divalent linker consisting of amino acids.
• L 1 is a divalent linker including an amino acid analog. In embodiments, L 1 is a divalent linker including an amino acid mimetic. In embodiments, L 1 is a divalent linker consisting of amino acid analogs. In embodiments, L 1 is a divalent linker consisting of amino acid mimetics.
• L 2 is substituted or unsubstituted Ci-C 2 o alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene, substituted or unsubstituted C3-C8
• L 2 is substituted or unsubstituted 3 to 8 membered heteroalkylene.
• L 2 is -CH 2 CH 2 OCH 2 -. In embodiments, L 2 is unsubstituted 3 to 8 membered heteroalkylene. In embodiments, L 2 is unsubstituted 3 to 6 membered heteroalkylene. In embodiments, L 2 is unsubstituted 3 to 5 membered heteroalkylene. In embodiments, L 2 is a divalent linker including one or more amino acids. In embodiments, L 2 is a divalent linker consisting of amino acids. In embodiments, L 2 is a divalent linker including an amino acid analog. In embodiments, L 2 is a divalent linker including an amino acid mimetic. In embodiments, L 2 is a divalent linker consisting of amino acid analogs. In embodiments, L 2 is a divalent linker consisting of amino acid mimetics.
• L 3 is a bond, substituted or unsubstituted Ci-C 2 o alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene, substituted or unsubstituted C3-C 8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C6-C1 0 arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene.
• L 3 is a substituted or unsubstituted 5 to 10 membered heteroarylene.
• L 3 is a bond.
• L 3 is a substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, L 3 is a unsubstituted 5 to 6 membered heteroarylene. In embodiments, L 3 is unsubstituted divalent triazole. In embodiments, L 3 is unsubstituted divalent 1H- 1,2, 3 -triazole. In embodiments, L 3 is unsubstituted divalent 2H- 1,2, 3 -triazole. In embodiments, L 3 is a divalent linker including one or more amino acids. In embodiments, L 3 is a divalent linker consisting of amino acids. In embodiments, L 3 is a divalent linker including an amino acid analog.
• L 3 is a divalent linker including an amino acid mimetic. In embodiments, L 3 is a divalent linker consisting of amino acid analogs. In embodiments, L 3 is a divalent linker consisting of amino acid mimetics.
• L 4 is a bond, substituted or unsubstituted C1-C2 0 alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C6-C1 0 arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene.
• L 4 is a substituted or unsubstituted 2 to 12 membered heteroalkylene.
• L 4 is a substituted or unsubstituted 2 to 32 membered heteroalkylene. In embodiments, L 4 is a bond. In embodiments, L 4 is a divalent linker including one or more amino acids. In embodiments, L 4 is a divalent linker consisting of amino acids. In embodiments, L 4 is a divalent linker including an amino acid analog. In embodiments, L 4 is a divalent linker including an amino acid mimetic. In embodiments, L 4 is a divalent linker consisting of amino acid analogs. In embodiments, L 4 is a divalent linker consisting of amino acid mimetics.
• L 5 is a bond, substituted or unsubstituted C1-C2 0 alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C6-C1 0 arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene.
• L 5 is a substituted or unsubstituted 2 to 12 membered heteroalkylene.
• L 5 is a substituted or unsubstituted 2 to 32 membered heteroalkylene. In embodiments, L 5 is a bond. In embodiments, L 5 is a divalent linker including one or more amino acids. In embodiments, L 5 is a divalent linker consisting of amino acids. In embodiments, L 5 is a divalent linker including an amino acid analog. In embodiments, L 5 is a divalent linker including an amino acid mimetic. In embodiments, L 5 is a divalent linker consisting of amino acid analogs. In embodiments, L 5 is a divalent linker consisting of amino acid mimetics. [0201] In embodiments, L 5 is a divalent oligomer of ethylene oxide.
• L 5 is a divalent polyethylene glycol. In embodiments, L 5 is a divalent oligomer of ethylene oxide having 2 to 30 linear atoms (carbon and oxygen) between the two termini connecting to the remainder of the compound. In embodiments, L 5 is a -(CH2)4C(0) H-. In embodiments, L 5 is a 2 to 8 membered substituted heteroalkylene. In embodiments, L 5 is a 3 to 6 membered substituted heteroalkylene. In embodiments, L 5 is a 5 to 6 membered substituted heteroalkylene. In embodiments, L 5 is a 5 to 7 membered oxo substituted heteroalkylene.
• L 5 is an unsubstituted Ci-C 6 alkylene.
• L 4 is a divalent oligomer of ethylene oxide.
• L 4 is a divalent polyethylene glycol.
• L 4 is a divalent oligomer of ethylene oxide having 2 to 30 linear atoms (carbon and oxygen) between the two termini connecting to the remainder of the compound.
• L 4 is -(CH 2 CH 2 0) b CH 2 CH 2 - and b is an integer from 1 to 16.
• L 4 is -(CH 2 CH 2 0) b CH 2 - and b is an integer from 1 to 16.
• L 4 is -(CH 2 CH 2 0) b - and b is an integer from 1 to 16. In embodiments, b is an integer from 2 to 15. In embodiments, b is an integer from 3 to 14. In embodiments, b is an integer from 4 to 12. In embodiments, b is an integer from 5 to 10. In embodiments, b is an integer from 5 to 8. In embodiments, b is an integer from 6 to 7. [0203] In embodiments, L 4 -L 5 is a 2 to 36 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 2 to 34 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 2 to 32 membered substituted heteroalkylene.
• L 4 -L 5 is a 2 to 30 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 2 to 28 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 2 to 24 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 2 to 30 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 2 to 22 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 2 to 20 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 2 to 18 membered substituted heteroalkylene.
• L 4 -L 5 is a 2 to 16 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 2 to 14 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 2 to 12 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 4 to 36 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 6 to 36 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 8 to 36 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 10 to 36 membered substituted heteroalkylene.
• L 4 -L 5 is a 12 to 36 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 14 to 36 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 16 to 36 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 18 to 36 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 20 to 36 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 22 to 36 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 24 to 36 membered substituted heteroalkylene.
• L 4 -L 5 is a 4 to 32 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 4 to 28 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 8 to 26 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 12 to 26 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 16 to 26 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 20 to 26 membered substituted heteroalkylene. In embodiments, L 4 -L 5 is a 22 to 26 membered substituted heteroalkylene.
• the linker is formed by a conjugation or bioconjugation reaction combining a first reactant moity covalently bonded to the rapamycin or rapamycin analog and a second reactant moiety covalently bonded to the active site mTOR inhibitor.
• the compound formed by such conjugation or bioconjugation reaction may be referred to as a conjugate.
• L 1 is L 2 -L 3 -L 4 -L 5 ;
• L 2 is -CH 2 CH 2 OCH 2 -;
• L 3 is 5 to 10 membered heteroarylene;
• L 4 is - (CH 2 CH 2 0)b-;
• b is an integer from 2 to 8;
• L 5 is L 2 -L 3 -L 4 -L 5 ;
• L 2 is -CH 2 CH 2 OCH 2 -;
• L 3 is 5 to 10 membered heteroarylene;
• L 4 is - (CH 2 CH 2 0)b-;
• b is an integer from 2 to 8;
• L 5 is an integer from 2 to 8;
• L 1 is
• L 1 is L 2 -L 3 -L 4 -L 5 ;
• L 2 is -CH 2 CH 2 OCH 2 -;
• L 3 is 5 membered heteroarylene;
• L 4 is - (CH 2 CH 2 0) b -;
• b is an integer from 4 to 8; and
• L 1 is L 2 -L 3 -L 4 -L 5 ;
• L 2 is -CH 2 CH 2 OCH 2 -;
• L 3 is triazolylene;
• L 4 is - (CH 2 CH 2 0) b -; b is an integer from 4 to 8; and
• L 1 is L 2 - L 3 -L 4 -L 5 ;
• L 2 is -CH 2 CH 2 OCH 2 -;
• L 3 is 5 to 10 membered heteroarylene;
• L 4 is - (CH 2 ) b -;
• b is an integer from 2 to 8; and
• L 5 is a bond.
• Conjugates described herein may be synthesized using bioconjugate or conjugate chemistry.
• Conjugate chemistry includes coupling two molecules together to form an adduct. Conjugation may be a covalent modification.
• Currently favored classes of conjugate chemistry reactions available with reactive known reactive groups are those which proceed under relatively mild conditions. These include, but are not limited to nucleophilic substitutions (e.g. , reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g. , enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g. , Michael reaction, Diels-Alder addition).
• the bioconjugation reaction is a click chemistry reaction (Angewandte Chemie International Edition 40 (1 1): 2004-2021).
• the bioconjugation reaction is a Huisgen cyclization of azides.
• the bioconjugation reaction is a copper catalyzed Huisgen cyclization of azides.
• Useful reactive functional groups used for conjugate chemistries herein include, for example: [0208] (a) carboxyl groups and various derivatives thereof including, but not limited to,
• N-hydroxysuccinimide esters N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters;
• haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom;
• a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion
• dienophile groups which are capable of participating in Diels-Alder reactions such as, for example, maleimido groups;
• amine or sulfhydryl groups which can be, for example, acylated, alkylated or oxidized;
• metal silicon oxide bonding and (m) metal bonding to reactive phosphorus groups (e.g. phosphines) to form, for example, phosphate diester bonds.
• reactive phosphorus groups e.g. phosphines
• the reactive functional groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group.
• L 1 is independently R 23 - substituted or unsubstituted alkylene, R 23 -substituted or unsubstituted heteroalkylene, R 23 - substituted or unsubstituted cycloalkylene, R 23 -substituted or unsubstituted heterocycloalkylene, R 23 -substituted or unsubstituted arylene, or R 23 -substituted or unsubstituted heteroarylene.
• L 1 is a
• L 1 is a bond. In embodiments, L 1 is -NH-. In embodiments, L 1 is -NR 23 -. In embodiments, L 1 is -S-. In embodiments, L 1 is -0-. In embodiments, L 1 is -C(O)- . In embodiments, L 1 is -NHC(O)- . In embodiments, L 1 is -C(0)NH-. In embodiments, L 1 is -NHC(0)NH-. In embodiments, L 1 is -NHC(NH)NH-. In embodiments, L 1 is -C(S)- . In embodiments, L 1 is R 23 - substituted or unsubstituted C1-C2 0 alkylene.
• L 1 is R 23 -substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 1 is R 23 -substituted or unsubstituted C3-C8 cycloalkylene. In embodiments, L 1 is R 23 -substituted or unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L 1 is R 23 -substituted or unsubstituted C 6 -Ci 0 arylene. In embodiments, L 1 is R 23 -substituted or unsubstituted 5 to 10 membered heteroarylene.
• L is R -substituted C1-C2 0 alkylene. In embodiments, L is R -substituted 2 to 20 membered heteroalkylene. In embodiments, L 1 is R 23 -substituted C3-C8 cycloalkylene. In embodiments, L 1 is R 23 -substituted 3 to 8 membered heterocycloalkylene. In embodiments, L 1 is R 23 -substituted C6-C1 0 arylene. In embodiments, L 1 is R 23 -substituted 5 to 10 membered heteroarylene. In embodiments, L 1 is unsubstituted C1-C2 0 alkylene.
• L 1 is unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 1 is unsubstituted C3-C8 cycloalkylene. In embodiments, L 1 is unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L 1 is unsubstituted C 6 -Ci 0 arylene. In embodiments, L 1 is unsubstituted 5 to 10 membered heteroarylene. In embodiments, L 1 is R 23 -substituted C1-C15 alkylene. In
• L 1 is R 23 -substituted 2 to 15 membered heteroalkylene. In embodiments, L 1 is R 23 -substituted C3-C6 cycloalkylene. In embodiments, L 1 is R 23 -substituted 3 to 6 membered heterocycloalkylene. In embodiments, L 1 is R 23 -substituted phenylene. In embodiments, L 1 is R 23 -substituted 5 to 6 membered heteroarylene. In embodiments, L 1 is unsubstituted C1-C15 alkylene. In embodiments, L 1 is unsubstituted 2 to 15 membered heteroalkylene. In
• L 1 is unsubstituted C3-C6 cycloalkylene. In embodiments, L 1 is unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, L 1 is unsubstituted phenylene. In embodiments, L 1 is unsubstituted 5 to 6 membered heteroarylene. In embodiments, L 1 is R 23 - substituted C1-C1 0 alkylene. In embodiments, L 1 is R 23 -substituted 2 to 10 membered heteroalkylene. In embodiments, L 1 is R 23 -substituted C4-C6 cycloalkylene.
• L 1 is R 23 -substituted 4 to 6 membered heterocycloalkylene. In embodiments, L 1 is R 23 -substituted phenylene. In embodiments, L 1 is R 23 -substituted 5 membered heteroarylene. In embodiments,
• L is R -substituted Ci-Cs alkylene. In embodiments, L is R -substituted 2 to 8 membered heteroalkylene. In embodiments, L 1 is R 23 -substituted C5-C6 cycloalkylene. In embodiments, L 1 is R 23 -substituted 5 to 6 membered heterocycloalkylene. In embodiments, L 1 is R 23 -substituted 6 membered heteroarylene. In embodiments, L 1 is R 23 -substituted C1-C6 alkylene. In
• L is R -substituted 2 to 6 membered heteroalkylene. In embodiments, L is R - substituted C6-C2 0 alkylene. In embodiments, L 1 is R 23 -substituted 6 to 20 membered heteroalkylene. In embodiments, L 1 is unsubstituted C1-C1 0 alkylene. In embodiments, L 1 is unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L 1 is unsubstituted C4-C6 cycloalkylene. In embodiments, L 1 is unsubstituted 4 to 6 membered heterocycloalkylene.
• L 1 is unsubstituted phenylene. In embodiments, L 1 is unsubstituted 5 membered heteroarylene. In embodiments, L 1 is unsubstituted Ci-Cs alkylene. In embodiments, L 1 is unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 1 is unsubstituted C5-C6 cycloalkylene. In embodiments, L 1 is unsubstituted 5 to 6 membered heterocycloalkylene. In embodiments, L 1 is unsubstituted 6 membered heteroarylene. In embodiments, L 1 is unsubstituted C1-C 6 alkylene. In embodiments, L 1 is unsubstituted 2 to 6 membered
• L 1 is unsubstituted C 6 -C 2 o alkylene. In embodiments, L 1 is unsubstituted 6 to 20 membered heteroalkylene. [0222] R is independently oxo,
• R 23 is independently -NH 2 . In embodiments, R 23 is independently - OH. In embodiments, R 23 is independently halogen. In embodiments, R 23 is independently - CN. In embodiments, R 23 is independently oxo. In embodiments, R 23 is independently -CF 3 . In embodiments, R 23 is independently -COOH. In embodiments, R 23 is independently -CONH 2 . In embodiments, R 23 is independently -N0 2 . In embodiments, R 23 is independently -SH. In embodiments, R 23 is independently -SO 3 H. In embodiments, R 23 is independently -SO 4 H. In embodiments, R 23 is independently -S0 2 NH 2 . In embodiments, R 23 is independently -NHNH 2 . In embodiments, R 23 is independently -ONH 2 . In embodiments, R 23 is independently
• R 23 is independently -NHS0 2 H.
• R 23 is independently -NHC(0)-OH.
• R 23 is
• R 23 is independently -NHOH. In embodiments, R 23 is independently -OCF 3 . In embodiments, R 23 is independently -OCHF 2 . In embodiments, R 23 is independently -CCI 3 . In embodiments, R 23 is independently -CBr 3 . In embodiments, R 23 is independently -CI 3 . In embodiments, R 23 is independently -F. In embodiments, R 23 is independently -CI. In embodiments, R 23 is independently -Br. In embodiments, R 23 is independently -I. In embodiments, R 23 is independently R -substituted C1-C4 alkyl. In embodiments, R is independently R -substituted 2 to 4 membered heteroalkyl. In embodiments, R 23 is independently R 24 -substituted C 3 -C6 cycloalkyl. In embodiments, R 23 is independently R 24 -substituted 3 to 6 membered
• R 23 is independently R 24 -substituted phenyl.
• R 23 is independently R 24 -substituted 5 to 6 membered heteroaryl.
• R 23 is independently unsubstituted C1-C4 alkyl. In embodiments, R 23 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 23 is independently unsubstituted C 3 -C6 cycloalkyl. In embodiments, R 23 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 23 is independently unsubstituted phenyl. In embodiments, R 23 is independently unsubstituted 5 to 6 membered heteroaryl. [0224] R is independently oxo,
• R 24 is independently -NH 2 . In embodiments, R 24 is independently - OH. In embodiments, R 24 is independently halogen. In embodiments, R 24 is independently - CN. In embodiments, R 24 is independently oxo. In embodiments, R 24 is independently -CF 3 . In embodiments, R 24 is independently -COOH. In embodiments, R 24 is independently -CONH 2 . In embodiments, R 24 is independently -N0 2 . In embodiments, R 24 is independently -SH. In embodiments, R 24 is independently -SO 3 H. In embodiments, R 24 is independently -SO 4 H. In embodiments, R 24 is independently -S0 2 NH 2 . In embodiments, R 24 is independently -NHNH 2 . In embodiments, R 24 is independently -ONH 2 . In embodiments, R 24 is independently
• R 24 is independently -NHS0 2 H.
• R 24 is independently -NHC(0)-OH.
• R 24 is
• R 24 is independently -NHOH. In embodiments, R 24 is independently -OCF 3 . In embodiments, R 24 is independently -OCHF 2 . In embodiments, R 24 is independently -CCI 3 . In embodiments, R 24 is independently -CBr 3 . In embodiments, R 24 is independently -CI 3 . In embodiments, R 24 is independently -F. In embodiments, R 24 is independently -CI. In embodiments, R 24 is independently -Br. In embodiments, R 24 is independently -I. In embodiments, R 24 is independently R -substituted C1-C4 alkyl. In embodiments, R is independently R -substituted 2 to 4 membered heteroalkyl. In embodiments, R 24 is independently R 25 -substituted C 3 -C6 cycloalkyl. In embodiments, R 24 is independently R 25 -substituted 3 to 6 membered
• R 24 is independently R 25 -substituted phenyl.
• R 24 is independently R 25 -substituted 5 to 6 membered heteroaryl.
• R 24 is independently unsubstituted C1-C4 alkyl. In embodiments, R 24 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 24 is independently unsubstituted C 3 -C6 cycloalkyl. In embodiments, R 24 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 24 is independently unsubstituted phenyl. In embodiments, R 24 is independently unsubstituted 5 to 6 membered heteroaryl.
• L 2 is independently a bond, R 26 -substituted or unsubstituted alkylene, R 26 -substituted or unsubstituted heteroalkylene, R 26 - substituted or unsubstituted cycloalkylene, R 26 -substituted or unsubstituted heterocycloalkylene, R 26 -substituted or unsubstituted arylene, or R 26 -substituted or unsubstituted heteroarylene.
• L 2 is a bond, R 26 -substituted or unsubstituted alkylene, R 26 -substituted or unsubstituted heteroalkylene, R 26 - substituted or unsubstituted cycloalkylene, R 26 -substituted or unsubstituted heterocycloalkylene, R 26 -substituted or unsubstituted arylene, or R 26 -substit
• L is a bond. In embodiments, L is -NH-. In embodiments, L is -NR -. In embodiments, L is -S-. In embodiments, L 2 is -0-. In embodiments, L 2 is -C(O)- . In embodiments, L 2 is -NHC(O)- . In embodiments, L 2 is -C(0)NH-. In embodiments, L 2 is -NHC(0)NH-. In embodiments, L 2 is -NHC(NH)NH-. In embodiments, L 2 is -C(S)- . In embodiments, L 2 is R 26 - substituted or unsubstituted C1-C20 alkylene.
• L 2 is R 26 -substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 2 is R 26 -substituted or unsubstituted C3-C8 cycloalkylene. In embodiments, L 2 is R 26 -substituted or unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L 2 is R 26 -substituted or unsubstituted C6-C10 arylene. In embodiments, L 2 is R 26 -substituted or unsubstituted 5 to 10 membered heteroarylene.
• L is R -substituted C1-C20 alkylene. In embodiments, L is R -substituted 2 to 20 membered heteroalkylene. In embodiments, L 2 is R 26 -substituted C3-C8 cycloalkylene. In embodiments, L 2 is R 26 -substituted 3 to 8 membered heterocycloalkylene. In embodiments, L 2 is R 26 -substituted C 6 -Ci 0 arylene. In embodiments, L 2 is R 26 -substituted 5 to 10 membered heteroarylene. In embodiments, L 2 is unsubstituted C1-C20 alkylene.
• L 2 is unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 2 is unsubstituted C3-C8 cycloalkylene. In embodiments, L 2 is unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L 2 is unsubstituted C6-C10 arylene. In embodiments, L 2 is unsubstituted 5 to 10 membered heteroarylene. In embodiments, L 2 is R 26 -substituted C1-C15 alkylene. In
• L 2 is R 26 -substituted 2 to 15 membered heteroalkylene. In embodiments, L 2 is R 26 -substituted C3-C6 cycloalkylene. In embodiments, L 2 is R 26 -substituted 3 to 6 membered heterocycloalkylene. In embodiments, L 2 is R 26 -substituted phenylene. In embodiments, L 2 is R 26 -substituted 5 to 6 membered heteroarylene. In embodiments, L 2 is unsubstituted C1-C15 alkylene. In embodiments, L 2 is unsubstituted 2 to 15 membered heteroalkylene. In
• L 2 is unsubstituted C3-C6 cycloalkylene. In embodiments, L 2 is unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, L 2 is unsubstituted phenylene. In embodiments, L 2 is unsubstituted 5 to 6 membered heteroarylene. In embodiments, L 2 is R 26 - substituted Ci-Ci 0 alkylene. In embodiments, L 2 is R 26 -substituted 2 to 10 membered heteroalkylene. In embodiments, L 2 is R 26 -substituted C4-C6 cycloalkylene.
• L 2 is R 26 -substituted 4 to 6 membered heterocycloalkylene. In embodiments, L 2 is R 26 -substituted phenylene. In embodiments, L 2 is R 26 -substituted 5 membered heteroarylene. In embodiments,
• L is R -substituted Ci-Cs alkylene. In embodiments, L is R -substituted 2 to 8 membered heteroalkylene. In embodiments, L 2 is R 26 -substituted C5-C6 cycloalkylene. In embodiments, L 2 is R 26 -substituted 5 to 6 membered heterocycloalkylene. In embodiments, L 2 is R 26 -substituted 6 membered heteroarylene. In embodiments, L 2 is R 26 -substituted C1-C6 alkylene. In
• L is R -substituted 2 to 6 membered heteroalkylene. In embodiments, L is R - substituted C 6 -C 2 o alkylene. In embodiments, L 2 is R 26 -substituted 6 to 20 membered heteroalkylene. In embodiments, L 2 is unsubstituted C1-C10 alkylene. In embodiments, L 2 is unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L 2 is unsubstituted C4-C6 cycloalkylene. In embodiments, L 2 is unsubstituted 4 to 6 membered heterocycloalkylene.
• L 2 is unsubstituted phenylene. In embodiments, L 2 is unsubstituted 5 membered heteroarylene. In embodiments, L 2 is unsubstituted Ci-Cs alkylene. In embodiments, L 2 is unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 2 is unsubstituted C5-C6 cycloalkylene. In embodiments, L 2 is unsubstituted 5 to 6 membered heterocycloalkylene. In embodiments, L 2 is unsubstituted 6 membered heteroarylene. In embodiments, L 2 is unsubstituted C1-C6 alkylene. In embodiments, L 2 is unsubstituted 2 to 6 membered
• L 2 is unsubstituted C6-C20 alkylene. In embodiments, L 2 is unsubstituted 6 to 20 membered heteroalkylene.
• R 26 is independently oxo
• R 26 is independently -NH 2 . In embodiments, R 26 is independently - OH. In embodiments, R 26 is independently halogen. In embodiments, R 26 is independently - CN. In embodiments, R 26 is independently oxo. In embodiments, R 26 is independently -CF 3 . In embodiments, R is independently -COOH. In embodiments, R is independently -CONH 2 . In embodiments, R 26 is independently -NO2. In embodiments, R 26 is independently -SH. In embodiments, R 26 is independently -SO 3 H. In embodiments, R 26 is independently -SO4H. In embodiments, R 26 is independently -SO2NH2. In embodiments, R 26 is independently -NHNH 2 . In embodiments, R 26 is independently -ONH 2 . In embodiments, R 26 is independently
• R 26 is independently -NHS0 2 H.
• R 26 is independently -NHC(0)-OH.
• R 26 is
• R 26 is independently -NHOH. In embodiments, R 26 is independently -OCF 3 . In embodiments, R 26 is independently -OCHF 2 . In embodiments, R 26 is independently -CCI 3 . In embodiments, R 26 is independently -CBr 3 . In embodiments, R 26 is independently -CI 3 . In embodiments, R 26 is independently -F. In embodiments, R 26 is independently -CI. In embodiments, R 26 is independently -Br. In embodiments, R 26 is independently -I. In embodiments, R 26 is
• R 27 2 ⁇ 2V independently R -substituted C1-C4 alkyl.
• R is independently R -substituted 2 to 4 membered heteroalkyl.
• R 26 is independently R 27 -substituted C3-C6 cycloalkyl.
• R 26 is independently R 27 -substituted 3 to 6 membered
• R 26 is independently R 27 -substituted phenyl.
• R 26 is independently R 27 -substituted 5 to 6 membered heteroaryl.
• R 26 is independently unsubstituted C1-C4 alkyl. In embodiments, R 26 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 26 is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R 26 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 26 is independently unsubstituted phenyl. In embodiments, R 26 is independently unsubstituted 5 to 6 membered heteroaryl.
• R 27 is independently oxo
• R 27 is independently -NH 2 . In embodiments, R 27 is independently - OH. In embodiments, R 27 is independently halogen. In embodiments, R 27 is independently - CN. In embodiments, R 27 is independently oxo. In embodiments, R 27 is independently -CF 3 . In embodiments, R is independently -COOH. In embodiments, R is independently -CONH 2 . In embodiments, R 27 is independently -NO2. In embodiments, R 27 is independently -SH. In embodiments, R 27 is independently -SO 3 H. In embodiments, R 27 is independently -SO4H. In embodiments, R 27 is independently -SO2NH2. In embodiments, R 27 is independently -NHNH 2 . In embodiments, R 27 is independently -ONH 2 . In embodiments, R 27 is independently
• R 27 is independently -NHS0 2 H.
• R 27 is independently -NHC(0)-OH.
• R 27 is
• R 27 is independently -NHOH. In embodiments, R 27 is independently -OCF 3 . In embodiments, R 27 is independently -OCHF 2 . In embodiments, R 27 is independently -CCI 3 . In embodiments, R 27 is independently -CBr 3 . In embodiments, R 27 is independently -CI 3 . In embodiments, R 27 is independently -F. In embodiments, R 27 is independently -CI. In embodiments, R 27 is independently -Br. In embodiments, R 27 is independently -I. In embodiments, R 27 is
• R 28 27 28 independently R -substituted C1-C4 alkyl. In embodiments, R is independently R -substituted 2 to 4 membered heteroalkyl. In embodiments, R 27 is independently R 28 -substituted C 3 -C6 cycloalkyl. In embodiments, R 27 is independently R 28 -substituted 3 to 6 membered
• R 27 is independently R 28 -substituted phenyl.
• R 27 is independently R 28 -substituted 5 to 6 membered heteroaryl.
• R 27 is independently unsubstituted C1-C4 alkyl. In embodiments, R 27 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 27 is independently unsubstituted C 3 -C6 cycloalkyl. In embodiments, R 27 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 27 is independently unsubstituted phenyl. In embodiments, R 27 is independently unsubstituted 5 to 6 membered heteroaryl.
• L 3 is independently a bond, R -substituted or unsubstituted alkylene, R -substituted or unsubstituted heteroalkylene, R - substituted or unsubstituted cycloalkylene, R 29 -substituted or unsubstituted heterocycloalkylene, R 29 -substituted or unsubstituted arylene, or R 29 -substituted or unsubstituted heteroarylene.
• L 3 is a
• L is a bond. In embodiments, L is -NH-. In embodiments, L is -NR -. In embodiments, L is -S-. In embodiments, L 3 is -0-. In embodiments, L 3 is -C(O)- . In embodiments, L 3 is -NHC(O)- . In embodiments, L 3 is -C(0)NH-. In embodiments, L 3 is -NHC(0)NH-. In embodiments, L 3 is -NHC(NH)NH-. In embodiments, L 3 is -C(S)- . In embodiments, L 3 is R 29 - substituted or unsubstituted C1-C2 0 alkylene.
• L 3 is R 29 -substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 3 is R 29 -substituted or unsubstituted C3-C8 cycloalkylene. In embodiments, L 3 is R 29 -substituted or unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L 3 is R 29 -substituted or unsubstituted C6-C1 0 arylene. In embodiments, L 3 is R 29 -substituted or unsubstituted 5 to 10 membered heteroarylene.
• L is R -substituted C1-C2 0 alkylene. In embodiments, L is R -substituted 2 to 20 membered heteroalkylene. In embodiments, L 3 is R 29 -substituted C3-C8 cycloalkylene. In embodiments, L 3 is R 29 -substituted 3 to 8 membered heterocycloalkylene. In embodiments, L 3 is R -substituted C6-C1 0 arylene. In embodiments, L is R -substituted 5 to 10 membered heteroarylene. In embodiments, L 3 is unsubstituted C1-C2 0 alkylene.
• L 3 is unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 3 is unsubstituted C 3 -C 8 cycloalkylene. In embodiments, L 3 is unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L 3 is unsubstituted C6-C1 0 arylene. In embodiments, L 3 is unsubstituted 5 to 10 membered heteroarylene. In embodiments, L 3 is R 29 -substituted C1-C15 alkylene. In
• L 3 is R 29 -substituted 2 to 15 membered heteroalkylene. In embodiments, L 3 is
• L is R -substituted C3-C6 cycloalkylene.
• L is R -substituted 3 to 6 membered heterocycloalkylene.
• L 3 is R 29 -substituted phenylene.
• L 3 is R 29 -substituted 5 to 6 membered heteroarylene.
• L 3 is unsubstituted C1-C15 alkylene.
• L 3 is unsubstituted 2 to 15 membered heteroalkylene.
• L 3 is unsubstituted C3-C6 cycloalkylene. In embodiments, L 3 is unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, L 3 is unsubstituted phenylene. In embodiments, L 3 is unsubstituted 5 to 6 membered heteroarylene. In embodiments, L 3 is R 29 - substituted C1-C1 0 alkylene. In embodiments, L 3 is R 29 -substituted 2 to 10 membered heteroalkylene. In embodiments, L 3 is R 29 -substituted C4-C6 cycloalkylene.
• L 3 is R -substituted 4 to 6 membered heterocycloalkylene. In embodiments, L is R -substituted phenylene. In embodiments, L 3 is R 29 -substituted 5 membered heteroarylene. In embodiments,
• L is R -substituted Ci-Cs alkylene. In embodiments, L is R -substituted 2 to 8 membered heteroalkylene. In embodiments, L 3 is R 29 -substituted C 5 -C 6 cycloalkylene. In embodiments, L 3
• L 3 is R -substituted 5 to 6 membered heterocycloalkylene. In embodiments, L is R -substituted 6 membered heteroarylene. In embodiments, L 3 is R 29 -substituted C1-C6 alkylene. In embodiments, L is R -substituted 2 to 6 membered heteroalkylene. In embodiments, L is R - substituted C6-C2 0 alkylene. In embodiments, L 3 is R 29 -substituted 6 to 20 membered heteroalkylene. In embodiments, L 3 is unsubstituted C1-C1 0 alkylene. In embodiments, L 3 is unsubstituted 2 to 10 membered heteroalkylene.
• L 3 is unsubstituted C4-C6 cycloalkylene. In embodiments, L 3 is unsubstituted 4 to 6 membered heterocycloalkylene. In embodiments, L 3 is unsubstituted phenylene. In embodiments, L 3 is unsubstituted 5 membered heteroarylene. In embodiments, L 3 is unsubstituted Ci-Cs alkylene. In embodiments, L 3 is unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 3 is unsubstituted C5-C6 cycloalkylene. In embodiments, L 3 is unsubstituted 5 to 6 membered heterocycloalkylene. In embodiments, L 3 is unsubstituted 6 membered heteroarylene. In embodiments, L 3 is unsubstituted C1-C6 alkylene. In embodiments, L 3 is unsubstituted 2 to 6 membered
• L 3 is unsubstituted C 6 -C 2 o alkylene. In embodiments, L 3 is unsubstituted 6 to 20 membered heteroalkylene.
• R 29 is independently oxo
• R 29 is independently -NH 2 . In embodiments, R 29 is independently - OH. In embodiments, R 29 is independently halogen. In embodiments, R 29 is independently - CN. In embodiments, R 29 is independently oxo. In embodiments, R 29 is independently -CF 3 . In embodiments, R 29 is independently -COOH. In embodiments, R 29 is independently -CONH 2 . In embodiments, R 29 is independently -N0 2 . In embodiments, R 29 is independently -SH. In embodiments, R 29 is independently -SO 3 H. In embodiments, R 29 is independently -SO 4 H. In embodiments, R 29 is independently -S0 2 NH 2 . In embodiments, R 29 is independently -NHNH 2 . In embodiments, R 29 is independently -ONH 2 . In embodiments, R 29 is independently
• R 29 is independently -NHS0 2 H.
• R 29 is independently -NHC(0)-OH.
• R 29 is
• R 29 is independently -NHOH. In embodiments, R 29 is independently -OCF 3 . In embodiments, R 29 is independently -OCHF 2 . In embodiments, R 29 is independently -CCI 3 . In embodiments, R 29 is independently -CBr 3 . In embodiments, R is independently -CI 3 . In embodiments, R is independently -F. In embodiments, R 29 is independently -CI. In embodiments, R 29 is independently -Br. In embodiments, R 29 is independently -I. In embodiments, R 29 is
• R 30 29 30 independently R -substituted C1-C4 alkyl.
• R is independently R -substituted 2 to 4 membered heteroalkyl.
• R 29 is independently R 30 -substituted C3-C6 cycloalkyl.
• R 29 is independently R 30 -substituted 3 to 6 membered
• R 29 is independently R 30 -substituted phenyl.
• R 29 is independently R 30 -substituted 5 to 6 membered heteroaryl.
• R 29 is independently unsubstituted C1-C4 alkyl. In embodiments, R 29 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 29 is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R 29 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 29 is independently unsubstituted phenyl. In embodiments, R 29 is independently unsubstituted 5 to 6 membered heteroaryl.
• R 30 is independently oxo
• R 30 is independently -NH 2 . In embodiments, R 30 is independently - OH. In embodiments, R 30 is independently halogen. In embodiments, R 30 is independently - CN. In embodiments, R 30 is independently oxo. In embodiments, R 30 is independently -CF 3 . In embodiments, R 30 is independently -COOH. In embodiments, R 30 is independently -CONH 2 . In embodiments, R 30 is independently -N0 2 . In embodiments, R 30 is independently -SH. In embodiments, R 30 is independently -SO 3 H. In embodiments, R 30 is independently -SO 4 H. In embodiments, R 30 is independently -S0 2 NH 2 . In embodiments, R 30 is independently -NHNH 2 . In embodiments, R 30 is independently -ONH 2 . In embodiments, R 30 is independently
• R 30 is independently -NHS0 2 H.
• R 30 is independently -NHC(0)-OH.
• R 30 is
• R 30 is independently -NHOH. In embodiments, R 30 is independently -OCF 3 . In embodiments, R 30 is independently -OCHF 2 . In embodiments, R 30 is independently -CCI 3 . In embodiments, R 30 is independently -CBr 3 . In embodiments, R is independently -CI 3 . In embodiments, R is independently -F. In embodiments, R 30 is independently -CI. In embodiments, R 30 is independently -Br. In embodiments, R 30 is independently -I. In embodiments, R 30 is
• R 31 30 31 independently R -substituted C1-C4 alkyl. In embodiments, R is independently R -substituted 2 to 4 membered heteroalkyl. In embodiments, R 30 is independently R 31 -substituted C 3 -C6 cycloalkyl. In embodiments, R 30 is independently R 31 -substituted 3 to 6 membered
• R 30 is independently R 31 -substituted phenyl.
• R 30 is independently R 31 -substituted 5 to 6 membered heteroaryl.
• R 30 is independently unsubstituted C1-C4 alkyl. In embodiments, R 30 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 30 is independently unsubstituted C 3 -C6 cycloalkyl. In embodiments, R 30 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 30 is independently unsubstituted phenyl. In embodiments, R 30 is independently unsubstituted 5 to 6 membered heteroaryl.
• L 4 is independently a bond
• L 4 is a
• L 4 is a bond. In embodiments, L 4 is -NH-. In embodiments, L 4 is -NR 32 -. In embodiments, L 4 is -S-. In embodiments, L 4 is -0-. In embodiments, L 4 is -C(O)- . In embodiments, L 4 is -NHC(O)- . In embodiments, L 4 is -C(0)NH-. In embodiments, L 4 is -NHC(0)NH-. In embodiments, L 4 is -NHC(NH)NH-. In embodiments, L 4 is -C(S)- . In embodiments, L 4 is R 32 - substituted or unsubstituted C1-C2 0 alkylene.
• L 4 is R 32 -substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 4 is R 32 -substituted or unsubstituted C 3 -C 8 cycloalkylene. In embodiments, L 4 is R 32 -substituted or unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L 4 is R 32 -substituted or unsubstituted C6-C1 0 arylene. In embodiments, L 4 is R 32 -substituted or unsubstituted 5 to 10 membered heteroarylene.
• L is R -substituted C1-C2 0 alkylene. In embodiments, L is R -substituted 2 to 20 membered heteroalkylene. In embodiments, L 4 is R 32 -substituted C3-C8 cycloalkylene. In embodiments, L 4 is R 32 -substituted 3 to 8 membered heterocycloalkylene. In embodiments, L 4 is R 32 -substituted C 6 -Ci 0 arylene. In embodiments, L 4 is R 32 -substituted 5 to 10 membered heteroarylene. In embodiments, L 4 is unsubstituted C1-C2 0 alkylene.
• L 4 is unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 4 is unsubstituted C3-C8 cycloalkylene. In embodiments, L 4 is unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L 4 is unsubstituted C6-C1 0 arylene. In embodiments, L 4 is unsubstituted 5 to 10 membered heteroarylene. In embodiments, L 4 is R 32 -substituted C1-C15 alkylene. In
• L 4 is R 32 -substituted 2 to 15 membered heteroalkylene. In embodiments, L 4 is R 32 -substituted C3-C6 cycloalkylene. In embodiments, L 4 is R 32 -substituted 3 to 6 membered heterocycloalkylene. In embodiments, L 4 is R 32 -substituted phenylene. In embodiments, L 4 is R 32 -substituted 5 to 6 membered heteroarylene. In embodiments, L 4 is unsubstituted C1-C15 alkylene. In embodiments, L 4 is unsubstituted 2 to 15 membered heteroalkylene. In
• L 4 is unsubstituted C3-C6 cycloalkylene. In embodiments, L 4 is unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, L 4 is unsubstituted phenylene. In embodiments, L 4 is unsubstituted 5 to 6 membered heteroarylene. In embodiments, L 4 is R 32 - substituted C1-C1 0 alkylene. In embodiments, L 4 is R 32 -substituted 2 to 10 membered heteroalkylene. In embodiments, L 4 is R 32 -substituted C4-C6 cycloalkylene.
• L 4 is R 32 -substituted 4 to 6 membered heterocycloalkylene. In embodiments, L 4 is R 32 -substituted phenylene. In embodiments, L 4 is R 32 -substituted 5 membered heteroarylene. In embodiments,
• L is R -substituted Ci-Cs alkylene. In embodiments, L is R -substituted 2 to 8 membered heteroalkylene. In embodiments, L 4 is R 32 -substituted C5-C6 cycloalkylene. In embodiments, L 4 is R 32 -substituted 5 to 6 membered heterocycloalkylene. In embodiments, L 4 is R 32 -substituted 6 membered heteroarylene. In embodiments, L 4 is R 32 -substituted C1-C6 alkylene. In
• L is R -substituted 2 to 6 membered heteroalkylene. In embodiments, L is R - substituted C6-C2 0 alkylene. In embodiments, L 4 is R 32 -substituted 6 to 20 membered heteroalkylene. In embodiments, L 4 is unsubstituted C1-C1 0 alkylene. In embodiments, L 4 is unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L 4 is unsubstituted C4-C6 cycloalkylene. In embodiments, L 4 is unsubstituted 4 to 6 membered heterocycloalkylene. In embodiments, L 4 is unsubstituted phenylene.
• L 4 is unsubstituted 5 membered heteroarylene. In embodiments, L 4 is unsubstituted Ci-Cs alkylene. In embodiments, L 4 is unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 4 is unsubstituted C 5 -C 6 cycloalkylene. In embodiments, L 4 is unsubstituted 5 to 6 membered heterocycloalkylene. In embodiments, L 4 is unsubstituted 6 membered heteroarylene. In embodiments, L 4 is unsubstituted Ci-Ce alkylene. In embodiments, L 4 is unsubstituted 2 to 6 membered
• L 4 is unsubstituted C6-C2 0 alkylene. In embodiments, L 4 is unsubstituted 6 to 20 membered heteroalkylene.
• R 32 is independently oxo
• R 32 is independently -NH 2 . In embodiments, R 32 is independently - OH. In embodiments, R 32 is independently halogen. In embodiments, R 32 is independently - CN. In embodiments, R 32 is independently oxo. In embodiments, R 32 is independently -CF 3 . In embodiments, R 32 is independently -COOH. In embodiments, R 32 is independently -CONH 2 . In embodiments, R 32 is independently -N0 2 . In embodiments, R 32 is independently -SH. In embodiments, R 32 is independently -SO 3 H. In embodiments, R 32 is independently -SO4H. In embodiments, R 32 is independently -S0 2 NH 2 . In embodiments, R 32 is independently -NHNH 2 . In embodiments, R 32 is independently -ONH 2 . In embodiments, R 32 is independently
• R 32 is independently -NHS0 2 H.
• R 32 is independently -NHC(0)-OH.
• R 32 is
• R 32 is independently -NHOH. In embodiments, R 32 is independently -OCF 3 . In embodiments, R 32 is independently -OCHF 2 . In embodiments, R 32 is independently -CCI 3 . In embodiments, R 32 is independently -CBr 3 . In embodiments, R 32 is independently -CI 3 . In embodiments, R 32 is independently -F. In embodiments, R 32 is independently -CI. In embodiments, R 32 is independently -Br. In embodiments, R 32 is independently -I. In embodiments, R 32 is
• R 33 32 33 independently R -substituted C1-C4 alkyl. In embodiments, R is independently R -substituted 2 to 4 membered heteroalkyl. In embodiments, R 32 is independently R 33 -substituted C 3 -C6 cycloalkyl. In embodiments, R 32 is independently R 33 -substituted 3 to 6 membered
• R 32 is independently R 33 -substituted phenyl.
• R 32 is independently R 33 -substituted 5 to 6 membered heteroaryl.
• R 32 is independently unsubstituted C1-C4 alkyl. In embodiments, R 32 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 32 is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 32 is independently unsubstituted phenyl. In embodiments, R 32 is independently unsubstituted 5 to 6 membered heteroaryl.
• R 33 is independently oxo
• R 33 is independently -NH 2 . In embodiments, R 33 is independently - OH. In embodiments, R 33 is independently halogen. In embodiments, R 33 is independently - CN. In embodiments, R 33 is independently oxo. In embodiments, R 33 is independently -CF 3 . In embodiments, R 33 is independently -COOH. In embodiments, R 33 is independently -CONH 2 . In embodiments, R 33 is independently -N0 2 . In embodiments, R 33 is independently -SH. In embodiments, R 33 is independently -SO 3 H. In embodiments, R 33 is independently -SO 4 H. In embodiments, R 33 is independently -S0 2 NH 2 . In embodiments, R 33 is independently -NHNH 2 . In embodiments, R 33 is independently -ONH 2 . In embodiments, R 33 is independently
• R 33 is independently -NHS0 2 H.
• R 33 is independently -NHC(0)-OH.
• R 33 is
• R 33 is independently -NHOH. In embodiments, R 33 is independently -OCF 3 . In embodiments, R 33 is independently -OCHF 2 . In embodiments, R 33 is independently -CCI 3 . In embodiments, R 33 is independently -CBr 3 . In embodiments, R 33 is independently -CI 3 . In embodiments, R 33 is independently -F. In embodiments, R 33 is independently -CI. In embodiments, R 33 is independently -Br. In embodiments, R 33 is independently -I. In embodiments, R 33 is
• R 34 33 34 independently R -substituted C1-C4 alkyl. In embodiments, R is independently R -substituted 2 to 4 membered heteroalkyl. In embodiments, R 33 is independently R 34 -substituted C 3 -C6 cycloalkyl. In embodiments, R 33 is independently R 34 -substituted 3 to 6 membered
• R 33 is independently R 34 -substituted phenyl.
• R 33 is independently R 34 -substituted 5 to 6 membered heteroaryl.
• R 33 is independently unsubstituted C1-C4 alkyl. In embodiments, R 33 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 33 is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 33 is independently unsubstituted phenyl. In embodiments, R 33 is independently unsubstituted 5 to 6 membered heteroaryl.
• L 5 is independently a bond, R 35 -substituted or unsubstituted alkylene, R 35 -substituted or unsubstituted heteroalkylene, R 35 - substituted or unsubstituted cycloalkylene, R 35 -substituted or unsubstituted heterocycloalkylene, R 35 -substituted or unsubstituted arylene, or R 35 -substituted or unsubstituted heteroarylene.
• L 5 is a
• L 5 is a bond. In embodiments, L 5 is -NH-. In embodiments, L 5 is -NR 35 -. In embodiments, L 5 is -S-. In embodiments, L 5 is -0-. In embodiments, L 5 is -C(O)- . In embodiments, L 5 is -NHC(O)- . In embodiments, L 5 is -C(0)NH-. In embodiments, L 5 is -NHC(0)NH-. In embodiments, L 5 is -NHC(NH)NH-. In embodiments, L 5 is -C(S)- . In embodiments, L 5 is R 35 - substituted or unsubstituted C1-C20 alkylene.
• L 5 is R 35 -substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 5 is R 35 -substituted or unsubstituted C3-C8 cycloalkylene. In embodiments, L 5 is R 35 -substituted or unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L 5 is R 35 -substituted or unsubstituted C6-C10 arylene. In embodiments, L 5 is R 35 -substituted or unsubstituted 5 to 10 membered heteroarylene.
• L 5 is R 35 -substituted C1-C20 alkylene. In embodiments, L 5 is R 35 -substituted 2 to 20 membered heteroalkylene. In embodiments, L 5 is R 35 -substituted C3-C8 cycloalkylene. In embodiments, L 5 is R 35 -substituted 3 to 8 membered heterocycloalkylene. In embodiments, L 5 is R 35 -substituted C6-C10 arylene. In embodiments, L 5 is R 35 -substituted 5 to 10 membered heteroarylene. In embodiments, L 5 is unsubstituted C1-C20 alkylene.
• L 5 is unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L 5 is unsubstituted C3-C8 cycloalkylene. In embodiments, L 5 is unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L 5 is unsubstituted C6-C10 arylene. In embodiments, L 5 is unsubstituted 5 to 10 membered heteroarylene. In embodiments, L 5 is R 35 -substituted C1-C15 alkylene. In
• L 5 is R 35 -substituted 2 to 15 membered heteroalkylene. In embodiments, L 5 is R 35 -substituted C3-C6 cycloalkylene. In embodiments, L 5 is R 35 -substituted 3 to 6 membered heterocycloalkylene. In embodiments, L 5 is R 35 -substituted phenylene. In embodiments, L 5 is R 35 -substituted 5 to 6 membered heteroarylene. In embodiments, L 5 is unsubstituted C1-C15 alkylene. In embodiments, L 5 is unsubstituted 2 to 15 membered heteroalkylene. In
• L 5 is unsubstituted C3-C6 cycloalkylene. In embodiments, L 5 is unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, L 5 is unsubstituted phenylene. In embodiments, L 5 is unsubstituted 5 to 6 membered heteroarylene. In embodiments, L 5 is R 35 - substituted C1-C1 0 alkylene. In embodiments, L 5 is R 35 -substituted 2 to 10 membered heteroalkylene. In embodiments, L 5 is R 35 -substituted C4-C6 cycloalkylene.
• L 5 is R 35 -substituted 4 to 6 membered heterocycloalkylene. In embodiments, L 5 is R 35 -substituted phenylene. In embodiments, L 5 is R 35 -substituted 5 membered heteroarylene. In embodiments, L 5 is R 35 -substituted Ci-Cs alkylene. In embodiments, L 5 is R 35 -substituted 2 to 8 membered heteroalkylene. In embodiments, L 5 is R 35 -substituted C 5 -C 6 cycloalkylene. In embodiments, L 5 is R 35 -substituted 5 to 6 membered heterocycloalkylene. In embodiments, L 5 is R 35 -substituted 6 membered heteroarylene. In embodiments, L 5 is R 35 -substituted C1-C6 alkylene. In embodiments, L 5 is R 35 -substituted phenylene. In embodiments, L
• L 5 is R 35 -substituted 2 to 6 membered heteroalkylene. In embodiments, L 5 is R 35 - substituted C6-C2 0 alkylene. In embodiments, L 5 is R 35 -substituted 6 to 20 membered heteroalkylene. In embodiments, L 5 is unsubstituted C1-C1 0 alkylene. In embodiments, L 5 is unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L 5 is unsubstituted C4-C6 cycloalkylene. In embodiments, L 5 is unsubstituted 4 to 6 membered heterocycloalkylene.
• L 5 is unsubstituted phenylene. In embodiments, L 5 is unsubstituted 5 membered heteroarylene. In embodiments, L 5 is unsubstituted Ci-Cs alkylene. In embodiments, L 5 is unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 5 is unsubstituted C5-C6 cycloalkylene. In embodiments, L 5 is unsubstituted 5 to 6 membered heterocycloalkylene. In embodiments, L 5 is unsubstituted 6 membered heteroarylene. In embodiments, L 5 is unsubstituted C1-C6 alkylene. In embodiments, L 5 is unsubstituted 2 to 6 membered
• L 5 is unsubstituted C6-C2 0 alkylene. In embodiments, L 5 is unsubstituted 6 to 20 membered heteroalkylene.
• R 35 is independently oxo
• R is independently -NH 2 . In embodiments, R is independently - OH. In embodiments, R 35 is independently halogen. In embodiments, R 35 is independently - CN. In embodiments, R 35 is independently oxo. In embodiments, R 35 is independently -CF 3 . In embodiments, R 35 is independently -COOH. In embodiments, R 35 is independently -CONH 2 . In embodiments, R 35 is independently -NO 2 . In embodiments, R 35 is independently -SH. In embodiments, R 35 is independently -SO 3 H. In embodiments, R 35 is independently -SO 4 H. In embodiments, R 35 is independently -SO 2 NH 2 . In embodiments, R 35 is independently -NHNH 2 . In embodiments, R 35 is independently -ONH 2 . In embodiments, R 35 is independently
• R 35 is independently -NHS0 2 H.
• R 35 is independently -NHC(0)-OH.
• R 35 is
• R 35 is independently -NHOH. In embodiments, R 35 is independently -OCF 3 . In embodiments, R 35 is independently -OCHF 2 . In embodiments, R 35 is independently -CCI 3 . In embodiments, R 35 is independently -CBr 3 . In embodiments, R 35 is independently -CI 3 . In embodiments, R 35 is independently -F. In embodiments, R 35 is independently -CI. In embodiments, R 35 is independently -Br. In embodiments, R 35 is independently -I. In embodiments, R 35 is independently R 36 -substituted C1-C4 alkyl. In embodiments, R 35 is independently R 36 -substituted 2 to 4 membered heteroalkyl. In embodiments, R 35 is independently R 36 -substituted C3-C6 cycloalkyl. In embodiments, R 35 is independently R 36 -substituted 3 to 6 membered
• R 35 is independently R 36 -substituted phenyl.
• R 35 is independently R 36 -substituted 5 to 6 membered heteroaryl.
• R 35 is independently unsubstituted C1-C4 alkyl. In embodiments, R 35 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 35 is independently unsubstituted C3-C6 cycloalkyl. In embodiments, R 35 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 35 is independently unsubstituted phenyl. In embodiments, R 35 is independently unsubstituted 5 to 6 membered heteroaryl.
• R 36 is independently oxo
• R is independently -NH 2 . In embodiments, R is independently - OH. In embodiments, R 36 is independently halogen. In embodiments, R 36 is independently - CN. In embodiments, R 36 is independently oxo. In embodiments, R 36 is independently -CF 3 . In embodiments, R 36 is independently -COOH. In embodiments, R 36 is independently -CONH 2 . In embodiments, R 36 is independently -NO2. In embodiments, R 36 is independently -SH. In embodiments, R 36 is independently -SO 3 H. In embodiments, R 36 is independently -SO4H. In embodiments, R 36 is independently -SO2NH2. In embodiments, R 36 is independently -NHNH 2 . In embodiments, R 36 is independently -ONH 2 . In embodiments, R 36 is independently
• R 36 is independently -NHS0 2 H.
• R 36 is independently -NHC(0)-OH.
• R 36 is
• R 36 is independently -NHOH. In embodiments, R 36 is independently -OCF 3 . In embodiments, R 36 is independently -OCHF 2 . In embodiments, R 36 is independently -CCI 3 . In embodiments, R 36 is independently -CBr 3 . In embodiments, R 36 is independently -CI 3 . In embodiments, R 36 is independently -F. In embodiments, R 36 is independently -CI. In embodiments, R 36 is independently -Br. In embodiments, R 36 is independently -I. In embodiments, R 36 is independently R 37 -substituted C1-C4 alkyl. In embodiments, R 36 is independently R 37 -substituted 2 to 4 membered heteroalkyl. In embodiments, R 36 is independently R 37 -substituted C 3 -C6 cycloalkyl. In embodiments, R 36 is independently R 37 -substituted 3 to 6 membered
• R 36 is independently R 37 -substituted phenyl.
• R 36 is independently R 37 -substituted 5 to 6 membered heteroaryl.
• R 36 is independently unsubstituted C1-C4 alkyl. In embodiments, R 36 is independently unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R 36 is independently unsubstituted C 3 -C6 cycloalkyl. In embodiments, R 36 is independently unsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R 36 is independently unsubstituted phenyl. In embodiments, R 36 is independently unsubstituted 5 to 6 membered heteroaryl.
• R is substituted heteroaryl
• L is L -L -L -L ;
• L 3 is 5 to 10 membered heteroarylene
• L 4 is -(CH 2 CH 2 0)b-
• b is an integer from 2 to 8
• blO is an integer from 1 to 6.
• R 3 is substituted bicyclic heteroaryl;
• L 1 is L 2 -L 3 -L 4 -L 5 ;
• L 2 is -CH 2 CH 2 OCH 2 -;
• L 3 is 5 to 10 membered heteroarylene;
• L 4 is -(CH 2 CH 2 0)b-;
• b is an integer from 2 to 8;
• b 10 is an integer from 1 to 6.
• R 3 is heteroaryl substituted with -NH 2 or -OH;
• L 1 is L 2 -L 3 -L 4 -L 5 ;
• L 2 is -CH 2 CH 2 OCH 2 -;
• L 3 is 5 to 10 membered heteroarylene;
• L 4 is -(CH 2 CH 2 0)b-;
• b is an integer from 2 to 8;
• b 10 is an integer from 1 to 6.
• R 3 is benzoxazolyl substituted with -NH 2 or -OH;
• L 1 is L 2 -L 3 -L 4 -L 5 ;
• L 2 is -CH 2 CH 2 OCH 2 -;
• L 3 is 5 to 10 membered heteroarylene;
• L 4 is - (CH 2 CH 2 0)b-;
• b is an integer from 2 to 8;
• L 5 is benzoxazolyl substituted with -NH 2 or -OH;
• L 1 is L 2 -L 3 -L 4 -L 5 ;
• L 2 is -CH 2 CH 2 OCH 2 -;
• L 3 is 5 to 10 membered heteroarylene;
• L 4 is - (CH 2 CH 2 0)b-;
• b is an integer from 2 to 8;
• L 5 is benzoxazolyl substituted with -NH 2 or -OH;
• L 1 is L 2 -L 3 -L 4 -L 5 ;
• R 3 is benzoxazolyl substituted with -NH 2 or -OH;
• L 1 is L 2 -L 3 -L 4 -L 5 ;
• L 2 is -CH 2 CH 2 OCH 2 -;
• L 3 is triazolylene;
• L 4 is - (CH 2 CH 2 0)b-;
• b is an integer from 4 to 8; and
• L 5 is benzoxazolyl substituted with -NH 2 or -OH;
• L 1 is L 2 -L 3 -L 4 -L 5 ;
• L 2 is -CH 2 CH 2 OCH 2 -;
• L 3 is triazolylene;
• L 4 is - (CH 2 CH 2 0)b-;
• b is an integer from 4 to 8; and
• L 5 is benzoxazolyl substituted with -NH 2 or -OH;
• L 1 is L 2 -L 3 -L 4 -L 5 ;
• L 2 is -CH
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -NH 2 .
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -OH.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently halogen.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently halogen.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -CN.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently oxo.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -COOH.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -CONH 2 .
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -N0 2 .
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -SH.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -SH.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -S0 4 H.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -S0 2 NH 2 .
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -NHNH 2 .
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -ONH 2 .
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -NHS0 2 H.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -NHC(0)-OH.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -NHC(0)-OH.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -NHOH.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -OCF 3 .
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -OCHF 2 .
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -CBr 3 .
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -CI 3 .
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -F.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -CI.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -Br.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -Br.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently -Br.
• R 58 22 25 28 31 34 and/or R are independently unsubstituted C1-C4 alkyl.
• R , R , R , R , R , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently unsubstituted 2 to 4 membered heteroalkyl.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently unsubstituted C 3 -C 6 cycloalkyl.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently unsubstituted 3 to 6 membered heterocycloalkyl.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently unsubstituted phenyl.
• R 22 , R 25 , R 28 , R 31 , R 34 , R 37 , R 40 , R 43 , R 46 , R 49 , R 52 , R 55 , and/or R 58 are independently unsubstituted 5 to 6 membered heteroaryl.
• a compound as described herein may include multiple instances of
• each variable may optional be different and be appropriately labeled to distinguish each group for greater clarity.
• each R R , R°, R y , R , X, m, n, and/or v may be referred to, for example, as R 3 1 , R 3'2 , R 3'3 , R 3'4 , R 3'5 , R 3'6 , R 3'7 , R 7' 1 , R 7'2 , R 7'3 , R 7'4 , R 7'5 , R 7'6 , R 7'7 , R 8 1 , r> 8.2 r> 8.3 r> 8.4 r> 8.5 r> 8.6 D 8.7 r> 9.1 r> 9.2 r> 9.3 r> 9.4 r> 9.5 r> 9.6 r> 9.7 r> 10.2 r> 10.3 r> 10.4 r> 10.5 l ⁇ , rv , rv , rv , rv , rv ,
• R 3 4 R 3. 5J R 3.6 R 3 DEFMITION OF R 7 IG ASSUMED BY R 7.1 S R 7J R 7.4 ⁇ R 7.5 ⁇ R 7. 6J R 7 ⁇ definition of R 8 is assumed by R 8 1 , R 8'2 , R 8'3 , R 8'4 , R 8'5 , R 8'6 , R 8'7 , the definition of R 9 is assumed by R 9' 1 , R 9 - 2 , R 9 - 3 , R 9 - 4 , R 9'5 , R 9'6 , R 9'7 , the definition of R 10 is assumed by R 10 1 , R 10'2 , R 10'3 , R 10'4 , R 10'5 , R 10 - 6 , R 10 - 7 , the definition of X is assumed by X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , the definition of X is assumed by
• V 1 2 3 of m is assumed by m , m ' , m , m ' , m ' , m ' , m
• n is assumed by n , n , n , n '4 , n '5 , n '6 , n '7
• v is assumed by V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 .
• the compound competes with rapamycin for binding to mTORC 1. In embodiments, the compound binds an overlapping region of mTORC 1 with the binding region of rapamycin. In embodiments, the compound competes with ATP for binding to mTOR. In embodiments, the compound competes with ATP for binding to mTORC 1. In embodiments, the compound competes with rapamycin and ATP for binding to mTORC 1.
• the compound is an mTORC 1 specific inhibitor. In embodiments, the compound has a slow off-rate from mTORC 1. In embodiments, the compound has an off-rate of slower than 0.1 per minute. In embodiments, the compound has an off-rate of slower than 0.01 per minute. In embodiments, the compound has an off-rate of slower than 0.001 per minute. In embodiments, the compound has an off-rate of slower than 0.0001 per minute. In embodiments, the compound-mTORC 1 complex has a half-life of at least 10 minutes. In embodiments, the compound-mTORC 1 complex has a half-life of at least 100 minutes. In embodiments, the compound-mTORC 1 complex has a half-life of at least 300 minutes.
• the compound-mTORC 1 complex has a half-life of at least 1000 minutes. In embodiments, the compound-mTORC 1 complex has a half-life of at least 3000 minutes. In embodiments, the compound-mTORC 1 complex has a half-life of at least 10000 minutes.
• the compound is M-1071. In embodiments, the compound is M-11 11. In embodiments, the compound is M-3059. In embodiments, the compound is M-11 15. In embodiments, the compound is not M-11 15. In embodiments, the compound is El 010. In embodiments, the compound is El 035. [0258] In embodiments, the active site mTOR inhibitor is a monovalent MLN0128.
• the active site mTOR inhibitor is wherein
• z20 is an integer from 0 to 4. In embodiments, z20 is 0. In embodiments, z20 is 1. In embodiments, z20 is 2. In embodiments, z20 is 3. In embodiments, z20 is 4. In embodiments, R 20 is independently - H2. In embodiments, R 20 is independently -OH. In embodiments, R 20 is independently halogen. In embodiments, R 20 is independently -CN. In embodiments, R 20 is independently oxo. In embodiments, R 20 is independently -CF 3 . In embodiments, R 20 is independently -COOH. In embodiments, R 20 is independently -CONH 2 . In embodiments, R 20 is independently -NO2.
• R 20 is independently -OCF 3 . In embodiments, R 20 is independently -OCHF 2 . In embodiments, R 20 is independently a halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN,
• R is independently a halogen, -CF 3 , -CN, -NH 2 , -OH, R 21 -substituted or unsubstituted C1-C4 alkyl, R 21 -substituted or unsubstituted 2 to 4 membered heteroalkyl, R 21 -substituted or unsubstituted C 3 -C 6 cycloalkyl, R 21 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 21 -substituted or unsubstituted phenyl, or R 21 -substituted or unsubstituted 5 to 6 membered heteroaryl.
• R 20 is independently a halogen, -CF 3 , -CN, -NH 2 , -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.
• R 20 is independently a halogen, -CF 3 , unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, unsubstituted methoxy, or unsubstituted ethoxy.
• R 20 is independently unsubstituted methyl.
• R 20 is independently unsubstituted ethyl.
• R 20 is independently unsubstituted methoxy. In embodiments, R 20 is independently unsubstituted ethoxy. In embodiments, R 20 is independently -CC1 3 . In embodiments, R 20 is independently -CBr 3 . In embodiments, R 20 is independently -CI 3 . In embodiments, R 20 is independently -F. In embodiments, R 20 is independently -CI. In embodiments, R 20 is independently -Br. In embodiments R 20 is independently -I. In embodiments, the active site mTOR inhibitor is
• R is as described herein, including in embodiments.
• the active site mTOR inhibito .
• the active site mTOR inhibitor is In embodiments, the active site mTOR inhibitor is . In embodiments, the active site mTOR inhibitor is In embodiments, the active site mTOR inhibitor n embodiments, the active site mTOR inhibitor is [0260]
• the active site mTOR inhibitor is wherein R zu is as described herein, including in embodiments.
• z20 is an integer from 0 to 5. In embodiments, z20 is 0. In embodiments, z20 is 1. In embodiments, z20 is 2. In embodiments, z20 is 3. In embodiments, z20 is 4. In embodiments, z20 is 5. In embodiments, R 20 is independently - H2. In embodiments, R 20 is independently -OH. In embodiments, R 20 is independently halogen. In
• R is independently -CN. In embodiments, R zu is independently oxo. In embodiments, R is independently -CF 3 . In embodiments, R is independently -COOH. In embodiments, R is independently 20 ⁇
• R zu is independently -NO2.
• R is independently -SH.
• R zu is independently -SO 3 H.
• R 20 is independently a halogen, -CF 3 , -CN, -NH 2 , -OH, R 21 -substituted or unsubstituted C1-C4 alkyl, R 21 -substituted or unsubstituted 2 to 4 membered heteroalkyl, R 21 -substituted or unsubstituted C 3 -C6 cycloalkyl, R 21 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, R 21 -substituted or unsubstituted phenyl, or R 21 -substituted or unsubstituted 5 to 6 membered heteroaryl.
• R 20 is independently a halogen, -CF 3 , -CN, -NH 2 , -OH, unsubstituted C1-C4 alkyl, or unsubstituted 2 to 4 membered heteroalkyl.
• R 20 is independently a halogen, -CF 3 , unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, unsubstituted methoxy, or unsubstituted ethoxy.
• R 20 is independently unsubstituted methyl.
• R 20 is independently unsubstituted ethyl.
• R 20 is independently unsubstituted methoxy. In embodiments, R 20 is independently unsubstituted ethoxy. In embodiments, R 20 is independently -CCI 3 . In embodiments, R 20 is independently -CBr 3 . In embodiments, R 20 is independently -CI 3 . In embodiments, R 20 is independently -F. In embodiments, R 20 is independently -CI. In embodiments, R 20 is independently -Br. In embodiments R 20 is independently -I. In embodiments, the active site mTOR inhibitor is
• the active site mTOR is as described herein.
• the active site mTOR is as described herein.
• the active site mTOR inhibitor is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoedoxifenofibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibibidididididididididididi
• the active site mTOR inhibitor is .
• the active site mTOR inhibitor is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
• the active site mTOR inhibitor (e.g., asTORi) has a weaker binding affinity for mTOR than MLN0128. In embodiments, the active site mTOR inhibitor has a binding affinity that results in preferential binding to mTORC 1 over mTORC2 that is greater than the same compound wherein the active site mTOR inhibitor is MLN0128. In embodiments, the active site mTOR inhibitor has a binding affinity that results in preferential binding to mTORC 1 over mTORC2 that is greater than the same compound wherein the active site mTOR inhibitor is PP242.
• the active site mTOR inhibitor has a binding affinity that results in preferential binding to mTORC 1 over mTORC2 that is greater than the same compound wherein the active site mTOR inhibitor is PP242 wherein the -OH substituent on the indoyly moiety is replaced with an unsubstituted methoxy moiety.
• the compound may include an active site mTOR inhibitor that results in a preferential binding of the compound to mTORCl over mTORC2 of at least 1.1-fold (e.g., at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 100000, 200000, 300000, 400000, 500000, 600000, 700000, 800000, 900000, or 1000000 fold).
• an active site mTOR inhibitor that results in a preferential binding of the compound to mTORCl over mTORC2 of at least 1.1-fold (e.g., at least
• the compound may include an active site mTOR inhibitor that results in a preferential inhibition of mTORCl over mTORC2 by the compound of at least 1.1-fold (e.g., at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 100000, 200000, 300000, 400000, 500000, 600000, 700000, 800000, 900000, or 1000000 fold).
• an active site mTOR inhibitor that results in a preferential inhibition of mTORCl over mTORC2 by the compound of at least 1.1-fold (e.g., at least
• the compound is included in a drug-eluting stent.
• the compound is a compound described herein.
• a drug-eluting stent comprising a compound as described herein.
• composition including a
• the pharmaceutically acceptable salt thereof is included in a therapeutically effective amount.
• the compound is included in a drug-eluting stent.
• the pharmaceutical composition includes a second agent (e.g. therapeutic agent).
• the pharmaceutical composition includes a second agent (e.g. therapeutic agent) in a therapeutically effective amount.
• the second agent is an anti-cancer agent.
• the second agent is an anti-autoimmune disease agent.
• the second agent is an anti-inflammatory disease agent.
• the second agent is an anti- neurodegenerative disease agent.
• the second agent is an anti-metabolic disease agent.
• the second agent is an anti-cardiovascular disease agent.
• the second agent is an anti-aging agent. In embodiments, the second agent is a longevity agent. In embodiments, the second agent is an agent for treating or preventing transplant rejection. In embodiments, the second agent is an agent for treating or preventing fungal infection. In embodiments, the second agent is immune system repressor. In
• the second agent is an mTOR modulator. In embodiments, the second agent is an mTOR inhibitor. In embodiments, the second agent is an active site mTOR inhibitor. In embodiments, the second agent is a rapamycin. In embodiments, the second agent is a rapamycin analog. In embodiments, the second agent is an mTORCl pathway inhibitor.
• a method of treating a disease associated with an aberrant level of mTORCl activity in a subject in need of such treatment includes administering to the subject a compound described herein.
• the method may include
• a compound as described herein for use as a medicament.
• the medicament is useful for treating a disease caused by an aberrantly high mTORCl activity (e.g., hyperactivity of mTORCl or increased level of activity of mTORCl or increased amount of mTORCl).
• the use includes administering to the subject a compound described herein.
• the use may include administering to the subject a therapeutically effective amount of a compound described herein (e.g., an mTORCl modulator (e.g., inhibitor) as described above).
• a compound as described herein for use in the treatment of a disease caused by aberrant levels of mTORCl activity in a subject in need of such treatment.
• the disease may be caused by an aberrantly high mTORCl activity (e.g., hyperactivity of mTORCl or increased level of activity of mTORCl or increased amount of mTORCl).
• the use includes administering to the subject a compound described herein.
• the use may include administering to the subject a therapeutically effective amount of a compound described herein (e.g., an mTORCl modulator (e.g., inhibitor) as described above).
• mTORCl hyperactivity is an increased amount of mTORCl activity compared to normal levels of mTORCl activity in a particular subject or a population of healthy subjects.
• the increased amount of mTORC 1 activity may result in, for example, excessive amounts of cell proliferation thereby causing the disease state.
• the subject of treatment for the disease is typically a mammal.
• the mammal treated with the compound e.g., compound described herein, mTORCl modulator (e.g., inhibitor)
• the compound may be a human, nonhuman primate, and/or non-human mammal (e.g., rodent, canine).
• a method of treating an mTORCl activity-associated disease in a subject in need of such treatment including administering a compound, or a pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. a claim, embodiment, example, table, figure, or claim) to the subject.
• the medicament may be useful for treating an mTORC 1 activity-associated disease in a subject in need of such treatment.
• the use may include
• a compound for use in the treatment of an mTORC 1 activity-associated disease in a subject in need of such treatment may include administering a compound, or a pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. an aspect, embodiment, example, table, figure, or claim) to the subject.
• the mTORC 1 activity-associated disease or disease associated with aberrant levels of mTORC 1 activity is cancer. In embodiments, the mTORC 1 activity-associated disease or disease associated with aberrant levels of mTORC 1 activity is an autoimmune disease. In embodiments, the mTORC 1 activity-associated disease or disease associated with aberrant levels of mTORC 1 activity is an inflammatory disease. In embodiments, the mTORC 1 activity- associated disease or disease associated with aberrant levels of mTORCl activity is a neurodegenerative disease. In embodiments, the mTORCl activity-associated disease or disease associated with aberrant levels of mTORC 1 activity is a metabolic disease.
• the mTORCl activity-associated disease or disease associated with aberrant levels of mTORCl activity is transplant rejection.
• the mTORCl activity-associated disease or disease associated with aberrant levels of mTORCl activity is fungal infection.
• the mTORCl activity-associated disease or disease associated with aberrant levels of mTORCl activity is an inflammatory disease.
• the mTORC 1 activity-associated disease or disease associated with aberrant levels of mTORCl activity is a cardiovascular disease.
• the mTORCl activity-associated disease or disease associated with aberrant levels of mTORCl activity is aging.
• the mTORCl activity-associated disease or disease associated with aberrant levels of mTORCl activity is dying of an age-related disease.
• the mTORCl activity-associated disease or disease associated with aberrant levels of mTORCl activity is Cancer (e.g., carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, solid cancers, lymphoid cancers; cancer of the kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, esophagus, liver; testicular cancer, glioma, hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML),
• Cancer e
• Encephalomyelitis Acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti- GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria, Axonal or neuronal neuropathies, Balo disease, Behcet's disease,
• Immunoregulatory lipoproteins Inclusion body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere's disease, Microscopic polyangiitis, Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic's), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatry Disorders Associated with Streptococcus),
• Transverse myelitis Type 1 diabetes, Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, Vitiligo, Wegener's granulomatosis (i.e., Granulomatosis with Polyangiitis (GPA), traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pe
• Vitiligo asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, atopic dermatitis, Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt- Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HTV- associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado- Joseph disease (Spinocerebellar ataxia type 3),
• Schizophrenia Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes dorsalis, diabetes (e.g., type I or type II), obesity, metabolic syndrome, a mitochondrial disease (e.g., dysfunction of mitochondria or aberrant mitochondrial function), fungal infection, transplant rejection, or a cardiovascular disease (e.g., congestive heart failure; arrhythmogenic syndromes (e.g., paroxysomal tachycardia, delayed after depolarizations, ventricular tachycardia, sudden tachycardia, exercise- induced arrhythmias, long QT syndromes, or bidirectional tachycardia); thromboembolic disorders (e.g., arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, or thromboembolic disorders in the chambers of the heart);
• arrhythmogenic syndromes e.g., par
• Atherosclerosis restenosis; peripheral arterial disease; coronary bypass grafting surgery; carotid artery disease; arteritis; myocarditis; cardiovascular inflammation; vascular inflammation;
• coronary heart disease CHD
• unstable angina U
• unstable refractory angina stable angina
• SA chronic stable angina
• acute coronary syndrome ACS
• myocardial infarction first or recurrent
• acute myocardial infarction AMI
• myocardial infarction non-Q wave myocardial infarction
• non-STE myocardial infarction coronary artery disease; ischemic heart disease; cardiac ischemia; ischemia; ischemic sudden death; transient ischemic attack; stroke; peripheral occlusive arterial disease; venous thrombosis; deep vein thrombosis; thrombophlebitis; arterial embolism; coronary arterial thrombosis; cerebral arterial thrombosis, cerebral embolism; kidney embolism; pulmonary embolism; thrombosis (e.g., associated with prosthetic valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis); thrombosis (e
• a method of treating a disease including administering an effective amount of a compound as described herein.
• a compound as described herein for use as a medicament e.g., for treatment of a disease.
• a compound as describe herein for use in the treatment of a disease e.g., including administering an effective amount of a compound as described herein.
• the disease is cancer.
• the disease is an autoimmune disease.
• the disease is an inflammatory disease.
• the disease is a neurodegenerative disease.
• the disease is a metabolic disease. In embodiments, the disease is fungal infection. In embodiments, the disease is transplant rejection. In embodiments, the disease is an inflammatory disease. In embodiments, the disease is a cardiovascular disease. In embodiments, the disease is Cancer (e.g., carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, solid cancers, lymphoid cancers; cancer of the kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, esophagus, liver; testicular cancer, glioma, hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non- Hodgkin's lymphomas (e.g.
• Acute Disseminated Encephalomyelitis Acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune
• AIED Autoimmune inner ear disease
• myocarditis Autoimmune myocarditis
• Autoimmune oophoritis Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria, Axonal or neuronal neuropathies, Balo disease, Behcet's disease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricial pemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogans syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST disease, Essential mixed cryoglobulinemia, Demyelinating neuropathies, Dermatitis herpetiformis, Dermatomyo
• Glomerulonephritis Goodpasture's syndrome, Granulomatosis with Polyangiitis (GPA) (formerly called Wegener's Granulomatosis), Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, Immunoregulatory lipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LA
• Transverse myelitis Type 1 diabetes, Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, Vitiligo, Wegener's granulomatosis (i.e., Granulomatosis with Polyangiitis (GPA), traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pe
• Vitiligo asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, atopic dermatitis, Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt- Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HTV- associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado- Joseph disease (Spinocerebellar ataxia type 3),
• Schizophrenia Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tabes dorsalis, diabetes (e.g., type I or type II), obesity, metabolic syndrome, a mitochondrial disease (e.g., dysfunction of mitochondria or aberrant mitochondrial function), fungal infection, transplant rejection, or a cardiovascular disease (e.g., congestive heart failure; arrhythmogenic syndromes (e.g., paroxysomal tachycardia, delayed after depolarizations, ventricular tachycardia, sudden tachycardia, exercise- induced arrhythmias, long QT syndromes, or bidirectional tachycardia); thromboembolic disorders (e.g., arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, or thromboembolic disorders in the chambers of the heart);
• arrhythmogenic syndromes e.g., par
• Atherosclerosis restenosis; peripheral arterial disease; coronary bypass grafting surgery; carotid artery disease; arteritis; myocarditis; cardiovascular inflammation; vascular inflammation;
• coronary heart disease CHD
• unstable angina U
• unstable refractory angina stable angina
• SA chronic stable angina
• acute coronary syndrome ACS
• myocardial infarction first or recurrent
• acute myocardial infarction AMI
• myocardial infarction non-Q wave myocardial infarction
• non-STE myocardial infarction coronary artery disease; ischemic heart disease; cardiac ischemia; ischemia; ischemic sudden death; transient ischemic attack; stroke; peripheral occlusive arterial disease; venous thrombosis; deep vein thrombosis; thrombophlebitis; arterial embolism; coronary arterial thrombosis; cerebral arterial thrombosis, cerebral embolism; kidney embolism; pulmonary embolism; thrombosis (e.g., associated with prosthetic valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis); thrombosis (e
• the disease is a polycystic disease. In embodiments, the disease is polycystic kidney disease. In embodiments, the disease is stenosis. In embodiments, the disease is restenosis. In embodiments, the disease is neointimal proliferation. In embodiments, the disease is neointimal hyperplasia.
• a method of treating aging in a subject in need of such treatment including administering a compound, or a pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. a claim, embodiment, example, table, figure, or claim) to the subject.
• a compound as described herein for use as a medicament in embodiments, the medicament may be useful for treating aging in a subject in need of such treatment.
• the use may include administering a compound, or a
• a compound for use in the treatment of aging in a subject in need of such treatment may include administering a compound, or a pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. an aspect, embodiment, example, table, figure, or claim) to the subject.
• a method of extending life span or inducing longevity in a subject in need of such treatment including administering a compound, or a pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. a claim, embodiment, example, table, figure, or claim) to the subject.
• a compound as described herein for use as a medicament may be useful for extending life span or inducing longevity in a subject in need of such treatment.
• the use may include administering a compound, or a pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. an aspect, embodiment, example, table, figure, or claim) to the subject.
• a compound for use in extending life span or inducing longevity in a subject in need of such treatment may include administering a compound, or a pharmaceutically acceptable salt thereof, as described herein, including embodiments (e.g. an aspect, embodiment, example, table, figure, or claim) to the subject.
• a method of treating a polycystic disease in a subject in need of such treatment includes administering to the subject a compound described herein.
• the method may include
• a therapeutically effective amount of a compound described herein e.g., an mTORCl modulator (e.g., inhibitor) as described above.
• a compound as described herein for use as a medicament is useful for treating a polycystic disease.
• the polycystic disease may be polycystic kidney disease.
• the use includes administering to the subject a compound described herein.
• the use may include administering to the subject a therapeutically effective amount of a compound described herein (e.g., an mTORCl modulator (e.g., inhibitor) as described above).
• a compound as described herein for use in the treatment of a polycystic disease in a subject in need of such treatment may be polycystic kidney disease.
• the use includes administering to the subject a compound described herein.
• the use may include administering to the subject a therapeutically effective amount of a compound described herein (e.g., an mTORCl modulator (e.g., inhibitor) as described above).
• a method of treating stenosis in a subject in need of such treatment includes administering to the subject a compound described herein.
• the compound is administered in a drug eluting stent.
• the method may include administering to the subject a therapeutically effective amount of a compound described herein (e.g., an mTORCl modulator (e.g., inhibitor) as described above).
• a compound as described herein for use as a medicament is useful for treating stenosis.
• the stenosis may be restenosis.
• the use includes administering to the subject a compound described herein.
• the compound is administered in a drug eluting stent.
• the use may include administering to the subject a therapeutically effective amount of a compound described herein (e.g., an mTORCl modulator (e.g., inhibitor) as described above).
• a compound as described herein for use in the treatment of stenosis in a subject in need of such treatment.
• the stenosis may be restenosis.
• the use includes administering to the subject a compound described herein.
• the compound is administered in a drug eluting stent.
• the use may include administering to the subject a therapeutically effective amount of a compound described herein (e.g., an mTORCl modulator (e.g., inhibitor) as described above).
• the disease is a disease described herein and the compound is a compound described herein.
• a method of modulating mTORCl activity in a subject in need thereof including administering to the subject an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
• the method includes inhibiting mTORCl activity.
• the method includes inhibiting mTORCl activity and not inhibiting mTORC2 activity.
• the method includes inhibiting mTORC 1 activity more than inhibiting mTORC2 activity.
• the method includes inhibiting mTORC 1 activity at least 1.1 fold as much as inhibiting mTORC2 activity (e.g., at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000,
• the mTORCl is in a cell.
• the cell is a mammalian cell, such as a human cell.
• the cell may be isolated in vitro, form part of a tissue in vitro, or may form part of an organism.
• Modulating mTORCl activity includes directly or indirectly modulating one or more functions of mTORCl and/or one or more downstream effects of mTORCl.
• the function or effect of mTORC 1 is altered compared to the function or effect of mTORC 1 when the modulator (e.g., compound as described herein) is not present.
• the mTORCl modulator e.g., compound as described herein, including in embodiments
• the mTORCl modulator (e.g., compound as described herein, including in embodiments) is an mTORCl inhibitor that decreases phosphorylation of S6 and/or S6K.
• an effective amount of mTORCl inhibitor is an amount sufficient to decrease mTORCl activity in a cell (e.g., in a subject) to reduce cell proliferation relative to the amount of cell proliferation in the absence of mTORCl inhibitor.
• an effective amount of mTORCl modulator (e.g., inhibitor) is an amount sufficient to increase cell death (e.g., apoptosis).
• the compound reduces activation of eIF4E.
• the compound inhibits phosphorylation of 4E-BP1. In embodiments, the compound does not reduce phosphorylation of Akt. In embodiments, the compound does not reduce phosphorylation of Akt-473 or a residue corresponding to Akt-473. In embodiments, the compound does not cause hyperglycemia. [0296] In an embodiment, modulating mTORCl activity includes direct binding of the mTORCl modulator to mTOR. In another embodiment, modulating mTORCl activity is accomplished indirectly. E. ADDITIONAL EMBODIMENTS
• a compound comprising a monovalent active site mTOR inhibitor covalently bound to a monovalent rapamycin or a monovalent rapamycin analog.
• L 1 is the divalent linker
• R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• R 3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
• R 3 is substituted benzoxazolyl, substituted pyrimidinyl, substituted thiophenyl, substituted furanyl, substituted indolyl, substituted benzoxadiazolyl, substituted benzodioxolyl, substituted benzodioxanyl, substituted thianaphthanyl, substituted pyrrolopyridinyl, substituted indazolyl, substituted quinolinyl, substituted quinoxalinyl, substituted pyridopyrazinyl, substituted quinazolinonyl, substituted benzoisoxazolyl, substituted imidazopyridinyl, substituted benzofuranyl, substituted
• benzothiophenyl substituted phenyl, substituted naphthyl, substituted biphenyl, substituted pyrrolyl, substituted pyrazolyl, substituted imidazolyl, substituted pyrazinyl, substituted oxazolyl, substituted isoxazolyl, substituted thiazolyl, substituted furylthienyl, substituted pyridyl, substituted pyrimidyl, substituted benzothiazolyl, substituted purinyl, substituted benzimidazolyl, substituted isoquinolyl, substituted thiadiazolyl, substituted oxadiazolyl, substituted pyrrolyl, substituted diazolyl, substituted triazolyl, substituted tetrazolyl, substituted benzothiadiazolyl, substituted isothiazolyl, substituted pyrazolopyrimidinyl, substituted pyrrolopyrimidinyl, substituted benzotriazolyl, or
• L 1 is L 2 -L 3 -L 4 -L 5 ;
• L 2 is connected directly to the monovalent rapamycin or the monovalent rapamycin analog;
• L 2 is substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• L 3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
• L 4 is a bond, substituted or unsubstituted alkylene, substituted
• L 2 is substituted or unsubstituted C1-C20 alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C6-C10 arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene;
• L 3 is a bond, substituted or unsubstituted C1-C20 alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene, substituted or unsubstituted C 3 -C 8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted C6-C10 arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene;
• L 4 is a substituted or unsubstituted 2 to 12 membered heteroalkylene; and L 5 is a substituted or unsubstituted 2 to 12 membered heteroalkylene.
• a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of one of embodiments 1 to 19.
• a method of inhibiting the activity of mTORC 1 in a patient comprising administering an effective amount of a compound of one of embodiments 1 to 19, or a pharmaceutically acceptable salt thereof, to the patient.
• a method of treating a disease associated with aberrant mTORCl activity in a patient in need of such treatment comprising administering a therapeutically effective amount of a compound of one of embodiments 1 to 19, or a pharmaceutically acceptable salt thereof, to the patient.
• a method of treating a disease in a subject comprising administering a compound of one of embodiments 1 to 19, or a pharmaceutically acceptable salt thereof, to the subject, wherein the disease is a cancer, autoimmune disease, inflammatory disease, metabolic disease, neurodegenerative disease, fungal infection, transplant rejection, aging, stenosis, neointimal proliferation, cardiovascular disease, or polycystic disease.
• the disease is a cancer, autoimmune disease, inflammatory disease, metabolic disease, neurodegenerative disease, fungal infection, transplant rejection, aging, stenosis, neointimal proliferation, cardiovascular disease, or polycystic disease.
• EXAMPLE 1 [0297] The action of MLN0128 on TORC2 is not thought to be necessary for its anti-cancer activity. This has been analyzed in a genetically engineered mouse model of Akt-driven lymphomagenesis 10 . A non-phosphorylatable mutant of 4E-BP1 which is constitutively able to inhibit eIF4E, blocks Akt-driven lymphomagenesis, suggesting that this single substrate of mTOR is sufficient to support cancer cell growth and survival. In some animals harboring the constitutive ly active Akt and constitutively active 4E-BP1, some tumors which still express the 4E-BP1 mutant (4EBP1 M ). Presumably, another pathway has been activated which bypasses the block imposed by 4EBP1 M . These cells offer a genetic test of the mechanism of action of the asTORi class of inhibitors. If the action of asTORi on cells is mediated by 4E-BP1
• kinase inhibitor drugs are the ability to inhibit kinase activity following drug washout 16 .
• the EGFR/HER2 inhibitor Lapatinib exhibits slow-off kinetics from EGFR which is thought to be caused by a required conformational change in the kinase to allow drug to be released. Regardless of the mechanism, it is thought that kinase inhibitors with slow off kinetics will be better able to robustly inhibit kinase signaling in a tumor. Rather than requiring high drug levels in the blood stream 24hr/day, such slow off drugs may demonstrate better target coverage than the more common rapidly dissociating kinase inhibitors.
• the second aspect of the design would be that linking Rapamycin to an asTORi (e.g., MLN0128) would result in binding to FKBP12 in cells, and in this large complex of an asTORi (e.g., MLN0128)-Rapa/FKBP12, an asTORi (e.g., MLN0128) would be diminished in its ability to bind to mTORC2 and thus would have reduced effects on Akt S473.
• an asTORi e.g., MLN0128
• Rapamycin cocrystal structure (1FAP) 18 revealed that the hydroxyl group at the C40 position of rapamycin is exposed to solvent region and is oriented toward the active site of mTOR (FIG. 4A).
• AsTORi e.g., MLN0128
• a tethering position was selected based on co-crystal structures of mTOR using PP242 as the model ATP site ligand, which is highly related to MLN0128 (FIG. 4A).
• MLN0128 was selected as the asTORi for this work, because 1) MLN0128 is a clinical candidate which has good mTOR selectivity and possesses sufficient drug-like properties; 2) our structure-activity relationship (SAR) knowledge of pyrazolo[3,4-if
• SAR structure-activity relationship
• Rapa-Link inhibitors M-1071, M-1 111, M-3059, M-1 115, etc.
• a drug-like cross-linker polyethylene glycol based
• propargyl ethyleneglycol introduced rapamycin (III-A) as a precursor (Scheme 3).
• AsTORi we prepared two types of compounds (II-c) with an attachment "A"; 1) Type A has an amino group at the terminal position; 2) Type B has a carboxylate at the terminal position. Those terminal functional groups will be used to connect the active site inhibitor to the cross-linker by amide formation reaction.
• cross-linkers we selected the polyethylene glycol (PEG) linker since it is found in a number of pharmaceuticals 20 .
• PEG polyethylene glycol
• azide PEG linkers to connect asTORi (lie -A) followed by triazole formation reaction with propargyl derivative of Rapamycin (III-A) (Scheme 1-A).
• a negative control compound M-1115 which is designed to have linker predicted to be too short to allow optimal dual binding to mTOR (FIG. 4B).
• RP-HPLC was carried out on a Waters Binary Gradient Module 2545 system equipped with an Agilent Zorbax 300-SB CI 8 column (5 ⁇ m, 4.6 X 250 mm) for analytical mode or a Waters XBridge Prep CI 8 column (5 ⁇ m, 30 X 250 mm) for preparative mode.
• l H NMR spectra for intermediates were recorded on a Varian Innova (400 MHz) spectrometer.
• l R NMR spectra, 'H-'H COSY, HSQC, and HMBC spectra for final compounds were recorded on a Bruker Avance (800 MHz) spectrometer.
• 13 C NMR spectra were recorded on a Bruker Avance (500 MHz) spectrometer (500 MHz for l R, 126 MHz for 13 C).
• the crude material was purified by silica gel column chromatography (silica gel: 25 g, solvent: 20-80% EtOAc in hexanes). Desired fractions were combined and evaporated in vacuo. The obtained material was dissolved into 50% CH 3 CN in water and lyophilized to give the titled compound (277 mg, 28%) as a colorless amorphous powder.
• Atom Atom Atom Type ⁇ ' ⁇ Major (3:1) ⁇ 13 C Major HMBC C to H ⁇ - ⁇ COSY

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