Targeted degradation of VAV1

Abstract

The present application discloses compounds of Formula I, which mediate the interaction between VAV1 protein and E3 ubiquitin ligase, thereby promoting the degradation of VAV1 protein, and can be used for the treatment of diseases mediated by VAV1 protein.

Description

TARGETED DEGRADATION OF VAV1TECHNICAL FIELD

[0001] Among other things, the present disclosure provides technologies, e.g., compounds, compositions, methods, etc. that are useful, e.g., for treating various disorder or disease by reducing the level of VAV1 protein (VAV1).BACKGROUND

[0002] The ubiquitin proteasome system can be manipulated with different small molecules to trigger targeted degradation of specific proteins of interest. Promoting the targeted degradation of proteins using small molecule degraders is emerging as a new modality in the treatment of diseases. One such modality is molecular glues bind to both the E3 ligase and the target protein, permitting subsequent degradation of the target protein. Examples of molecular glues for the E3 ligase cereblon include: Thalidomide, Lenalidomide and Pomalidomide, all of which are immunomodulatory imide drugs (IMiDs) approved by the FDA for use in hematological cancers.

[0003] VAV1 is a dominant signal transduction protein in the adaptive immune system. It is a positive regulator of immune receptor signaling in both T cells and B cells. Thus, reduction in VAV1 can reduce immune cell activation, immune cell proliferation and the production of various cytokines. For at least these reasons, degradation of VAV1 can be therapeutically beneficial in a variety of disease conditions. Therefore, we need more new, effective compounds for treating various disorder or disease related to VAV1 protein.SUMMARY

[0004] In some embodiments, the present disclosure provides a compound having the structure of formula I:

[0005]

[0006] I

[0007] or a salt thereof, wherein:

[0008] X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F;

[0009] R2 is F, Cl, methyl, or C2 alkynyl;

[0010] L1 is:

[0011] 1) a bond, with the provision that R1 is optionally substituted

[0012]

[0013] , , ; or

[0014] 2) an optionally substituted C1-4 alkyl or C1-4 heteroalkyl having 1-4 heteroatoms; and

[0015] 2a) One atom of L1 taken together with X1 or X2 to form an additional ring fused with the ring containing X1 and X2, wherein the fused ring system includes 8 or 10 ring atoms, wherein the additional ring has 0 heteroatom, and is optionally further substituted with 1-4 substituents;

[0016] R1 is independently selected from the group consisting of hydrogen, hydroxyl, halogen, -OR’ , -S(O)0-2R’, -S(O)0-2N(R’)R’’, -C(O)OR’, -N(R’)R’’, -N(R0)C(O)N(R’)R’’, -OC(O)N(R’)R’’, -NR’C(O)R’’ and -C(O)NR’R’’; or:

[0017] 2b) One atom of L1taken together with X1or X2to form an additional ring fused with the ring containing X1and X2, wherein the fused ring system includes 10 ring atoms, wherein the additional ring has the moiety of  ,and is optionally further substituted with 1-4 substituents，wherein “*” indicates the attachment to the ring containing X1 and X2;

[0018] R1 is empty;

[0019] each of X1 and X2 is independently -C(R4)-, wherein R4 is hydrogen or F;

[0020] each of R0, R’ or R’’ is independently selected from an optionally substituted group consisting of H, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, or R’ is optionally taken together with the carbon atom directly attached to R1 to form an additional 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;

[0021] each substituent is independently selected from halogen, hydroxyl, cyano, oxo, C1-3 haloalkyl, or R#; and

[0022] two substituents are optionally and independently taken together to form a covalent bond, or:

[0023] two or more substituents on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-8 membered ring having, in addition to the atom, 0-4 heteroatoms; or:

[0024] two or more substituents on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;

[0025] R#is independently H, halogen, C1-6aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, C5-8aryl, 5-8 membered heteroaryl having 1-4 heteroatoms, and combinations thereof, wherein each combination independently has 1-8 carbon atoms and 0-4 heteroatoms.

[0026] In some embodiments, the present disclosure provides a compound having the structure of formula Ia:

[0027]

[0028] Ia

[0029] or a salt thereof, wherein:

[0030] X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F;

[0031] R2 is F, Cl, methyl, or C2 alkynyl;

[0032] L1 is:

[0033] 1) a bond, with the provision that R1 is optionally substituted , , ; or

[0034] 2) an optionally substituted C1-4 alkyl or C1-4 heteroalkyl having 1-4 heteroatoms; and

[0035] 2a) One atom of L1 taken together with X1 or X2 to form an additional ring fused with the ring containing X1 and X2, wherein the fused ring system includes 8 or 10 ring atoms, wherein the additional ring has 0 heteroatom, and is optionally further substituted with 1-4 substituents;

[0036] R1 is independently selected from the group consisting of hydrogen, hydroxyl, halogen, -OR’ , -S(O)0-2R’, -S(O)0-2N(R’)R’’, -C(O)OR’, -N(R’)R’’, -N(R0)C(O)N(R’)R’’, -OC(O)N(R’)R’’, -NR’C(O)R’’ and -C(O)NR’R’’. In some embodiments, X3 is -C(R3)-, wherein R3 is hydrogen or F. In some embodiments, R2 is Cl. In some embodiments, R2 is Cl; and X3 is -C(R3)-, wherein R3 is hydrogen or F.

[0037] In some embodiments, the present disclosure provides a compound having the structure of formula Ia-1, Ia-2:

[0038]

[0039] Ia-1                                                                                 Ia-2

[0040] or a salt thereof, wherein each variable is independently as described in formula Ia. In some embodiments, X3 is -C(R3)-, wherein R3 is hydrogen or F. In some embodiments, R2 is Cl. In some embodiments, R2 is Cl; and X3 is -C(R3)-, wherein R3 is hydrogen or F.

[0041] In some embodiments, the present disclosure provides a compound having the structure of formula II-1:

[0042]

[0043] II-1

[0044] or a salt thereof, wherein:

[0045] X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F;

[0046] R2 is F, Cl, methyl, or C2 alkynyl;

[0047] each of X1 and X2 is independently -C(R4)-, wherein R4 is hydrogen or F;

[0048] R1 is optionally substituted , , ;

[0049] each substituent is independently selected from halogen, hydroxyl, cyano, oxo, C1-3 haloalkyl, or R#; and

[0050] two substituents are optionally and independently taken together to form a covalent bond, or:

[0051] two or more substituents on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-8 membered ring having, in addition to the atom, 0-4 heteroatoms; or:

[0052] two or more substituents on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;

[0053] R# is independently H, halogen, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, C5-8 aryl, 5-8 membered heteroaryl having 1-4 heteroatoms, and combinations thereof, wherein each combination independently has 1-8 carbon atoms and 0-4 heteroatoms.

[0054] In some embodiments, the present disclosure provides a compound having the structure of formula II-1’:

[0055]

[0056] II-1’

[0057] or a salt thereof, wherein:

[0058] X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F;

[0059] R2 is F, Cl, methyl, or C2 alkynyl;

[0060] R1 is  , , ;

[0061] x1 is 0-4;

[0062] each of X1 and X2 is independently -C(R4)-, wherein R4 is hydrogen or F;

[0063] each Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms.

[0064] In some embodiments, the present disclosure provides a compound having the structure of formula II-1’-1, II-1’-2 :

[0065]

[0066] II-1’-1                                                  II-1’-2

[0067] or a salt thereof, wherein each variable is independently as described in formula II-1’.  In some embodiments, R3 is −H.  In some embodiments, R3 is −F.

[0068] In some embodiments, the present disclosure provides a compound having the structure of formula II-1a:

[0069]

[0070] II-1a

[0071] or a salt thereof, wherein Q is CH, or N; each other variable is independently as described in formula II-1’.

[0072] In some embodiments, the present disclosure provides a compound having the structure of formula II-1b:

[0073]

[0074] II-1b

[0075] or a salt thereof, wherein Q is CH, or N; each other variable is independently as described in formula II-1’.

[0076] In some embodiments, the present disclosure provides a compound having the structure of formula II-1c:

[0077]

[0078] II-1c

[0079] or a salt thereof, wherein Q is CH, or N; each other variable is independently as described in formula II-1’.

[0080] In some embodiments, the present disclosure provides a compound having the structure of formula II-1d:

[0081]

[0082] II-1d

[0083] or a salt thereof, wherein each variable is independently as described in formula II-1’.

[0084] In some embodiments, the present disclosure provides a compound having the structure of formula II-1d-1 or II-1d-2:

[0085]

[0086] II-1d-1                                                              II-1d-2

[0087] or a salt thereof, wherein each variable is independently as described in formula II-1’.

[0088] In some embodiments, the present disclosure provides a compound having the structure of formula II-1e:

[0089]

[0090] II-1e

[0091] or a salt thereof, wherein each variable is independently as described in formula II-1’.

[0092] In some embodiments, the present disclosure provides a compound having the structure of formula II-1e-1:

[0093]

[0094] II-1e-1

[0095] or a salt thereof, wherein each variable is independently as described in formula II-1’.

[0096] In some embodiments, the present disclosure provides a compound having the structure of formula II-1e-2:

[0097]

[0098] II-1e-2

[0099] or a salt thereof, wherein each variable is independently as described in formula II-1’.

[0100] In some embodiments, the present disclosure provides a compound having the structure of formula II:

[0101]

[0102] II

[0103] or a salt thereof, wherein:

[0104] X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F;

[0105] R2 is F, Cl, methyl, or C2 alkynyl;

[0106] L1 is an optionally substituted C1-4 alkyl or C1-4 heteroalkyl having 1-4 heteroatoms; and

[0107] 2a) One atom of L1 taken together with X1 or X2 to form an additional ring fused with the ring containing X1 and X2, wherein the fused ring system includes 8 or 10 ring atoms, wherein the additional ring has 0 heteroatom, and is optionally further substituted with 1-4 substituents;

[0108] R1 is independently selected from the group consisting of hydrogen, hydroxyl, halogen, -OR’, -S(O)0-2R’, -S(O)0-2N(R’)R’’, -C(O)OR’, -N(R’)R’’, -N(R0)C(O)N(R’)R’’, -OC(O)N(R’)R’’, -NR’C(O)R’’ and -C(O)NR’R’’; or:

[0109] 2b) One atom of L1taken together with X1or X2 to form an additional ring fused with the ring containing X1 and X2, wherein the fused ring system includes 10 ring atoms, wherein the additional ring has the moiety of  ,and is optionally further substituted with 1-4 substituents，wherein “*” indicates the attachment to the ring containing X1 and X2;

[0110] R1 is empty;

[0111] each of X1 and X2 is independently -C(R4)-, wherein R4 is hydrogen or F;

[0112] each of R0, R’ or R’’ is independently selected from an optionally substituted group consisting of H, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, or R’ is optionally taken together with the carbon atom directly attached to R1 to form an additional 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;

[0113] each substituent is independently selected from halogen, hydroxyl, cyano, oxo, C1-3 haloalkyl, or R#; and

[0114] two substituents are optionally and independently taken together to form a covalent bond, or:

[0115] two or more substituents on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-8 membered ring having, in addition to the atom, 0-4 heteroatoms; or:

[0116] two or more substituents on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;

[0117] R# is independently H, halogen, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, C5-8 aryl, 5-8 membered heteroaryl having 1-4 heteroatoms, and combinations thereof, wherein each combination independently has 1-8 carbon atoms and 0-4 heteroatoms.

[0118] In some embodiments, the present disclosure provides a compound having the structure of formula II-2:

[0119]

[0120] II-2

[0121] or a salt thereof, wherein:

[0122] X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F;

[0123] R2 is F, Cl, methyl, or C2 alkynyl;

[0124] R1 is independently selected from the group consisting of hydrogen, hydroxyl, halogen, -OR’, -S(O)0-2R’, -S(O)0-2N(R’)R’’, -C(O)OR’, -N(R’)R’’, -N(R0)C(O)N(R’)R’’, -OC(O)N(R’)R’’, -NR’C(O)R’’ and -C(O)NR’R’’; or:

[0125] R4 is hydrogen or F;

[0126] q is 1-3;

[0127] x2 is 0-4;

[0128] each of R0, R’ or R’’ is independently selected from an optionally substituted group consisting of H, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, or R’ is optionally taken together with the carbon atom directly attached to R1 to form an additional 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;

[0129] each Rs is independently selected from halogen, hydroxyl, cyano, oxo, C1-3 haloalkyl, or R#; and

[0130] two Rs are optionally and independently taken together to form a covalent bond, or:

[0131] two or more Rs on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-8 membered ring having, in addition to the atom, 0-4 heteroatoms; or:

[0132] two or more Rs on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;

[0133] R# is independently H, halogen, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, C5-8 aryl, 5-8 membered heteroaryl having 1-4 heteroatoms, and combinations thereof, wherein each combination independently has 1-8 carbon atoms and 0-4 heteroatoms.

[0134] In some embodiments, the present disclosure provides a compound having the structure of formula II-2, wherein:

[0135] X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F;

[0136] R2 is F, Cl, methyl, or C2 alkynyl;

[0137] R1 is independently selected from the group consisting of hydrogen, hydroxyl, halogen, –OR’, -S(O)0-2R’, -S(O)0-2N(R’)R’’, -C(O)OR’, -N(R’)R’’, -N(R0)C(O)N(R’)R’’, -OC(O)N(R’)R’’, -NR’C(O)R’’ and -C(O)NR’R’’; or:

[0138] R4 is hydrogen or F;

[0139] q is 1-3;

[0140] x is 0-4;

[0141] each of R0, R’ or R’’ is independently selected from an optionally substituted group consisting of H, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, or R’ is optionally taken together with the carbon atom directly attached to R1 to form an additional 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;

[0142] each Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms.

[0143] In some embodiments, the present disclosure provides a compound having the structure of formula II-2a:

[0144]

[0145] II-2a

[0146] or a salt thereof, wherein:

[0147] X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F;

[0148] R1 is independently selected from the group consisting of hydrogen, hydroxyl, halogen, -OR’, -S(O)0-2R’, -S(O)0-2N(R’)R’’, -C(O)OR’, -N(R’)R’’, -N(R0)C(O)N(R’)R’’, -OC(O)N(R’)R’’, -NR’C(O)R’’ and -C(O)NR’R’’; or:

[0149] R4 is hydrogen or F;

[0150] q is 1-3;

[0151] x is 0-4;

[0152] each of R0, R’ or R’’ is independently selected from an optionally substituted group consisting of H, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, or R’ is optionally taken together with the carbon atom directly attached to R1 to form an additional 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;

[0153] each Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms.

[0154] In some embodiments, the present disclosure provides a compound having the structure of formula II-2a-1:

[0155]

[0156] II-2a-1

[0157] or a salt thereof, wherein or a salt thereof, wherein each variable is independently as described in formula II-2a.

[0158] In some embodiments, the present disclosure provides a compound having the structure of formula II-2a-1-1:

[0159]

[0160] II-2a-1-1

[0161] or a salt thereof, wherein or a salt thereof, wherein each variable is independently as described in formula II-2a.

[0162] In some embodiments, the present disclosure provides a compound having the structure of formula II-2a-1-2:

[0163]

[0164] II-2a-1-2

[0165] or a salt thereof, wherein or a salt thereof, wherein each variable is independently as described in formula II-2a.

[0166] In some embodiments, the present disclosure provides a compound having the structure of formula I-2a-2:

[0167]

[0168] II-2a-2

[0169] or a salt thereof, wherein each variable is independently as described in formula II-2a.

[0170] In some embodiments, the present disclosure provides a compound having the structure of formula II-2b-1and II-2b-2:

[0171]

[0172] II-2b-1                                                 II-2b-2

[0173] or a salt thereof, wherein each variable is independently as described in formula II-2a.

[0174] In some embodiments, the present disclosure provides a compound having the structure of formula II-2b-1-1:

[0175]

[0176] II-2b-1-1

[0177] or a salt thereof, wherein each variable is independently as described in formula II-2a.  In some embodiments, R3 is −H. In some embodiments, R3 is −F.

[0178] In some embodiments, the present disclosure provides a compound having the structure of formula II-2b-1-2:

[0179]

[0180] II-2b-1-2

[0181] or a salt thereof, wherein each variable is independently as described in formula II-2a. In some embodiments, R3 is −H. In some embodiments, R3 is −F.

[0182] In some embodiments, the present disclosure provides a compound having the structure of formula II-2b-2-1:

[0183]

[0184] II-2b-2-1

[0185] or a salt thereof, wherein each variable is independently as described in formula II-2a. In some embodiments, R3 is −H. In some embodiments, R3 is −F.

[0186] In some embodiments, the present disclosure provides a compound having the structure of formula II-2b-2-2:

[0187]

[0188] II-2b-2-2

[0189] or a salt thereof, wherein each variable is independently as described in formula II-2a. In some embodiments, R3 is −H. In some embodiments, R3 is −F.

[0190] In some embodiments, the present disclosure provides a compound having the structure of formula II-2b-3:

[0191]

[0192] II-2b-3

[0193] or a salt thereof, wherein each variable is independently as described in formula II-2a.

[0194] In some embodiments, the present disclosure provides a compound having the structure of formula II-2c-1and II-2c-2:

[0195]

[0196] II-2c-1                                              II-2c-2

[0197] or a salt thereof, wherein each variable is independently as described in formula II-2a.

[0198] In some embodiments, the present disclosure provides a compound having the structure of formula II-3:

[0199]

[0200] II-3

[0201] or a salt thereof, wherein:

[0202] X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F;

[0203] R2 is F, Cl, methyl, or C2 alkynyl;

[0204] R4 is hydrogen or F;

[0205] x’ is 0-4;

[0206] each Rs is independently selected from halogen, hydroxyl, cyano, oxo, C1-3 haloalkyl, or R#; and

[0207] two Rs are optionally and independently taken together to form a covalent bond, or:

[0208] two or more Rs on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-8 membered ring having, in addition to the atom, 0-4 heteroatoms; or:

[0209] two or more Rs on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;

[0210] R# is independently H, halogen, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, C5-8 aryl, 5-8 membered heteroaryl having 1-4 heteroatoms, and combinations thereof, wherein each combination independently has 1-8 carbon atoms and 0-4 heteroatoms.

[0211] In some embodiments, the present disclosure provides a compound having the structure of formula II-3, wherein:

[0212] X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F;

[0213] R2 is F, Cl, methyl, or C2 alkynyl;

[0214] R4 is hydrogen or F;

[0215] x’ is 0-4;

[0216] each Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms; or:

[0217] two or more Rs on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-6 membered ring having, in addition to the atom, 0-4 heteroatoms.

[0218] In some embodiments, the present disclosure provides a compound having the structure of formula II-3a:

[0219]

[0220] II-3a

[0221] or a salt thereof, wherein:

[0222] R3 is hydrogen or F;

[0223] R4 is hydrogen or F;

[0224] x’ is 0-4;

[0225] each Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms; or:

[0226] two or more Rs on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-6 membered ring having, in addition to the atom, 0-4 heteroatoms.

[0227] In some embodiments, the present disclosure provides a compound having the structure of formula II-3a-1:

[0228]

[0229] II-3a-1

[0230] or a salt thereof, wherein each variable is independently as described in formula II-3a. In some embodiments, R3 is −H. In some embodiments, R3 is −F.

[0231] In some embodiments, the present disclosure provides a compound having the structure of formula II-3a-2:

[0232]

[0233] II-3a-2

[0234] or a salt thereof, wherein each variable is independently as described in formula II-3a. In some embodiments, R3 is −H. In some embodiments, R3 is −F.

[0235] In some embodiments, the present disclosure provides a compound having the structure of formula II-3b:

[0236]

[0237] II-3b

[0238] or a salt thereof, wherein:

[0239] R4 is hydrogen or F;

[0240] x’ is 0-4;

[0241] each Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms; or:

[0242] two or more Rs on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-6 membered ring having, in addition to the atom, 0-4 heteroatoms.

[0243] In some embodiments, each of X1 and X2 is independently -C(R4)-, wherein R4 is hydrogen or F. In some embodiments, R4 is hydrogen. In some embodiments, R4 is F. In some embodiments, X1 is CH. In some embodiments, X1 is independently CD (“D” means deuterium.). In some embodiments, X1 is CF. In some embodiments, X2 is CH. In some embodiments, X2 is independently CD (“D” means deuterium.). In some embodiments, X2 is CF. In some embodiments, one of X1 and X2 is -C(R4)-, and the other is taken together with one atom of L1 to form an additional ring, wherein L1 is an optionally substituted C1-4 alkyl or C1-4 heteroalkyl having 1-4 heteroatoms, the ring and R4 are each independently as described herein.

[0244] In some embodiments, R2 is F. In some embodiments, R2 is Cl. In some embodiments, R2 is methyl. In some embodiments, R2 is C2 alkynyl.

[0245] In some embodiments, X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F. In some embodiments, X3 is N. In some embodiments, X3 is independently -C(R3)-, wherein R3 is hydrogen or F. In some embodiments, X3 is independently CH. In some embodiments, X3 is independently CD (“D” means deuterium.). In some embodiments, X3 is independently CF.

[0246] In some embodiments, when L1 is a bond, R1 is independently , , or  ,wherein x1 and each Rs is independently as described herein. For example, in some embodiments, when L1 is a bond, R1 is  ,wherein x1 and each Rs is independently as described herein. In some embodiments, when L1 is a bond, R1 is ,wherein x1 and each Rs is independently as described herein.In some embodiments, when L1 is a bond, R1 is ,wherein x1 and each Rs is independently as described herein. In some embodiments, when L1 is a bond, R1 is  ,wherein x1 and each Rs is independently as described herein.In some embodiments, x1 is 0. For example, in some embodiments, when L1 is a bond, R1 is  .In some embodiments, when L1 is a bond, R1 is .In some embodiments, when L1 is a bond, R1 is  .In some embodiments, when L1 is a bond, R1 is  .

[0247] In some embodiments, x1 is 1. For example, in some embodiments, when L1 is a bond, R1 is  .In some embodiments, when L1 is a bond, R1 is  .In some embodiments, when L1 is a bond, R1 is  .In some embodiments, when L1 is a bond, R1 is  .In some embodiments, when L1 is a bond, R1 is .In some embodiments, when L1 is a bond, R1 is .In some embodiments, when L1 is a bond, R1 is .In some embodiments, when L1 is a bond, R1 is  .In some embodiments, when L1 is a bond, R1 is .In some embodiments, when L1 is a bond, R1 is  .In some embodiments, when L1 is a bond, R1 is .

[0248] In some embodiments, x1 is 2. For example, in some embodiments, when L1 is a bond, R1 is .In some embodiments, when L1 is a bond, R1 is  .In some embodiments, when L1 is a bond, R1 is  .

[0249] In some embodiments, Q is CH. In some embodiments, Q is N.

[0250] In some embodiments, one atom of L1taken together with X1or X2 to form an additional ring fused with the ring containing X1 and X2, wherein the fused ring system includes 8 or 10 ring atoms, wherein the additional ring has the moiety of  ,and is optionally further substituted with 1-4 substituents, wherein q is 1-3; “*” indicates the attachment to the ring containing X1 and X2; and each substituent is independently as described herein.For example, in some embodiments, the moiety is independently , ,or  ,wherein x is 0-4; each Rs is independently as described herein. In some embodiments, the moiety is  ,wherein x is 0-4; each Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms. In some embodiments, the moiety is  ,wherein x is 0-4; each Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms. In some embodiments, the moiety is ,wherein x is 0-4; each Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms.

[0251] In some embodiments, the moiety has none substituent. In some embodiments, the moiety is substituted with 1 substituent, and the substituent is as described herein. For example, in some embodiments, the moiety is ,wherein q and Rs is independently as described herein. In some embodiments, the moiety is ,wherein q is 1-3; “*” indicates the attachment to the ring containing X1 and X2; Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms. In some embodiments, the moiety is substituted with 2-4 substituents. In some embodiments, the moiety  is substituted with 2-4 Rs, wherein each Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms.

[0252] In some embodiments, the substituent of the moiety  is independently halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms. For example, in some embodiments, the substituent is halo (e.g., F, Cl, Br, I). In some embodiments, the substituent is F. In some embodiments, the substituent is hydroxyl. In some embodiments, the substituent is C1-3 aliphatic. In some embodiments, the substituent is C1-3 alkyl. In some embodiments, the substituent is methyl. In some embodiments, the substituent is C1-3 heteroaliphatic having 1-3 heteroatoms. In some embodiments, the moiety is  .In some embodiments, the moiety  is  .In some embodiments, the moiety   is  .In some embodiments, the moiety  is  .In some embodiments, the moiety is  .In some embodiments, the moiety  is  .In some embodiments, the moiety  is  .In some embodiments, the moiety  is  .In some embodiments, the moiety  is  .In some embodiments, the moiety is  .In some embodiments, the moiety  is  .In some embodiments, the moiety is  .In some embodiments, the moiety is  .In some embodiments, the moiety is  .In some embodiments, the moiety is  .In some embodiments, the moiety  is  . In some embodiments, the moiety is  .In some embodiments, the moiety is  .

[0253] In some embodiments, one atom of L1 taken together with X1 or X2 to form an additional ring fused with the ring containing X1 and X2, wherein the fused ring system includes 8 or 10 ring atoms, wherein the additional ring has the moiety of ,and R’ as a part of R1, is taken together with the carbon atom directly attached to R1 to form an additional 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms. In some embodiments, the 3-8 membered ring is saturated or partially unsaturated, monocyclic ring. In some embodiments, the 3-8 membered ring is saturated monocyclic ring. In some embodiments, the 3-8 membered ring is 3 membered. In some embodiments, the 3-8 membered ring is 4 membered. In some embodiments, the 3-8 membered ring is 5 membered. In some embodiments, the 3-8 membered ring is 6 membered. In some embodiments, the 3-8 membered ring is 7 membered. In some embodiments, the 3-8 membered ring is 8 membered. In some embodiments, the 3-8 membered ring is  .

[0254] In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.

[0255] In some embodiments, one atom of L1 taken together with X1 or X2 to form an additional ring fused with the ring containing X1 and X2, wherein the fused ring system includes 10 ring atoms, wherein the additional ring has the moiety of  , and is optionally further substituted with 1-4 substituents，wherein “*” indicates the attachment to the ring containing X1 and X2; and each substituent is independently as described herein. In some embodiments, the moiety has none substituent. In some embodiments, the moiety has 1 substituent (e.g., the moiety is ). In some embodiments, the moiety has 2 substituents. For example, in some embodiments, the moiety is ,wherein “*” indicates the attachment to the ring containing X1 and X2; each Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms, or two or more Rs on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-6 membered ring having, in addition to the atom, 0-4 heteroatoms. In some embodiments, the moiety  ,wherein “*” indicates the attachment to the ring containing X1 and X2; each Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms, or two or more Rs on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-6 membered ring having, in addition to the atom, 0-4 heteroatoms. In some embodiments, the moiety is .In some embodiments, the moiety is .In some embodiments, the moiety is .In some embodiments, the moiety is .

[0256] In some embodiments, the 3-8 membered ring having, in addition to the atom or intervening atoms, 0-4 heteroatoms is saturated or partially unsaturated, monocyclic or bicyclic ring having 0-4 heteroatoms. In some embodiments, the 3-8 membered ring is saturated or partially unsaturated, monocyclic ring. In some embodiments, the 3-8 membered ring is saturated monocyclic ring. In some embodiments, the 3-8 membered ring is 3 membered. In some embodiments, the 3-8 membered ring is 4 membered. In some embodiments, the 3-8 membered ring is 5 membered. In some embodiments, the 3-8 membered ring is 6 membered. In some embodiments, the 3-8 membered ring is 7 membered. In some embodiments, the 3-8 membered ring is 8 membered. In some embodiments, the 3-8 membered ring having, in addition to the atom or intervening atoms, 0 heteroatom (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, etc.). In some embodiments, the 3-8 membered ring having, in addition to the atom or intervening atoms, 1-4 heteroatom.

[0257] In some embodiments, R1 is independently selected from the group consisting of hydrogen, hydroxyl, halogen, –C(O)OH, -OR’ , -S(O)0-2R’, -S(O)0-2N(R’)R’’, -C(O)OR’, -N(R’)R’’, -N(R0)C(O)N(R’)R’’, -OC(O)N(R’)R’’, -NR’C(O)R’’ and -C(O)NR’R’’. In some embodiments, R1 is independently selected from the group consisting of –C(O)OH, -OR’ , -S(O)0-2R’, -S(O)0-2N(R’)R’’, -C(O)OR’, -N(R’)R’’, -N(R0)C(O)N(R’)R’’, -OC(O)N(R’)R’’, -NR’C(O)R’’ and -C(O)NR’R’’. For example, in some embodiments, R1 is -C(O)NR’R’’, wherein R’ or R’’ is independently as described herein. In some embodiments, R1 is -C(O)NR’R’’, wherein each of R’ or R’’ is independently C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms. In some embodiments, R1 is -C(O)NH2. In some embodiments, R1 is -C(O)N(CH3)H. In some embodiments, R1 is -C(O)N(CH3)2. In some embodiments, R1 is -C(O)N(H)-CH2-CF3. In some embodiments, R1 is -C(O)N(H)-( 3-6 membered cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl)). In some embodiments, R1 is -C(O)N(H)-( 3-6 membered heterocyclyl having 1-4 heteroatoms). In some embodiments, R1is  .In some embodiments, R1 is .In some embodiments, R1 is  .In some embodiments, R1 is  .In some embodiments, R1 is -C(O)OH.

[0258] In some embodiments, R’ and R’’ are the same. In some embodiments, R’ and R’’ are different.

[0259] In some embodiments, the moiety of ,wherein R1 is independently selected from the group consisting of hydrogen, hydroxyl, halogen, –C(O)OH, -OR’ , -S(O)0-2R’, -S(O)0-2N(R’)R’’, -C(O)OR’, -N(R’)R’’, -N(R0)C(O)N(R’)R’’, -OC(O)N(R’)R’’, -NR’C(O)R’’ and -C(O)NR’R’’. For example, in some embodiments, R1 is -C(O)NR’R’’. In some embodiments, R1 is -C(O)NR’R’’, wherein each of R’ or R’’ is independently C1-6 aliphatic (e.g., C1-3 alkyl, etc.）, C1-6 heteroaliphatic having 1-4 heteroatoms (e.g., C1-3 alkoxyl, etc.). In some embodiments, R1 is -C(O)NH2. In some embodiments, R1 is -C(O)N(CH3)H. In some embodiments, R1 is -C(O)N(CH3)2. In some embodiments, R1 is -C(O)N(H)-CH2-CF3. In some embodiments, R1 is -C(O)N(H)-( 3-6 membered cycloalkyl). In some embodiments, R1 is -C(O)N(H)-( 3-6 membered heterocyclyl having 1-4 heteroatoms). In some embodiments, R1 is -C(O)OH.

[0260] In some embodiments, each of R0, R’ or R’’ is independently optionally substituted C1-6 aliphatic (e.g., C1-3 alkyl, C1-3 haloalkyl etc.). In some embodiments, each of R0, R’ or R’’ is independently C1-6 aliphatic (e.g., C1-3 alkyl, etc.）In some embodiments, each of R0, R’ or R’’ is independently optionally substituted C1-6 heteroaliphatic having 1-4 heteroatoms. In some embodiments, each of R0, R’ or R’’ is independently C1-6 heteroaliphatic having 1-4 heteroatoms (e.g., C1-3 alkoxyl, etc.). In some embodiments, each of R0, R’ or R’’ is independently 3-6 membered cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl).

[0261] . In some embodiments, each of R0, R’ or R’’ is independently 3-6 membered heterocyclyl having 1-4 heteroatoms. In some embodiments, R’ is optionally taken together with the carbon atom directly attached to R1 to form an additional 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;

[0262] In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4.

[0263] In some embodiments, x1 is 0. In some embodiments, x1 is 1. In some embodiments, x1 is 2. In some embodiments, x1 is 3. In some embodiments, x1 is 4.

[0264] In some embodiments, x’ is 0. In some embodiments, x’ is 1. In some embodiments, x’ is 2. In some embodiments, x’ is 3. In some embodiments, x’ is 4.

[0265] In some embodiments, the optionally substituent is halogen. In some embodiments, the optionally substituent is F. In some embodiments, the optionally substituent is Cl. In some embodiments, the optionally substituent is hydroxyl. In some embodiments, the optionally substituent is cyano. In some embodiments, the optionally substituent is oxo. In some embodiments, the optionally substituent is =S. In some embodiments, the optionally substituent is =NR#, wherein R# is as described herein. In some embodiments, the optionally substituent is C1-3 haloalkyl (e.g., -CF3, CHF2, etc.). In some embodiments, the optionally substituent is R#, wherein R# is as described herein.

[0266] In some embodiments, the optionally substituent is Rs. In some embodiments, each Rs is independently as described herein.

[0267] In some embodiments, Rs is not −H.

[0268] In some embodiments, when there are two or more Rs, they can be the same or different and each is independently as described herein. For example, in some embodiments, two or more Rs is same. In some embodiments, two or more Rs is independently different. In some embodiments, at least one Rs is different from others.

[0269] In some embodiments, each Rs is same and is not hydrogen. In some embodiments, each Rs is different. In some embodiments, at least one Rs is not hydrogen. In some embodiments, only one Rs is hydrogen. In some embodiments, each Rs is not hydrogen. In some embodiments, each Rs is independently R# and at least one of R# is not hydrogen.

[0270] In some embodiments, Rs is halogen. In some embodiments, Rs is −F. In some embodiments, Rs is −Cl. In some embodiments, Rs is −Br. In some embodiments, Rs is −I. In some embodiments, Rs is −CN. In some embodiments, Rs is oxo. In some embodiments, Rs is arylsulfonyl.

[0271] In some embodiments, Rs is R#, and R# is independently as described herein.

[0272] In some embodiments, Rs is independently −H or C1-6 aliphatic. In some embodiments, Rs is –H. In some embodiments, Rs is C1-6 aliphatic. In some embodiments, Rs is C1-6 alkyl. In some embodiments, independently C1-6 straight-chain alkyl. In some embodiments, Rs is C1-3 alkyl. In some embodiments, Rs is methyl. In some embodiments, Rs is ethyl. In some embodiments, Rs is n-propyl, isopropyl. , n-butyl, or t-butyl.

[0273] In some embodiments, each Rs is C1-6 heteroaliphatic having 1-4 heteroatoms. In some embodiments, Rs is −OCH3.

[0274] In some embodiments, Rs is independently C1-6aliphatic, C1-6heteroaliphatic having 1-4 heteroatoms; or:

[0275] two Rsgroups are optionally and independently taken together to form a covalent bond, or:

[0276] two or more Rsgroups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-8 membered ring having, in addition to the atom, 0-4 heteroatoms; or:

[0277] two or more Rsgroups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms.

[0278] In some embodiments, each Rs is independently an optionally substituted 3-6 membered carbocyclic ring. In some embodiments, a carbocyclic ring is saturated. In some embodiments, it is partially unsaturated. In some embodiments, Rsis saturated or partially unsaturated C3-6 cycloalkyl. For example, in some embodiments, Rsis cyclopropyl. In some embodiments, Rs is cyclobutyl. In some embodiments, Rsis cyclopentyl. In some embodiments, Rsis cyclohexyl. In some embodiments, Rs is cycloheptyl.

[0279] In some embodiments, each Rs is independently an optionally substituted 3-6 (e.g., 3-6, 3-5, 4-7, 3, 4, 5, 6, etc.) membered heterocyclyl having 1-4 heteroatoms. In some embodiments, a heterocyclyl group is monocyclic. In some embodiments, it is bicyclic. In some embodiments, a heterocyclyl group is saturated. In some embodiments, it is partially unsaturated. In some embodiments, a heterocyclyl ring has one heteroatom. In some embodiments, a heterocyclyl ring has two or more heteroatoms. In some embodiments, a heterocyclyl ring has three or more heteroatoms. In some embodiments, a heterocyclyl ring has four or more heteroatoms. In some embodiments, a heteroatom is nitrogen. In some embodiments, a heteroatom is oxygen. In some embodiments, a heteroatom is sulfur. In some embodiments, each heteroatom is independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In some embodiments, each heteroatom is independently selected from oxygen, nitrogen, and sulfur.

[0280] In some embodiments, each Rs is independently a 5-8 membered aryl. In some embodiments, an aryl ring is monocyclic. In some embodiments, an aryl ring is bicyclic. In some embodiments, Rsis phenyl.

[0281] In some embodiments, Rsis a 5-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is a 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0282] As appreciated by those skilled in the art, compounds of the present disclosure may be provided in various forms, e.g., salts, esters, solvates, prodrugs, etc. In some embodiments, a provided compound is in a salt form. In some embodiments, a provided compound is a pharmaceutically acceptable salt form. In some embodiments, a provided compound is in a solvate form. In some embodiments, a provided compound is in a solvate form of a salt form. In some embodiments, a provided compound is a prodrug. In some embodiments, a provided compound is an ester. In some embodiments, a compound is provided as a single stereoisomer. In some embodiments, a compound is provided in a mixture or two or more stereoisomers.

[0283] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0284] Technologies of the present disclosure may be understood more readily by reference to the following detailed description of certain embodiments.

[0285] Definitions

[0286] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.

[0287] As used herein in the present disclosure, unless otherwise clear from context, (i) the term “a” or “an” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising”, “comprise”, “including” (whether used with “not limited to” or not), and “include” (whether used with “not limited to” or not) may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; (iv) the term “another” may be understood to mean at least an additional / second one or more; (v) the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (vi) where ranges are provided, endpoints are included. Unless otherwise clear from context, isomers of compounds are included. As those skilled in the art, compounds may be provided, administered, or delivered in various forms, e.g., salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, esters, prodrugs, tautomers, etc.

[0288] Aliphatic: As used herein, “aliphatic” means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or a substituted or unsubstituted monocyclic, bicyclic, or polycyclic hydrocarbon ring that is completely saturated or that contains one or more units of unsaturation (but not aromatic), or combinations thereof. In some embodiments, aliphatic groups contain 1-50 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-20 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-9 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-7 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0289] Alkenyl: As used herein, the term “alkenyl” refers to an aliphatic group, as defined herein, having one or more double bonds.

[0290] Alkyl: As used herein, the term “alkyl” is given its ordinary meaning in the art and may include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In some embodiments, alkyl has 1-100 carbon atoms. In certain embodiments, a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C1-C20for straight chain, C2-C20for branched chain), and alternatively, about 1-10. In some embodiments, cycloalkyl rings have from about 3-10 carbon atoms in their ring structure where such rings are monocyclic, bicyclic, or polycyclic, and alternatively about 5, 6 or 7 carbons in the ring structure. In some embodiments, an alkyl group may be a lower alkyl group, wherein a lower alkyl group comprises 1-4 carbon atoms (e.g., C1-C4for straight chain lower alkyls).

[0291] Alkynyl: As used herein, the term “alkynyl” refers to an aliphatic group, as defined herein, having one or more triple bonds.

[0292] Animal: As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans, at any stage of development. In some embodiments, “animal” refers to non-human animals, at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate and / or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish and / or worms. In some embodiments, an animal may be a transgenic animal, a genetically-engineered animal and / or a clone.

[0293] Aryl: The term “aryl", as used herein, used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, bicyclic or polycyclic ring systems having a total of five to thirty ring members, wherein at least one ring in the system is aromatic. In some embodiments, an aryl group is a monocyclic, bicyclic or polycyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, each monocyclic ring unit is aromatic. In some embodiments, an aryl group is a biaryl group. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0294] Characteristic portion: As used herein, the term “characteristic portion”, in the broadest sense, refers to a portion of a substance whose presence (or absence) correlates with presence (or absence) of a particular feature, attribute, or activity of the substance. In some embodiments, a characteristic portion of a substance is a portion that is found in the substance and in related substances that share the particular feature, attribute or activity, but not in those that do not share the particular feature, attribute or activity. In certain embodiments, a characteristic portion shares at least one functional characteristic with the intact substance. For example, in some embodiments, a “characteristic portion” of a protein or polypeptide is one that contains a continuous stretch of amino acids, or a collection of amino acids, in some embodiments, a collection of continuous stretches of amino acids, that together are characteristic of a protein or polypeptide. In some embodiments, each such continuous stretch generally contains at least 2, 5, 10, 15, 20, 50, or more amino acids. In general, a characteristic portion of a substance (e.g., of a protein, antibody,etc.) is one that, in addition to the sequence and / or structural identity specified above, shares at least one functional characteristic with the relevant intact substance. In some embodiments, a characteristic portion may be biologically active.

[0295] Characteristic sequence element: As used herein, the phrase “characteristic sequence element” refers to a sequence element found in a polymer (e.g., in a polypeptide or nucleic acid) that represents a characteristic portion of that polymer. In some embodiments, presence of a characteristic sequence element correlates with presence or level of a particular activity or property of the polymer. In some embodiments, presence (or absence) of a characteristic sequence element defines a particular polymer as a member (or not a member) of a particular family or group of such polymers. A characteristic sequence element typically comprises at least two monomers (e.g., amino acids or nucleotides). In some embodiments, a characteristic sequence element includes at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, or more monomers (e.g., contiguously linked monomers). In some embodiments, a characteristic sequence element includes at least first and second stretches of contiguous monomers spaced apart by one or more spacer regions whose length may or may not vary across polymers that share the sequence element.

[0296] Comparable: The term “comparable” is used herein to describe two (or more) sets of conditions or circumstances that are sufficiently similar to one another to permit comparison of results obtained or phenomena observed. In some embodiments, comparable sets of conditions or circumstances are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will appreciate that sets of conditions are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under the different sets of conditions or circumstances are caused by or indicative of the variation in those features that are varied.

[0297] Cycloaliphatic: The term “cycloaliphatic,” “carbocycle,” “carbocyclyl,” “carbocyclic radical,” and “carbocyclic ring,” are used interchangeably, and as used herein, refer to saturated or partially unsaturated, but non-aromatic, cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having, unless otherwise specified, from 3 to 30 ring members. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, a cycloaliphatic group has 3–6 carbons. In some embodiments, a cycloaliphatic group is saturated and is cycloalkyl. The term “cycloaliphatic” may also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl. In some embodiments, a cycloaliphatic group is bicyclic. In some embodiments, a cycloaliphatic group is tricyclic. In some embodiments, a cycloaliphatic group is polycyclic. In some embodiments, “cycloaliphatic” refers to C3-C6monocyclic hydrocarbon, or C8-C10bicyclic or polycyclic hydrocarbon, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule, or a C9-C16polycyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.

[0298] Heteroaliphatic: The term “heteroaliphatic”, as used herein, is given its ordinary meaning in the art and refers to aliphatic groups as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like). In some embodiments, one or more units selected from C, CH, CH2, and CH3are independently replaced by one or more heteroatoms (including oxidized and / or substituted forms thereof). In some embodiments, a heteroaliphatic group is heteroalkyl. In some embodiments, a heteroaliphatic group is heteroalkenyl.

[0299] Comparable: The term “comparable” is used herein to describe two (or more) sets of conditions or circumstances that are sufficiently similar to one another to permit comparison of results obtained or phenomena observed. In some embodiments, comparable sets of conditions or circumstances are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will appreciate that sets of conditions are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under the different sets of conditions or circumstances are caused by or indicative of the variation in those features that are varied.

[0300] Cycloaliphatic: The term “cycloaliphatic,” “carbocycle,” “carbocyclyl,” “carbocyclic radical,” and “carbocyclic ring,” are used interchangeably, and as used herein, refer to saturated or partially unsaturated, but non-aromatic, cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having, unless otherwise specified, from 3 to 30 ring members. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In some embodiments, a cycloaliphatic group has 3–6 carbons. In some embodiments, a cycloaliphatic group is saturated and is cycloalkyl. The term “cycloaliphatic” may also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl. In some embodiments, a cycloaliphatic group is bicyclic. In some embodiments, a cycloaliphatic group is tricyclic. In some embodiments, a cycloaliphatic group is polycyclic. In some embodiments, “cycloaliphatic” refers to C3-C6monocyclic hydrocarbon, or C8-C10bicyclic or polycyclic hydrocarbon, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule, or a C9-C16polycyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.

[0301] Heteroaliphatic: The term “heteroaliphatic”, as used herein, is given its ordinary meaning in the art and refers to aliphatic groups as described herein in which one or more carbon atoms are independently replaced with one or more heteroatoms (e.g., oxygen, nitrogen, sulfur, silicon, phosphorus, and the like). In some embodiments, one or more units selected from C, CH, CH2, and CH3are independently replaced by one or more heteroatoms (including oxidized and / or substituted forms thereof). In some embodiments, a heteroaliphatic group is heteroalkyl. In some embodiments, a heteroaliphatic group is heteroalkenyl.

[0302] Heteroatom: The term “heteroatom", as used herein, means an atom that is not carbon or hydrogen. In some embodiments, a heteroatom is boron, oxygen, sulfur, nitrogen, phosphorus, or silicon (including oxidized forms of nitrogen, sulfur, phosphorus, or silicon; charged forms of nitrogen (e.g., quaternized forms, forms as in iminium groups, etc.), phosphorus, sulfur, oxygen; etc.). In some embodiments, a heteroatom is silicon, phosphorus, oxygen, sulfur or nitrogen. In some embodiments, a heteroatom is silicon, oxygen, sulfur or nitrogen. In some embodiments, a heteroatom is oxygen, sulfur or nitrogen.

[0303] Halogen: As used herein, the terms “halo,” “halogen” as used herein, are used interchangeably and refer to fluorine, chlorine, bromine, or iodine.

[0304] Heterocycle: As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring", as used herein, are used interchangeably and refer to a monocyclic, bicyclic or polycyclic ring moiety (e.g., 3-30 membered) that is saturated or partially unsaturated and has one or more heteroatom ring atoms. In some embodiments, a heterocyclyl group is a stable 5– to 7–membered monocyclic or 7– to 10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur and nitrogen, the nitrogen may be N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be monocyclic, bicyclic or polycyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0305] Optionally Substituted: As described herein, compounds of the disclosure may contain optionally substituted, substituted and / or unsubstituted moieties. In general, the term “substituted,” means that one or more hydrogens of the designated moiety are independently replaced with a substituent. Unless otherwise indicated, an “optionally substituted” group may independently have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with two or more substituents, the substituents may be either the same or different at every position. In some embodiments, an optionally substituted group is unsubstituted. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. Certain substituents are described below.

[0306] Suitable monovalent substituents on a substitutable atom, e.g., a suitable carbon atom, are independently halogen, hydroxyl, cyano, C1-3 haloalkyl, or R#; wherein R#is independently H, halogen, C1-6 aliphatic, C1-6heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl having 1-4 heteroatoms, C5-8aryl, 5-8 membered heteroaryl having 1-4 heteroatoms, and combinations thereof, wherein each combination independently has 1-8 carbon atoms and 0-4 heteroatoms.

[0307] Suitable divalent substituents, e.g., on a suitable carbon atom, are independently the following: oxo (=O), =S, =NR#, wherein each occurrence of R#is independently halogen, C1-6 aliphatic, C1-6heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, C5-8aryl, 5-8 membered heteroaryl having 1-4 heteroatoms, and combinations thereof, wherein each combination independently has 1-8 carbon atoms and 0-4 heteroatoms. In some embodiments, divalent substituents is =NR#. In some embodiments, divalent substituents is =O. In some embodiments, divalent substituents is =S.

[0308] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0309] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, an active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0310] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0311] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0312] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, a provided compound comprises one or more acidic groups, and a pharmaceutically acceptable salt is an alkali, alkaline earth metal, or ammonium (e.g., an ammonium salt of N(R)3, wherein each R is independently defined and described in the present disclosure) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In some embodiments, a pharmaceutically acceptable salt is a sodium salt. In some embodiments, a pharmaceutically acceptable salt is a potassium salt. In some embodiments, a pharmaceutically acceptable salt is a calcium salt. In some embodiments, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate. In some embodiments, a provided compound comprises two or more acid groups. In some embodiments, a pharmaceutically acceptable salt, or generally a salt, of such a compound comprises two or more cations, which can be the same or different. In some embodiments, in a pharmaceutically acceptable salt (or generally, a salt), all ionizable hydrogen (e.g., in an aqueous solution with a pKa no more than about 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2; in some embodiments, no more than about 7; in some embodiments, no more than about 6; in some embodiments, no more than about 5; in some embodiments, no more than about 4; in some embodiments, no more than about 3) in the acidic groups are replaced with cations.

[0313] Polypeptide: As used herein refers to a polymeric chain of amino acids. In some embodiments, a polypeptide has an amino acid sequence that occurs in nature. In some embodiments, a polypeptide has an amino acid sequence that does not occur in nature. In some embodiments, a polypeptide has an amino acid sequence that is engineered in that it is designed and / or produced through action of the hand of man. In some embodiments, a polypeptide may comprise or consist of natural amino acids, non-natural amino acids, or both. In some embodiments, a polypeptide may comprise or consist of only natural amino acids or only non-natural amino acids. In some embodiments, a polypeptide may comprise D-amino acids, L-amino acids, or both. In some embodiments, a polypeptide may comprise only D-amino acids. In some embodiments, a polypeptide may comprise only L-amino acids. In some embodiments, a polypeptide may include one or more pendant groups or other modifications, e.g., modifying or attached to one or more amino acid side chains, at the polypeptide’s N-terminus, at the polypeptide’s C-terminus, or any combination thereof. In some embodiments, such pendant groups or modifications may be selected from the group consisting of acetylation, amidation, lipidation, methylation, pegylation, etc., including combinations thereof. In some embodiments, a polypeptide may be cyclic, and / or may comprise a cyclic portion. In some embodiments, a polypeptide is not cyclic and / or does not comprise any cyclic portion. In some embodiments, a polypeptide is linear. In some embodiments, a polypeptide may be or comprise a stapled polypeptide. In some embodiments, the term “polypeptide” may be appended to a name of a reference polypeptide, activity, or structure; in such instances it is used herein to refer to polypeptides that share the relevant activity or structure and thus can be considered to be members of the same class or family of polypeptides. For each such class, the present specification provides and / or those skilled in the art will be aware of exemplary polypeptides within the class whose amino acid sequences and / or functions are known; in some embodiments, such exemplary polypeptides are reference polypeptides for the polypeptide class or family. In some embodiments, a member of a polypeptide class or family shows significant sequence homology or identity with, shares a common sequence motif (e.g., a characteristic sequence element) with, and / or shares a common activity (in some embodiments at a comparable level or within a designated range) with a reference polypeptide of the class; in some embodiments with all polypeptides within the class). For example, in some embodiments, a member polypeptide shows an overall degree of sequence homology or identity with a reference polypeptide that is at least about 30-40%, and is often greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more and / or includes at least one region (e.g., a conserved region that may in some embodiments be or comprise a characteristic sequence element) that shows very high sequence identity, often greater than 90% or even 95%, 96%, 97%, 98%, or 99%. Such a conserved region usually encompasses at least 3-4 and often up to 20 or more amino acids; in some embodiments, a conserved region encompasses at least one stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more contiguous amino acids. In some embodiments, a relevant polypeptide may comprise or consist of a fragment of a parent polypeptide. In some embodiments, a useful polypeptide as may comprise or consist of a plurality of fragments, each of which is found in the same parent polypeptide in a different spatial arrangement relative to one another than is found in the polypeptide of interest (e.g., fragments that are directly linked in the parent may be spatially separated in the polypeptide of interest or vice versa, and / or fragments may be present in a different order in the polypeptide of interest than in the parent), so that the polypeptide of interest is a derivative of its parent polypeptide.

[0314] Protecting group: The term “protecting group,” as used herein, is well known in the art and includes those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Also included are those protecting groups specially adapted for nucleoside and nucleotide chemistry described in Current Protocols in Nucleic Acid Chemistry, edited by Serge L. Beaucage et al. 06 / 2012, the entirety of Chapter 2 is incorporated herein by reference. Suitable amino–protecting groups include methyl carbamate, ethyl carbamante, 9–fluorenylmethyl carbamate (Fmoc), 9–(2–sulfo)fluorenylmethyl carbamate, 9–(2,7–dibromo)fluoroenylmethyl carbamate, 2,7–di–t–butyl–[9–(10,10–dioxo–10,10,10,10–tetrahydrothioxanthyl)]methyl carbamate (DBD–Tmoc), 4–methoxyphenacyl carbamate (Phenoc), 2,2,2–trichloroethyl carbamate (Troc), 2–trimethylsilylethyl carbamate (Teoc), 2–phenylethyl carbamate (hZ), 1–(1–adamantyl)–1–methylethyl carbamate (Adpoc), 1,1–dimethyl–2–haloethyl carbamate, 1,1–dimethyl–2,2–dibromoethyl carbamate (DB–t–BOC), 1,1–dimethyl–2,2,2–trichloroethyl carbamate (TCBOC), 1–methyl–1–(4–biphenylyl)ethyl carbamate (Bpoc), 1–(3,5–di–t–butylphenyl)–1–methylethyl carbamate (t–Bumeoc), 2–(2’– and 4’–pyridyl)ethyl carbamate (Pyoc), 2–(N,N–dicyclohexylcarboxamido)ethyl carbamate, t–butyl carbamate (BOC), 1–adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1–isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4–nitrocinnamyl carbamate (Noc), 8–quinolyl carbamate, N–hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p–methoxybenzyl carbamate (Moz), p–nitobenzyl carbamate, p–bromobenzyl carbamate, p–chlorobenzyl carbamate, 2,4–dichlorobenzyl carbamate, 4–methylsulfinylbenzyl carbamate (Msz), 9–anthrylmethyl carbamate, diphenylmethyl carbamate, 2–methylthioethyl carbamate, 2–methylsulfonylethyl carbamate, 2–(p–toluenesulfonyl)ethyl carbamate, [2–(1,3–dithianyl)]methyl carbamate (Dmoc), 4–methylthiophenyl carbamate (Mtpc), 2,4–dimethylthiophenyl carbamate (Bmpc), 2–phosphonioethyl carbamate (Peoc), 2–triphenylphosphonioisopropyl carbamate (Ppoc), 1,1–dimethyl–2–cyanoethyl carbamate, m–chloro–p–acyloxybenzyl carbamate, p–(dihydroxyboryl)benzyl carbamate, 5–benzisoxazolylmethyl carbamate, 2–(trifluoromethyl)–6–chromonylmethyl carbamate (Tcroc), m–nitrophenyl carbamate, 3,5–dimethoxybenzyl carbamate, o–nitrobenzyl carbamate, 3,4–dimethoxy–6–nitrobenzyl carbamate, phenyl(o–nitrophenyl)methyl carbamate, phenothiazinyl–(10)–carbonyl derivative, N’–p–toluenesulfonylaminocarbonyl derivative, N’–phenylaminothiocarbonyl derivative, t–amyl carbamate, S–benzyl thiocarbamate, p–cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p–decyloxybenzyl carbamate, 2,2–dimethoxycarbonylvinyl carbamate, o–(N,N–dimethylcarboxamido)benzyl carbamate, 1,1–dimethyl–3–(N,N–dimethylcarboxamido)propyl carbamate, 1,1–dimethylpropynyl carbamate, di(2–pyridyl)methyl carbamate, 2–furanylmethyl carbamate, 2–iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p–(p’–methoxyphenylazo)benzyl carbamate, 1–methylcyclobutyl carbamate, 1–methylcyclohexyl carbamate, 1–methyl–1–cyclopropylmethyl carbamate, 1–methyl–1–(3,5–dimethoxyphenyl)ethyl carbamate, 1–methyl–1–(p–phenylazophenyl)ethyl carbamate, 1–methyl–1–phenylethyl carbamate, 1–methyl–1–(4–pyridyl)ethyl carbamate, phenyl carbamate, p–(phenylazo)benzyl carbamate, 2,4,6–tri–t–butylphenyl carbamate, 4–(trimethylammonium)benzyl carbamate, 2,4,6–trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3–phenylpropanamide, picolinamide, 3–pyridylcarboxamide, N–benzoylphenylalanyl derivative, benzamide, p–phenylbenzamide, o–nitophenylacetamide, o–nitrophenoxyacetamide, acetoacetamide, (N’–dithiobenzyloxycarbonylamino)acetamide, 3–(p–hydroxyphenyl)propanamide, 3–(o–nitrophenyl)propanamide, 2–methyl–2–(o–nitrophenoxy)propanamide, 2–methyl–2–(o–phenylazophenoxy)propanamide, 4–chlorobutanamide, 3–methyl–3–nitrobutanamide, o–nitrocinnamide, N–acetylmethionine derivative, o–nitrobenzamide, o–(benzoyloxymethyl)benzamide, 4,5–diphenyl–3–oxazolin–2–one, N–phthalimide, N–dithiasuccinimide (Dts), N–2,3–diphenylmaleimide, N–2,5–dimethylpyrrole, N–1,1,4,4–tetramethyldisilylazacyclopentane adduct (STABASE), 5–substituted 1,3–dimethyl–1,3,5–triazacyclohexan–2–one, 5–substituted 1,3–dibenzyl–1,3,5–triazacyclohexan–2–one, 1–substituted 3,5–dinitro–4–pyridone, N–methylamine, N–allylamine, N–[2–(trimethylsilyl)ethoxy]methylamine (SEM), N–3–acetoxypropylamine, N–(1–isopropyl–4–nitro–2–oxo–3–pyroolin–3–yl)amine, quaternary ammonium salts, N–benzylamine, N–di(4–methoxyphenyl)methylamine, N–5–dibenzosuberylamine, N–triphenylmethylamine (Tr), N–[(4–methoxyphenyl)diphenylmethyl]amine (MMTr), N–9–phenylfluorenylamine (PhF), N–2,7–dichloro–9–fluorenylmethyleneamine, N–ferrocenylmethylamino (Fcm), N–2–picolylamino N’–oxide, N–1,1–dimethylthiomethyleneamine, N–benzylideneamine, N–p–methoxybenzylideneamine, N–diphenylmethyleneamine, N–[(2–pyridyl)mesityl]methyleneamine, N–(N’,N’–dimethylaminomethylene)amine, N,N’–isopropylidenediamine, N–p–nitrobenzylideneamine, N–salicylideneamine, N–5–chlorosalicylideneamine, N–(5–chloro–2–hydroxyphenyl)phenylmethyleneamine, N–cyclohexylideneamine, N–(5,5–dimethyl–3–oxo–1–cyclohexenyl)amine, N–borane derivative, N–diphenylborinic acid derivative, N–[phenyl(pentacarbonylchromium– or tungsten)carbonyl]amine, N–copper chelate, N–zinc chelate, N–nitroamine, N–nitrosoamine, amine N–oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o–nitrobenzenesulfenamide (Nps), 2,4–dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2–nitro–4–methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3–nitropyridinesulfenamide (Npys), p–toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,–trimethyl–4–methoxybenzenesulfonamide (Mtr), 2,4,6–trimethoxybenzenesulfonamide (Mtb), 2,6–dimethyl–4–methoxybenzenesulfonamide (Pme), 2,3,5,6–tetramethyl–4–methoxybenzenesulfonamide (Mte), 4–methoxybenzenesulfonamide (Mbs), 2,4,6–trimethylbenzenesulfonamide (Mts), 2,6–dimethoxy–4–methylbenzenesulfonamide (iMds), 2,2,5,7,8–pentamethylchroman–6–sulfonamide (Pmc), methanesulfonamide (Ms), β–trimethylsilylethanesulfonamide (SES), 9–anthracenesulfonamide, 4–(4’,8’–dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0315] Suitably protected carboxylic acids further include, but are not limited to, silyl–, alkyl–, alkenyl–, aryl–, and arylalkyl–protected carboxylic acids. Examples of suitable silyl groups include trimethylsilyl, triethylsilyl, t–butyldimethylsilyl, t–butyldiphenylsilyl, triisopropylsilyl, and the like. Examples of suitable alkyl groups include methyl, benzyl, p–methoxybenzyl, 3,4–dimethoxybenzyl, trityl, t–butyl, tetrahydropyran–2–yl. Examples of suitable alkenyl groups include allyl. Examples of suitable aryl groups include optionally substituted phenyl, biphenyl, or naphthyl. Examples of suitable arylalkyl groups include optionally substituted benzyl (e.g., p–methoxybenzyl (MPM), 3,4–dimethoxybenzyl, O–nitrobenzyl, p–nitrobenzyl, p–halobenzyl, 2,6–dichlorobenzyl, p–cyanobenzyl), and 2– and 4–picolyl.

[0316] Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t–butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p–methoxybenzyloxymethyl (PMBM), (4–methoxyphenoxy)methyl (p–AOM), guaiacolmethyl (GUM), t–butoxymethyl, 4–pentenyloxymethyl (POM), siloxymethyl, 2–methoxyethoxymethyl (MEM), 2,2,2–trichloroethoxymethyl, bis(2–chloroethoxy)methyl, 2–(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3–bromotetrahydropyranyl, tetrahydrothiopyranyl, 1–methoxycyclohexyl, 4–methoxytetrahydropyranyl (MTHP), 4–methoxytetrahydrothiopyranyl, 4–methoxytetrahydrothiopyranyl S,S–dioxide, 1–[(2–chloro–4–methyl)phenyl]–4–methoxypiperidin–4–yl (CTMP), 1,4–dioxan–2–yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a–octahydro–7,8,8–trimethyl–4,7–methanobenzofuran–2–yl, 1–ethoxyethyl, 1–(2–chloroethoxy)ethyl, 1–methyl–1–methoxyethyl, 1–methyl–1–benzyloxyethyl, 1–methyl–1–benzyloxy–2–fluoroethyl, 2,2,2–trichloroethyl, 2–trimethylsilylethyl, 2–(phenylselenyl)ethyl, t–butyl, allyl, p–chlorophenyl, p–methoxyphenyl, 2,4–dinitrophenyl, benzyl, p–methoxybenzyl, 3,4–dimethoxybenzyl, o–nitrobenzyl, p–nitrobenzyl, p–halobenzyl, 2,6–dichlorobenzyl, p–cyanobenzyl, p–phenylbenzyl, 2–picolyl, 4–picolyl, 3–methyl–2–picolyl N–oxido, diphenylmethyl, p,p’–dinitrobenzhydryl, 5–dibenzosuberyl, triphenylmethyl, α–naphthyldiphenylmethyl, p–methoxyphenyldiphenylmethyl, di(p–methoxyphenyl)phenylmethyl, tri(p–methoxyphenyl)methyl, 4–(4’–bromophenacyloxyphenyl)diphenylmethyl, 4,4’,4’’–tris(4,5–dichlorophthalimidophenyl)methyl, 4,4’,4’’–tris(levulinoyloxyphenyl)methyl, 4,4’,4’’–tris(benzoyloxyphenyl)methyl, 3–(imidazol–1–yl)bis(4’,4’’–dimethoxyphenyl)methyl, 1,1–bis(4–methoxyphenyl)–1’–pyrenylmethyl, 9–anthryl, 9–(9–phenyl)xanthenyl, 9–(9–phenyl–10–oxo)anthryl, 1,3–benzodithiolan–2–yl, benzisothiazolyl S,S–dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t–butyldimethylsilyl (TBDMS), t–butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri–p–xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t–butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p–chlorophenoxyacetate, 3–phenylpropionate, 4–oxopentanoate (levulinate), 4,4–(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4–methoxycrotonate, benzoate, p–phenylbenzoate, 2,4,6–trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9–fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2–trichloroethyl carbonate (Troc), 2–(trimethylsilyl)ethyl carbonate (TMSEC), 2–(phenylsulfonyl) ethyl carbonate (Psec), 2–(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl p–nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p–methoxybenzyl carbonate, alkyl 3,4–dimethoxybenzyl carbonate, alkyl o–nitrobenzyl carbonate, alkyl p–nitrobenzyl carbonate, alkyl S–benzyl thiocarbonate, 4–ethoxy–1–napththyl carbonate, methyl dithiocarbonate, 2–iodobenzoate, 4–azidobutyrate, 4–nitro–4–methylpentanoate, o–(dibromomethyl)benzoate, 2–formylbenzenesulfonate, 2–(methylthiomethoxy)ethyl, 4–(methylthiomethoxy)butyrate, 2–(methylthiomethoxymethyl)benzoate, 2,6–dichloro–4–methylphenoxyacetate, 2,6–dichloro–4–(1,1,3,3–tetramethylbutyl)phenoxyacetate, 2,4–bis(1,1–dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)–2–methyl–2–butenoate, o–(methoxycarbonyl)benzoate, α–naphthoate, nitrate, alkyl N,N,N’,N’–tetramethylphosphorodiamidate, alkyl N–phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4–dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). For protecting 1,2– or 1,3–diols, the protecting groups include methylene acetal, ethylidene acetal, 1–t–butylethylidene ketal, 1–phenylethylidene ketal, (4–methoxyphenyl)ethylidene acetal, 2,2,2–trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p–methoxybenzylidene acetal, 2,4–dimethoxybenzylidene ketal, 3,4–dimethoxybenzylidene acetal, 2–nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1–methoxyethylidene ortho ester, 1–ethoxyethylidine ortho ester, 1,2–dimethoxyethylidene ortho ester, α–methoxybenzylidene ortho ester, 1–(N,N–dimethylamino)ethylidene derivative, α–(N,N’–dimethylamino)benzylidene derivative, 2–oxacyclopentylidene ortho ester, di–t–butylsilylene group (DTBS), 1,3–(1,1,3,3–tetraisopropyldisiloxanylidene) derivative (TIPDS), tetra–t–butoxydisiloxane–1,3–diylidene derivative (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

[0317] In some embodiments, a hydroxyl protecting group is acetyl, t-butyl, t­butoxymethyl, methoxymethyl, tetrahydropyranyl, 1 -ethoxyethyl, 1 -(2-chloroethoxy)ethyl, 2- trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6- dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4,4'-dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifiuoroacetyl, pivaloyl, 9- fluorenylmethyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl (MMTr), 4,4'-dimethoxytrityl, (DMTr) and 4,4',4''-trimethoxytrityl (TMTr), 2-cyanoethyl (CE or Cne), 2-(trimethylsilyl)ethyl (TSE), 2-(2-nitrophenyl)ethyl, 2-(4-cyanophenyl)ethyl 2-(4-nitrophenyl)ethyl (NPE), 2-(4-nitrophenylsulfonyl)ethyl, 3,5-dichlorophenyl, 2,4-dimethylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2,4,6-trimethylphenyl, 2-(2-nitrophenyl)ethyl, butylthiocarbonyl, 4,4',4''-tris(benzoyloxy)trityl, diphenylcarbamoyl, levulinyl, 2-(dibromomethyl)benzoyl (Dbmb), 2-(isopropylthiomethoxymethyl)benzoyl (Ptmt), 9-phenylxanthen-9-yl (pixyl) or 9-(p-methoxyphenyl)xanthine-9-y1 (MOX). In some embodiments, each of the hydroxyl protecting groups is, independently selected from acetyl, benzyl, t- butyldimethylsilyl, t-butyldiphenylsilyl and 4,4'-dimethoxytrityl. In some embodiments, the hydroxyl protecting group is selected from the group consisting of trityl, monomethoxytrityl and 4,4'-dimethoxytrityl group. In some embodiments, a protecting group is attached to a sulfur atom of an phosphorothioate group. In some embodiments, a protecting group is attached to an oxygen atom of an internucleotide phosphorothioate linkage. In some embodiments, a protecting group is attached to an oxygen atom of the internucleotide phosphate linkage. In some embodiments a protecting group is 2-cyanoethyl (CE or Cne), 2-trimethylsilylethyl, 2-nitroethyl, 2-sulfonylethyl, methyl, benzyl, o-nitrobenzyl, 2-(p-nitrophenyl)ethyl (NPE or Npe), 2-phenylethyl, 3-(N-tert-butylcarboxamido)-1-propyl, 4-oxopentyl, 4-methylthio-l-butyl, 2-cyano-1,1-dimethylethyl, 4-N-methylaminobutyl, 3-(2-pyridyl)-1-propyl, 2-[N-methyl-N-(2-pyridyl)]aminoethyl, 2-(N-formyl,N-methyl)aminoethyl, or 4-[N-methyl-N-(2,2,2-trifluoroacetyl)amino]butyl.

[0318] Subject: As used herein, the term “subject” or “test subject” refers to any organism to which a compound or composition is administered in accordance with the present disclosure e.g., for experimental, diagnostic, prophylactic and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.) and plants. In some embodiments, a subject is a human. In some embodiments, a subject may be suffering from and / or susceptible to a disease, disorder and / or condition.

[0319] Susceptible to: An individual who is “susceptible to” a disease, disorder and / or condition is one who has a higher risk of developing the disease, disorder and / or condition than does a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition is predisposed to have that disease, disorder and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may not have been diagnosed with the disease, disorder and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may exhibit symptoms of the disease, disorder and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may not exhibit symptoms of the disease, disorder and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0320] Therapeutic agent: As used herein, the term “therapeutic agent” in general refers to any agent that elicits a desired effect (e.g., a desired biological, clinical, or pharmacological effect) when administered to a subject. In some embodiments, an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population. In some embodiments, an appropriate population is a population of subjects suffering from and / or susceptible to a disease, disorder or condition. In some embodiments, an appropriate population is a population of model organisms. In some embodiments, an appropriate population may be defined by one or more criterion such as age group, gender, genetic background, preexisting clinical conditions, prior exposure to therapy. In some embodiments, a therapeutic agent is a substance that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms or features of a disease, disorder, and / or condition in a subject when administered to the subject in an effective amount. In some embodiments, a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans. In some embodiments, a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans. In some embodiments, a therapeutic agent is a provided compound.

[0321] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0322] Treat: As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0323] Unsaturated: The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0324] Ring: The term "Ring," as used herein, unless otherwise specified, refer to including variety rings (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form monocyclic, bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such ring including fused, spiro, bridge ring cyclic groups and each ring is independently aromatic, saturated or partially unsaturated.

[0325] As those skilled in the art will appreciate, methods and compositions described herein relating to provided compounds generally also apply to tautomers, pharmaceutically acceptable salts, solvates, etc. of such compounds. In some embodiments, a compound may be provided as a tautomer, salt, solvate, or a combination (e.g., a solvate of a salt) thereof.

[0326] Description of Certain Embodiments

[0327] Among other things, the present disclosure provides compounds and compositions and methods thereof. In some embodiments, present disclosure provides technologies that are useful for preventing or treating various conditions, disorders or diseases. Certain embodiments of provided technologies are described below as examples.

[0328] As described herein, one or more isotopes may be independently enriched, independently at one or more positions. In some embodiments, an enrichment is about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 100%, 150%, 200%, 500%, 1000%, 2000%, 5000% more than a natural abundance as applicable. In some embodiments, an enrichment is about or at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 85, 90, 95, 99, 100, 150, 200, 500, 1000, 2000, 5000 fold more than a natural abundance as applicable. In some embodiments, a level of an isotope at a position is about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 99% of all compound molecules in a composition. For example, in some embodiments, designation of an atom as deuterium indicates that for that atom, at least 5% of all compound molecules are deuterated. In some embodiments, about or at least about 10%, 20%, 30%, 40% or 50% all compound molecules are deuterated at designated positions. In some embodiments, a percentage is about or at least about 60%, 70%, 80%, 85%, 90%, 95%, or 99% of all compound molecules. In some embodiments, a compound may have two or more positions deuterated, each of which independently has a percentage of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 99% of all compound molecules in a composition. Various technologies can be utilized to provide enriched levels of isotopes. In some embodiments, reagents having enriched levels of one or more isotopes are utilized in preparation of provided compounds or composition. In some embodiments, an enrich level is about or at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 85, 90, 95, 99, 100, 150, 200, 500, 1000, 2000, 5000 fold more than a reference preparation prepared without utilizing any reagent that has an enriched level of an isotope. In some embodiments, the isotope is D.

[0329] In some embodiments, a provided compound is selected from below:

[0330] Table C1. Certain compounds as examples.

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344] .

[0345] Table C2. Certain compounds as examples.

[0346]

[0347]

[0348] .

[0349] Table C3. Certain compounds as examples.

[0350]

[0351]

[0352] .

[0353] Table C4. Certain compounds as examples.

[0354]

[0355]

[0356] .

[0357] In some embodiments, is  .In some embodiments,  is  .In some embodiments, is  .  In some embodiments,  is  .  In some embodiments,  is  .In some embodiments, configuration of the chiral center in  is the same as Compound 054. In some embodiments, configuration of the chiral center in is the same as Compound 055.

[0358] In some embodiments,  is  . In some embodiments,  is  . In some embodiments,  is  . In some embodiments,  is  . In some embodiments,  is  .

[0359] For example, in some embodiments, a compound is Compound 054, which is an enantiomer of  and which, when characterized by chiral HPLC, elutes earlier than the other enantiomer, wherein the chiral HPLC comprises the following parameters (“Parameter Set 1”):

[0360] the column is DAICEL CHIRALCEL® OD, size 4.6*150 mm, particle size 5 um;

[0361] the mobile phase is a 10:90 (v / v) mixture of Mobile Phase A and Mobile Phase B, wherein Mobile Phase A is n-Hexane with 0.05% (e.g., v / v) DEA, and Mobile Phase B is EtOH with 0.05% (e.g., v / v) DEA;

[0362] the follow rate is about 1.0 mL / min; and

[0363] the column temperature is 35 °C.

[0364] Various detection technologies can be utilized in HPLC, e.g., UV (e.g., at 214 nm and / or 254 nm), MS, etc. In some embodiments, a provided compound is an enantiomer of  ,wherein when the compound is characterized by chiral HPLC, it has a retention time of about or no more than about 6 minutes, wherein the chiral HPLC comprises Parameter Set 1. In some instances, it has a retention time of about 6 minutes. In some instances, it has a retention time of about 5.9 minutes. In some instances, it has a retention time of about 5.85 minutes. In some embodiments, a provided compound is an enantiomer of  ,wherein when the compound is assessed for reducing VAV1 protein levels in Jurkat cells, it can reduce VAV1 protein levels more than the other enantiomer (e.g., after treatment of Jurkat cells in RPMI 1640 medium supplemented with 10% Fetal Bovine Serum and 1% penicillin / streptomycin 6 hours at 37 ℃) at one or more concentrations (e.g., 5 nM, 15 nM, 133 nM, etc.). Certain technologies for assessing reduction of protein levels are provided in the Examples.  In some embodiments, the present disclosure provides a composition, e.g., a pharmaceutical composition, enriched for Compound 054 or a salt thereof relative to the other enantiomer or a salt thereof.  For example, in some embodiments, enantiomeric purity of Compound 054 in a composition is more than 50%. In some embodiments, enantiomeric purity of Compound 054 in a composition is about or at least about 55%, 60%, 70%, 80%, 90%, 95% or 99%. In some embodiments, it is about or at least about 55%.  In some embodiments, it is about or at least about 55%.  In some embodiments, it is about or at least about 60%.  In some embodiments, it is about or at least about 70%.  In some embodiments, it is about or at least about 80%.  In some embodiments, it is about or at least about 90%.  In some embodiments, it is about or at least about 95%.  In some embodiments, it is about or at least about 99%.  In some embodiments, enantiomeric purity of Compound 054 is assessed by HPLC comprising Parameter Set 1.

[0365] In some embodiments, a compound is Compound 055, which is an enantiomer of  and which, when characterized by chiral HPLC, elutes later than the other enantiomer, wherein the chiral HPLC comprises Parameter Set 1. Various detection technologies can be utilized in HPLC, e.g., UV (e.g., at 214 nm and / or 254 nm), MS, etc. In some embodiments, a provided compound is an enantiomer of  ,wherein when the compound is characterized by chiral HPLC, it has a retention time of about or more than about 9 minutes, wherein the chiral HPLC comprises Parameter Set 1. In some instances, it has a retention time of about 9-10 minutes. In some instances, it has a retention time of about 10 minutes. In some instances, it has a retention time of about 9.7 minutes. In some instances, it has a retention time of about 9.71 minutes. In some embodiments, a provided compound is an enantiomer of ,wherein when the compound is assessed for reducing VAV1 protein levels in Jurkat cells, it can reduce VAV1 protein levels less than the other enantiomer (e.g., after treatment of Jurkat cells in RPMI 1640 medium supplemented with 10% Fetal Bovine Serum and 1% penicillin / streptomycin 6 hours at 37 ℃) at one or more concentrations (e.g., 5 nM, 15 nM, 133 nM, etc.). Certain technologies for assessing reduction of protein levels are provided in the Examples.  In some embodiments, the present disclosure provides a composition, e.g., a pharmaceutical composition, enriched for Compound 055 or a salt thereof relative to the other enantiomer or a salt thereof.  For example, in some embodiments, enantiomeric purity of Compound 055 in a composition is more than 50%. In some embodiments, enantiomeric purity of Compound 055 in a composition is about or at least about 55%, 60%, 70%, 80%, 90%, 95% or 99%. In some embodiments, it is about or at least about 55%.  In some embodiments, it is about or at least about 55%.  In some embodiments, it is about or at least about 60%.  In some embodiments, it is about or at least about 70%.  In some embodiments, it is about or at least about 80%.  In some embodiments, it is about or at least about 90%.  In some embodiments, it is about or at least about 95%.  In some embodiments, it is about or at least about 99%.  In some embodiments, enantiomeric purity of Compound 055 is assessed by HPLC comprising Parameter Set 1.

[0366] In some embodiments, the present disclosure provides a method for characterizing a compound or composition, comprising utilizing chiral HPLC comprising one or more parameters in Parameter Set 1 (e.g., the column, the mobile phase, etc.). In some embodiments, the present disclosure provides a method for characterizing a compound or composition, comprising utilizing chiral HPLC comprising Parameter Set 1. In some embodiments, the present disclosure provides a method for assessing a composition, comprising utilizing chiral HPLC one or more parameters in Parameter Set 1 (e.g., the column, the mobile phase, etc.). In some embodiments, the present disclosure provides a method for assessing a composition, comprising utilizing chiral HPLC comprising Parameter Set 1. In some embodiments, a compound is Compound 054 or a salt thereof. In some embodiments, a composition comprises Compound 054 or a salt thereof. In some embodiments, a compound is Compound 055 or a salt thereof. In some embodiments, a composition comprises Compound 055 or a salt thereof. In some embodiments, identify of a compound, e.g., Compound 054, Compound 055, etc., is confirmed.  In some embodiments, enantiomeric purity, e.g., of Compound 054, Compound 055, etc., is assessed.  In some embodiments, a method comprises determining enantiomeric purity, and / or determining whether to release a composition (e.g., a preparation of Compound 054, a commercial batch of Compound 054, a preparation of Compound 055, a commercial batch of Compound 055, etc.) for a use, e.g., a commercial use.  In some embodiments, when enantiomeric purity is about or above a certain level (e.g., a purity as described herein (e.g., 95% or more)), a composition is released; in some embodiments, when enantiomeric purity is about or below a certain level (e.g., a purity as described herein (e.g., 80% or lower)), a composition is rejected.

[0367] In some embodiments, a system is an in vivo system. In some embodiments, a system is an in vitro system. In some embodiments, a system is or comprises a cell. In some embodiments, a system is or comprises a diseased cell, e.g., a cancer cell. In some embodiments, a system is or comprises a tissue. In some embodiments, a system is or comprises an organ. In some embodiments, a system is or comprises a sample. In some embodiments, a system is or comprises an organism. In some embodiments, a system is or comprises an animal. In some embodiments, a system is or comprises a subject. In some embodiments, a system is a human.

[0368] Methods of Use

[0369] In one aspect, this disclosure features methods of degrading VAV1 in a subject, which include administering to the subject an effective amount of a compound described herein, or pharmaceutically acceptable salt thereof. In some embodiments, the compound mediates the interaction of a VAV1 protein with an E3 ligase, thereby increasing degradation of the VAV 1 protein. In some embodiments, VAV1 is a regulator of T-cells. In an embodiment, the compound interacts with the E3 ligase prior to the interaction of VAV1 with the E3 ligase. In some embodiments, the E3 ligase comprises cereblon.

[0370] In another aspect, this disclosure features methods of degrading VAV1, which include: (i) contacting a compound described herein or a pharmaceutically acceptable salt thereof with an E3 ligase; and (ii) interacting the contacted E3 ligase with VAV1, thereby degrading VAV1.

[0371] In some embodiments, the compounds described herein can bind to a specific amino acid sequence of VAV1, thereby causing degradation of VAV1. In other embodiments, such degradation of VAV1 is mediated by the compound interacting with both the specific amino acid sequence of VAV1 and an E3 ligase. In other embodiments, the E3 ligase comprises cereblon.

[0372] In a further aspect, this disclosure features methods of treating a variety of disorders which include administering the Compounds and pharmaceutical compositions described herein. Such disorders include, without limitation, autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, myasthenia gravis) and transplantation setting disease (e.g., graft-versus-host disease). Other disorders include those caused by or associated with deregulated lymphocyte development or activation.

[0373] In an aspect, this disclosure features methods of treating a disorder caused by or associated with deregulated lymphocyte development or activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, myasthenia gravis). In some embodiments, the disorder is transplantation setting disease (e.g., graft-versus-host disease). In some embodiments, the disorder is a malignancy (e.g., T cell or B cell malignancy). In some embodiment, the lymphocyte is T-cell.

[0374] In an aspect, this disclosure features methods of treating a disorder caused by or associated with dysregulation of T-cell receptor signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the T-cell receptor signaling are enhanced CD69 surface expression, IFNγ or IL-2.

[0375] In an aspect, this disclosure features methods of treating a disorder caused by or associated with VAV1 polymorphisms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0376] In an aspect, this disclosure features methods of treating a disorder caused by or associated with immunopathology in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is autoimmune disorder. In some embodiments, the autoimmune disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus, erythematosus, Hashimoto’s thyroiditis, myasthenia gravis, diabetes type I or II, and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying aberrant reactions (e.g., inflammatory bowel disease, Crohn’s disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis. In some embodiments, the disorder is a cancer, tumour or other malignancy, optionally wherein the disorder is a T cell or B cell malignancy. In some embodiments, the disorder is selected from the group consisting of: leukemia, lymphoma, T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK cell leukemia, hairy-cell leukemia, nasal and nasal -type NK / T cell lymphoma, mycosis fungoides and Sezary syndrome, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma unspecified, adult T-cell leukemia / lymphoma (HTLV1+), anaplastic large cell lymphoma, primary cutaneous CD-30 positive T-cell lymphoproliferative disorders, cutaneous T-cell lymphoma, subcutaneous panniculitis like T-cell lymphoma, intestinal T-cell lymphoma (+enteropathy), hepatosplenic gamma / delta T-cell lymphoma, and non-Hodgkin lymphomas (e.g., B-cell non-Hodgkin lymphomas; e.g., Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma). Transplantation setting diseases include graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, graft vessel disease, graft atherosclerosis, and transplant coronary disease.

[0377] In an aspect, the disclosure features methods of treating a disorder caused by or associated with VAV1 polymorphisms in a subject in need thereof or caused by or associated with immunopathology in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0378] In some embodiments, the disorder is T-cell mediated. In some embodiments, the disorder is selected from the group consisting of Diabetes Type I or II, pernicious anemia, uveitis, psoriasis, alopecia areata, ulcerative colitis, Chron’s disease, atherosclerosis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphea, Alzheimer’s disease, Acute Graft-vs. Host Disease or T-cell mediated kidney disease.

[0379] In some embodiments, the disorder is T / B-cell mediated. In some embodiments, the disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, myasthenia gravis, Sjogren’s syndrome, Grave’s disease, an allergic disorder (e.g., asthma, allergic contact dermatitis, rhinitis or contact dermatitis), an autoimmune liver disease (e.g., biliary sclerosis or sclerosing cholangitis), chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto’s thyroiditis, amyloidosis, inflammatory eye diseases, pemphigus, systemic lupus erythematosus, Chronic Graft vs. Host Disease, lupus nephritis, pulmonary arterial hypertension or vasculitis.

[0380] In some embodiments, the disorder is selected from the group consisting of ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus or axial spondylarthritis. In preferred embodiments, the disorder is ulcerative colitis.

[0381] In some embodiments, the disorder is selected from the group consisting of B-cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia or acute myeloid leukemia. In preferred embodiments, the disorder is chronic lymphocytic leukemia.

[0382] In an aspect, the disclosure relates to a method of treating an ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus or axial spondylarthritis, the method comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In preferred embodiments, the disorder is ulcerative colitis.

[0383] In an aspect, the disclosure relates to a method of treating B-cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia or acute myeloid leukemia, the method comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In preferred embodiments, the method is a method of treating chronic lymphocytic leukemia.

[0384] In some embodiments, the disclosure relates to a method of treating patients exhibiting CD226 overexpression.

[0385] In some embodiments, the disclosure relates to a method of treating patients having a CD226 risk variant.

[0386] In some embodiments, the disclosure relates to a method of treating patients having a CD226 polymorphism.

[0387] In some embodiments, the disclosure relates to a method of treating patients having a Gly307Ser (G307S) amino acid substitution in CD226 (rs763361T allele).

[0388] In an aspect, the disclosure relates to a method of treating a disorder caused by or associated with dysregulation of lymphocyte development or activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound that binds cereblon and degrades VAV1 or a pharmaceutically acceptable salt thereof.

[0389] In some embodiments, the lymphocyte is T-cell. In some embodiments, the lymphocyte is B-cell.

[0390] In an aspect, the disclosure relates to a method of treating a disorder caused by or associated with dysregulation of T-cell receptor signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound that binds cereblon and degrades VAV1 or a pharmaceutically acceptable salt thereof.

[0391] In an aspect, the disclosure relates to a method of treating a disorder caused by or associated with VAV1 polymorphisms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound that binds cereblon and degrades VAV1 or a pharmaceutically acceptable salt thereof.

[0392] In an aspect, the disclosure relates to a method of treating a disorder caused by or associated with immunopathology in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound that binds cereblon and degrades VAV1 or a pharmaceutically acceptable salt thereof.

[0393] In some embodiments, the disorder is autoimmune disorder.

[0394] In some embodiments, the autoimmune disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus, erythematosus, Hashimoto’s thyroiditis, myasthenia gravis, diabetes type I or II, and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying aberrant reactions (e.g., inflammatory bowel disease, Crohn’s disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.

[0395] In an aspect, the disclosure provides a compound or pharmaceutically acceptable salt for use in any of the above-recited methods of treatment. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound or pharmaceutically acceptable salt thereof as described herein. In a further aspect, the disclosure provides the use of a compound or pharmaceutically acceptable salt for the manufacture of a medicament for any of the above-recited methods of treatment. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound or pharmaceutically acceptable salt thereof as described herein.

[0396] In some embodiments, stereoisomers, e.g., enantiomers, may have different properties, activities, etc. Among other things, the present disclosure encompasses the insight that, as demonstrated herein, stereoisomers (e.g., enantiomers) with respect to the chiral center in  can demonstrate different properties, activities, PK, PD, etc., in various uses despite reports that the two configurations of the chiral center can interconvert under various conditions. For example, as demonstrated in the Examples, Compound 054 can more potently reduce VAV1 protein levels under certain circumstances. In some embodiments, the present disclosure provides uses of stereochemically enriched or pure compositions.  In some embodiments, a composition, e.g., a pharmaceutical composition is stereochemically enriched for a stereoisomer. In some embodiments, a provided compound is of high stereochemical purity.  In some embodiments, a provided compound is of high enantiomeric purity.  In some embodiments, a provided compound is of high diastereomeric purity.  In some embodiments, a stereochemical purity, or an enantiomeric purity, or a diastereomeric purity, is about or at least about 60%, 70%, 80%, 90%, 95%, or 99%.  In some embodiments, a stereochemical purity, or an enantiomeric purity, or a diastereomeric purity, is about or at least about 60%.  In some embodiments, it is about or at least about 70%. In some embodiments, it is about or at least about 75%. In some embodiments, it is about or at least about 80%. In some embodiments, it is about or at least about 85%. In some embodiments, it is about or at least about 90%. In some embodiments, it is about or at least about 91%. In some embodiments, it is about or at least about 91%. In some embodiments, it is about or at least about 92%. In some embodiments, it is about or at least about 93%. In some embodiments, it is about or at least about 94%. In some embodiments, it is about or at least about 95%. In some embodiments, it is about or at least about 96%. In some embodiments, it is about or at least about 97%. In some embodiments, it is about or at least about 98%. In some embodiments, it is about or at least about 99%. For example, in some embodiments, Compound 054 is of an enantiomeric purity level as described herein. In some embodiments, Compound 055 is of an enantiomeric purity level as described herein. In some embodiments, a compound comprises , and the configuration of the chiral center in it is the same as Compound 054, and the stereochemical purity, e.g., the enantiomeric purity, with respect to the chiral center is of a level as described herein.  In some embodiments, a compound comprises  , and the configuration of the chiral center in it is the same as Compound 055, and the stereochemical purity, e.g., the enantiomeric purity, with respect to the chiral center is of a level as described herein.  In some embodiments, a compound is  or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and is of an enantiomeric purity as described herein (e.g., about 90%, 95%, 96%, 97%, 98%, 99% or more). In some embodiments, the present disclosure provides compositions, e.g., pharmaceutical compositions, that comprise a compound which is  or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), wherein the enantiomeric purity of the compound is as described herein (e.g., about 90%, 95%, 96%, 97%, 98%, 99% or more). In some embodiments, a compound is  or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and is of an enantiomeric purity as described herein (e.g., about 90%, 95%, 96%, 97%, 98%, 99% or more). In some embodiments, the present disclosure provides compositions, e.g., pharmaceutical compositions, that comprise a compound which is or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), wherein the enantiomeric purity of the compound is as described herein (e.g., about 90%, 95%, 96%, 97%, 98%, 99% or more).

[0397] In some embodiments, the present disclosure provides compounds of high purity.  In some embodiments, purity of a compound is about or at least about 90% (wt%).  In some embodiments, it is about or at least about 91% (wt%). In some embodiments, it is about or at least about 92% (wt%). In some embodiments, it is about or at least about 93% (wt%). In some embodiments, it is about or at least about 94% (wt%). In some embodiments, it is about or at least about 95% (wt%). In some embodiments, it is about or at least about 96% (wt%). In some embodiments, it is about or at least about 97% (wt%). In some embodiments, it is about or at least about 98% (wt%). In some embodiments, it is about or at least about 99% (wt%). In some embodiments, purity is assessed using NMR, e.g., 1H NMR.

[0398] Pharmaceutical Compositions and Administration

[0399] In some embodiments, the present disclosure provides a pharmaceutical composition that comprises a provided compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a pharmaceutical composition that delivers a provided compound or a pharmaceutically acceptable salt thereof, and comprises a pharmaceutically acceptable carrier.

[0400] In some embodiments, compounds in pharmaceutical compositions are provided as pharmaceutically acceptable salts. In some embodiments, salts can be formed with many acids, e.g., hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, benzenesulfonic, etc. In some embodiments, salts can be formed with bases. In some embodiments, salts are alkali, alkaline earth metal, or ammonium salts, e.g., sodium, calcium, diethanolamine, ethanolamine, trialkylamine salts, etc. In some embodiments, salts are more soluble in aqueous or other protonic solvents than corresponding free acid or base forms.

[0401] In some embodiments, pharmaceutically acceptable salt is a solid, e.g., a tablet, power, etc. In some embodiments, a pharmaceutical composition may be a lyophilized powder. In some embodiments, pharmaceutical compositions or formulations are tablets (coated or uncoated), capsules (hard or soft), microbeads, powder, granules and / or crystals.

[0402] Pharmaceutical compositions can include solvents (aqueous or non-aqueous), solutions (aqueous or non-aqueous), emulsions (e.g., oil-in-water or water-in-oil), suspensions, syrups, elixirs, dispersion and suspension media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration or in vivo contact or delivery. Aqueous and non-aqueous solvents, solutions and suspensions may include suspending agents and thickening agents. In some embodiments, a pharmaceutically acceptable salt is a liquid. In some embodiments, pharmaceutically acceptable carriers include liquids such as water, saline, glycerol, sugars and ethanol. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present in such vehicles. In some embodiments, a pharmaceutical composition comprises a provided compound or a pharmaceutically acceptable salt thereof dissolved in a pharmaceutically acceptable buffer. In some embodiments, a buffer is a saline buffer. In some embodiments, a buffer has a pH around 7.4. In some embodiments, a pharmaceutically acceptable salt is a gel, suspension, or ointment.

[0403] Supplementary active compounds (e.g., preservatives, antibacterial, antiviral and antifungal agents) can also be incorporated into pharmaceutical compositions.

[0404] Various technologies, e.g., routes, modes, dosage regimens, etc. may be utilized to administer and / or deliver provided compounds and compositions in accordance with the present disclosure. In some embodiments, a route and / or mode of administration can vary depending upon desired results. One with skill in the art, i.e., a physician, is aware that dosage regimens can be adjusted to provide a desired response, e.g., a therapeutic response. In some embodiments, a method of administration is intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intrathecal, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin. In some embodiments, a mode of administration is left to discretion of a practitioner. Pharmaceutical compositions can be formulated to be compatible with a particular route of administration or delivery as set forth herein or known to one of skill in the art. In some embodiments, methods and uses of the present disclosure include delivery and administration systemically, regionally or locally, or by any suitable route, for example, by injection or infusion or orally. In some embodiments, delivery of a pharmaceutical composition in vivo may generally be accomplished via injection using a conventional syringe, although other delivery methods such as convection-enhanced delivery can also be used (see, e.g., U.S. Pat. No. 5,720,720). In some embodiments, compounds and compositions may be delivered subcutaneously, epidermally, intradermally, intrathecally, intraorbitally, intramucosally, intraperitoneally, intravenously, intra-pleurally, intraarterially, orally, intrahepatically, via the portal vein, or intramuscularly. In some embodiments, modes of administration include oral and pulmonary administration, suppositories, and transdermal applications. In some embodiments, a compound or composition is administered orally. In some embodiments, a compound or composition is administered intravenously.

[0405] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. In some embodiments, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.

[0406] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0407] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component with the remainder being the injectable excipient and the like.

[0408] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or Formulation. All such known transdermal formulations and ingredients are included within the scope of the disclosure provided herein.

[0409] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0410] In some embodiments, provided compositions are suitable for parenteral administration. In some embodiments, such compositions comprise aqueous and non-aqueous solutions, suspensions or emulsions of active compounds, which preparations are typically sterile and can be isotonic with blood of intended recipients. Some examples include water, buffered saline, Hanks' solution, Ringer's solution, dextrose, fructose, ethanol, animal, vegetable or synthetic oils. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Additionally, suspensions of active compounds may be prepared as appropriate oil injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Optionally, a suspension may also contain suitable stabilizers or agents which increase solubility to allow for the preparation of highly concentrated solutions.

[0411] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0412] Co-solvents and adjuvants may be added to compositions and formulations. Some examples of co-solvents contain hydroxyl groups or other polar groups, for example, alcohols, such as isopropyl alcohol; glycols, such as propylene glycol, polyethyleneglycol, polypropylene glycol, glycol ether; glycerol; polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Adjuvants include, for example, surfactants such as, soya lecithin and oleic acid; sorbitan esters such as sorbitan trioleate; and polyvinylpyrrolidone.

[0413] After pharmaceutical compositions have been prepared, they may be placed in an appropriate container and labeled for treatment. Such labeling can include amount, frequency, and method of administration.

[0414] Certain useful technologies for formulating pharmaceutical compositions and delivery systems appropriate for compounds, compositions, methods and uses of the present disclosure are described in e.g., Remington: The Science and Practice of Pharmacy. 21st Edition. Philadelphia, PA. Lippincott Williams & Wilkins, 2005, and can be utilized in accordance with the present disclosure.

[0415] In some embodiments, the present disclosure provides methods for delivering provided compounds and compositions into cells, animals or subjects. In some embodiments, such methods include contacting a system (e.g., a cell or tissue of a subject) with, or administering or delivering to a system (e.g., a subject such as a mammal or human) a provided compound, e.g., a compound of formula I, II, III, or a salt thereof, or a composition thereof.

[0416] A compound or composition described herein can be administered in a sufficient or effective amount to a subject (or a cell, tissue or organ thereof) in need thereof. Doses can vary and may depend upon type, onset, progression, severity, frequency, duration, or probability of a condition, disorder or disease to which treatment or prevention is directed, a clinical endpoint desired, previous or simultaneous treatments, general health, age, gender, race, immunological competency, etc. of a subject and other factors that will be appreciated by a skilled artisan. Dose amount, number, frequency or duration may be increased or reduced, as indicated by efficacy, any adverse side effects, complications or other risk factors of a treatment or therapy and the status of a subject. A skilled artisan will appreciate factors that may influence dosage and timing required to provide an amount sufficient for providing a therapeutic or prophylactic benefit. A dose or dosage regimen to achieve a therapeutic effect may vary based on several factors including route of administration, amount to achieve a therapeutic effect, specific condition, disorder or disease treated, any host immune response to administered compound or composition, stability of administered compound or composition, etc.

[0417] An effective amount or a sufficient amount can be provided in a single administration, may require multiple administrations, and, can be, administered alone or in combination with another composition (e.g., comprising or delivering another therapeutic agent). For example, an amount may be increased as indicated by the need of a subject, type, status and severity of a condition, disorder or disease treated and / or side effects (if any) of treatment. In some embodiments, amounts considered effective include amounts that result in a reduction of the use of, improvement of efficacy of, and / or reduction of side effects of another treatment, therapeutic regimen or protocol.

[0418] In some embodiments, a compound or composition is utilized in combination with another therapy. For example, for treating cancer, a compound or composition may be utilized in combination with another cancer therapy. In some embodiments, such another therapy is a cancer therapy. In some embodiments, it is or comprises surgery. In some embodiments, it is or comprises radiation therapy. In some embodiments, it is or comprises chemotherapy. In some embodiments, it is or comprises immunotherapy. In some embodiments, another therapy is or comprises a therapeutic agent. In some embodiments, a compound or composition is utilized in combination with another therapeutic agent. In some embodiments, a therapeutic agent is a drug, e.g., a cytotoxic agent, a chemotherapeutic agent, a radiation therapeutic agent, an immunotherapy agent, etc. In some embodiments, it is or comprises an antibody agent. EXEMPLIFICATION

[0419] Certain examples of provided technologies (e.g., compounds, compositions, methods (methods of preparation, use, assessment, etc.), etc.) are described herein. Those skilled in the art reading the present disclosure appreciate that various technologies, including those described below and modifications, variants and derivatives thereof, are available for manufacturing, characterizing and / or assessing provided technologies in accordance with the present disclosure.

[0420] In some embodiments, an Example may utilize one or more of the following abbreviations:

[0421] EA (EtOAc): ethyl acetate;

[0422] ACN (MeCN): acetonitrile;

[0423] DCM: dichloromethane;

[0424] NBS: N-Bromosuccinimide;

[0425] AIBN: 2,2'-Azobis(2-methylpropionitrile);

[0426] THF: tetrahydrofuran;

[0427] TEA (Et3N): triethylamine;

[0428] DCE: 1,2-dichloroethane;

[0429] DME: 1,2-dimethoxy-ethan;

[0430] DIPEA (DIEA): N,N-Diisopropylethylamine;

[0431] Pd(dppf)Cl2: [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0432] DEA: Diethanolamine

[0433] Example 1. Preparation of Int-1.

[0434]

[0435] To a solution of 3-Bromo-2-chlorotoluene in DCE (100 mL) was added NBS (16.67 g, 93.68 mmol) and AIBN (0.70 g, 4.26 mmol), The mixture was stirred at 90 °C for 16 h. The reaction mixture was filtered and the filtered cake was washed with ethyl acetate (2 x 75 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give Int-1-1 (17.8 g) as a colorless liquid. 1H NMR (400 MHz, Chloroform-d) δ 7.59 (dd, J = 8.0, 1.5 Hz, 1H), 7.39 (dd, J = 7.7, 1.5 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 4.61 (s, 2H).

[0436] To a solution of Int-1-1 (5.2 g, 18.29 mmol) and trimethylsilanecarbonitrile (3.43 mL, 27.43 mmol) in DCM (60 mL) was added TBAF (27.43 mL, 1.0 M in THF) dropwise at 0 °C, the mixture was stirred at 20 °C for l.5 h. The reaction mixture was washed with water (3 x 60 mL), the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give Int-1-2 (3.47 g) as a white solid.

[0437] To a mixture of Int-1-2 (3.47 g, 15.06 mmol) and tert-Butyl acrylate (2.15 mL, 15.06 mmol) in THF (50 mL) was added NaOMe (0.16 g, 3.01mmol) at 0 °C. The reaction was stirred at 20 °C for 2 h. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (3 x 80 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give Int-1-3 (5.79 g) as a yellow oil.

[0438] To a solution of Int-1-3 (5.79 g, 16.14 mmol) in Acetic acid (50 mL) was added H2SO4 (3.46 mL) at 25°C. The mixture was stirred at 90 °C for 3 h. Cooled to 25°C, the reaction mixture was poured into ice water (300 mL) and filtered cake was washed with water (2 x 50 mL). The filter cake was dried under reduced pressure to afford compound Int-1 (2 g) as a white solid. 1H NMR: (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.72 (dd, J= 8.0, 0.8 Hz, 1H), 7.38 (dd, J= 7.8,1.6 Hz,1H),7.30-7.26 (m,1H),4.32 (dd, J= 12.5,5.0 Hz,1H),2.83 - 2.73 (m, 1H), 2.53 -2.53 (m,1H),2.30-2.34(m,1H),2.03-1.97(m,1H). LCMS (ESI): m / z, 301.9 [M+H]+.

[0439] Example 2. Synthesis of Compound 031

[0440]

[0441] To a solution of 5-bromo-2,3-dihydro-1H-indene-1-carboxylic acid (50 mg, 0.207 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (63 mg, 0.249 mmol) in dioxane (1 mL) were added Pd(dppf)Cl2 (15 mg, 0.021 mmol) and KOAc (61 mg, 0.622 mmol) under N2. The mixture was stirred at 100 oC for 2 h. The mixture was concentrated to give a residue and purified by Combi-flash (silica gel, 10-50% EtOAc in PE) to give compound 031-1 (50 mg) as a yellow solid. LCMS (ESI): 289.1 [M+H]+.

[0442] To a solution of Int-1 (70 mg, 0.231 mmol) and compound 031-1 (73 mg, 0.255 mmol) in DMF (1 mL) was added K3PO4 (147 mg, 0.694 mmol) and Pd(dtbpf)Cl2 (15 mg, 0.023 mmol) under N2. The mixture was stirred at 100 oC for 2 h. The mixture was concentrated to give a residue and purified by Combi-flash (silica gel, 0-25% MeOH in DCM) and then purified by prep-HPLC to give compound 031 (15.2 mg) as a white solid. LCMS (ESI): m / z, 384.1 [M+H]+.

[0443] Example 3. Synthesis of Compound 032

[0444]

[0445] To a solution of 5-bromo-2,3-dihydro-1H-indene-1-carboxylic acid (70 mg, 0.29 mmol) in DMF (1 mL) was added HATU (132 mg, 0.348 mmol). The mixture was stirred at 20oC for 15 min. To the mixture was added dimethylamine hydrochloride (31 mg, 0.377 mmol) and DIPEA (113 mg, 0.871 mmol) and stirred for another 2h. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated to give a residue and purified by Combi-flash (silica gel, 10-70% EtOAc in PE) to give compound 032-1 (65 mg) as a yellow gum. LCMS (ESI): m / z, 270.0 [M+H]+.

[0446] To a solution of compound 032-1 (70 mg, 0.261 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (79 mg, 0.313 mmol) in dioxane (1 mL) was added KOAc (77 mg, 0.783 mmol) and Pd(dppf)Cl2 (19 mg, 0.026 mmol) under N2. The mixture was stirred at 100 oC for 2 h. The mixture was concentrated to give a residue and purified by Combi-flash (silica gel, 0-50% EtOAc in PE) to give compound 032-2 (55 mg) as a yellow gum. LCMS (ESI): m / z, 316.2 [M+H]+.

[0447] To a solution of Int-1 (50 mg, 0.165 mmol) and 032-2 (52 mg, 0.165 mmol) in DMF (1 mL) were added K3PO4 (105 mg, 0.496 mmol) and Pd(dppf)Cl2 (11 mg, 0.017 mmol) under N2. The mixture was stirred at 100 oC for 2 h. The mixture was concentrated to give a crude. The mixture was stirred at 100oC for 2 h. The mixture was concentrated to give a residue and purified by Combi-flash (silica gel, 0-15% MeOH in DCM) and then purified by prep-HPLC to give compound 032 (15 mg %) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 10.91 (brs, 1H), 7.32-7.42 (m, 2H), 7.24-7.31 (m, 2H), 7.14-7.20 (m, 2H), 4.49 (t, J = 8.0 Hz, 1H), 4.34 (dd, J = 12.0, 4.8 Hz, 1H), 3.24 (s, 3H), 2.97-3.07 (m, 1H), 2.85-2.96 (m, 4H), 2.73-2.85 (m, 1H), 2.52-2.60 (m, 1H), 2.17-2.40 (m, 3H), 2.00-2.10(m, 1H). LCMS (ESI): m / z, 411.1 [M+H]+.

[0448] Example 4. Synthesis of Compound 033

[0449]

[0450] To a solution of 5-bromo-2,3-dihydro-1H-indene-1-carboxylic acid (90 mg, 0.373 mmol) in DMF (1 mL) was added HATU (170 mg, 0.448 mmol). The mixture was stirred at 20oC for 15 min. To the mixture was added NH4Cl (26 mg, 0.485 mmol) and DIPEA (145 mg, 1.120 mmol) and stirred for 2 h. The mixture was concentrated to give a residue and purified by Combi-flash (silica gel, 0-15% MeOH in DCM) to give compound 033-1 (70 mg) as a yellow solid. LCMS (ESI): m / z, 242.0 [M+H]+.

[0451] To a solution of compound 033-1 (70 mg, 0.261 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (79 mg, 0.313 mmol) in dioxane (1 mL) was added KOAc (77 mg, 0.783 mmol) and Pd(dppf)Cl2 (19 mg, 0.026 mmol) under N2. The mixture was stirred at 100oC for 2 h. The mixture was concentrated to give a residue and purified by Combi-flash (silica gel, 0-50% EtOAc in PE) to give compound 033-2 (60 mg) as a yellow gum. LCMS (ESI): m / z, 316.2 [M+H]+.

[0452] To a solution of Int-1 (60 mg, 0.198 mmol) and 033-2 (63 mg, 0.218 mmol) in DMF (1 mL) were added K3PO4 (126 mg, 0.595 mmol) and Pd(dppf)Cl2 (13 mg, 0.020 mmol) under N2. The mixture was stirred at 100oC for 2 h. The mixture was concentrated to give a residue and purified by Combi-flash (silica gel, 0-15% MeOH in DCM) and then purified by prep-HPLC (FA) to give compound 033 (17 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 10.94 (brs, 1H), 7.63-7.69 (m, 1H), 7.33-7.42 (m, 3H), 7.27-7.32 (m, 1H), 7.25 (s, 1H), 7.17-7.21 (m, 1H), 7.01-7.07 (m, 1H), 4.34 (dd, J = 12.0, 4.8 Hz, 1H), 3.92 (t, J = 7.6 Hz, 1H), 2.98-3.09 (m, 1H), 2.75-2.96 (m, 2H), 2.52-2.60 (m, 1H), 2.17-2.38 (m, 3H), 2.00-2.10(m, 1H). LCMS (ESI): m / z, 383.1 [M+H]+.

[0453] Example 5. Synthesis of Compound 035

[0454]

[0455] To a solution of Int-1 (387.39 mg, 1.280 mmol) and 4-(2-Pyridinyl)phenylboronic acid pinacol ester (300 mg, 1.067 mmol) in DMF (4 mL) was added K3PO4 (679.44 mg, 3.201 mmol) and Pd(dppf)Cl2 (78.07 mg, 0.107 mmol). The mixture was stirred at 100oC for 4 h under N2. The mixture was concentrated and the residue was purified by Combi-flash (silica gel, 0-12% MeOH in DCM) to give compound 035-1 (218.3 mg) as a yellow solid. LCMS (ESI) m / z 377.1 [M+H]+.

[0456] To a solution of 035-1 (90 mg, 0.239 mmol) in DCM (3 mL) was added M-CPBA (48.48 mg, 0.239 mmol) at 25oC and stirred for 4 h. The mixture was concentrated to remove the solvent. The residue was purified by pre-HPLC to give compound 035 (20.8 mg) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 8.49 – 8.25 (m, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7.78 – 7.64 (m, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.41 (dt, J = 24.4, 7.1 Hz, 5H), 4.36 (dd, J = 12.3, 5.1 Hz, 1H), 2.80 (ddd, J = 17.8, 12.6, 5.2 Hz, 1H), 2.58 (s, 1H), 2.36 (dt, J = 13.8, 7.1 Hz, 1H), 2.15 – 1.93 (m, 1H). LCMS (ESI): m / z, 393.1[M+H]+.

[0457] According to a similar procedure of Compound 035, the following compounds were prepared using the corresponding substrates.

[0458]

[0459] Example 6. Synthesis of Compound 036

[0460]

[0461] To a solution of methyl 5-bromo-2-methyl-1,3-dihydroindene-2-carboxylate (6 g, 22.293 mmol) in MeOH (30 mL) was added NaOH (133.760 mL, 133.760 mmol，1M). The mixture was stirred at 20 oC for 2 h. The mixture was treated with 1N HCl until pH=7. The mixture was concentrated to give a residue and purified by Combi-flash to give compound 036-1 (4.6 g) as a yellow solid.

[0462] To a solution of compound 036-1 (1 g, 3.920 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.19 g, 4.704 mmol) in dioxane (20 mL) was added KOAc (1.15 g, 11.760 mmol) and Pd(dppf)Cl2 (0.29 g, 0.392 mmol) under N2. The mixture was stirred at 90 oC for 16 h. The mixture was concentrated to give a residue and purified by Combi-flash (silica gel, 0-5% MeOH in DCM) to give compound 036-2 (580 mg) as a yellow solid. LCMS (ESI): m / z, 303.2[M+H]+.

[0463] To a solution of Int-1 (432.54 mg, 1.430 mmol) and compound 036-2 (360 mg, 1.191 mmol) in DMF (8 mL) was added K3PO4 (758.63 mg, 3.574 mmol) and Pd(dppf)Cl2 (87.17 mg, 0.119 mmol), and then stirred at 100oC for 4 h under N2. The mixture was concentrated to remove the solvent. The residue was purified by Combi-flash (silica gel, 0-12% MeOH in DCM), and then purified by prep-HPLC. Compound 036 (280.6 mg) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 10.93 (s, 1H), 7.48 – 7.11 (m, 6H), 4.34 (dd, J = 12.1, 5.0 Hz, 1H), 3.43 (d, J = 16.1 Hz, 4H), 2.83 (d, J = 16.0 Hz, 2H), 2.34 (qd, J = 12.8, 4.3 Hz, 1H), 2.06 (dtt, J = 13.3, 5.3, 2.3 Hz, 1H), 1.33 (s, 3H). LCMS (ESI): m / z, 398.1[M+H]+.

[0464] Example 7. Synthesis of Compound 037

[0465]

[0466] To a solution of compound 036 (100 mg, 0.251 mmol) in DMF (2 mL) was added HATU (114.69 mg, 0.302 mmol). The mixture was stirred at 20 oC for 15 min. To the mixture was added NH4Cl (17.48 mg, 0.327 mmol) and DIPEA (97.46 mg, 0.754 mmol). The mixture was stirred at 20 oC for 2 h. The organic layer was concentrated to give a residue and purified by pre-HPLC to give compound 037 (45.6 mg) as a white solid. LCMS (ESI): m / z, 397.1[M+H]+.

[0467] Example 8. Synthesis of Compound 038

[0468]

[0469] To a solution of compound 036 (100 mg, 0.251 mmol) in DMF (1 mL) was added HATU (114.69 mg, 0.302 mmol). The mixture was stirred at 20 oC for 15 min. To the mixture was added dimethylamine hydrochloride (26.64 mg, 0.327 mmol) and DIPEA (97.46 mg, 0.754 mmol). The mixture was stirred at 20 oC for 2 h. The organic layer was concentrated to give a residue and purified by pre-HPLC to give compound 038 (49.9 mg) as a white solid. LCMS (ESI): m / z, 425.1[M+H]+.

[0470] Example 9. Synthesis of Compound 054 and Compound 055

[0471]

[0472] Compound 035 (1000 mg, 2.546 mmol) was separated by SFC [Column: DAICEL CHIRALCEL®OD, 40*250 mm 10 um; Mobile Phase: EtOH; flow rate: 90 mL / min; wavelength:214 nm / 254 nm; column temperature: RT, injection: 7 mL (11.1 mg / mL); cycle time: 13 min] to obtained the first eluted enantiomer Compound 054 (416 mg) and the second eluted enantiomer Compound 055 (401 mg).

[0473] Additional separation: Column: DAICEL CHIRALCEL®OD, 4.6*150 mm 5 um; Mobile Phase A: n-Hexane + (0.05%) DEA; Mobile Phase B: EtOH + (0.05%) DEA; A:B = 10:90; flow: 1.0 mL / min; wave length: 214 nm / 254 nm; column temperature: 35 oC, run time: 12 min. The first eluted enantiomer, with a retention time of 5.85 minutes, was designated as Compound 054. The second eluted enantiomer, with a retention time of 9.71 minutes, was designated as Compound 055. One of Compound 054 and Compound 055 corresponds to enantiomer Compound 035-A, while the other corresponds to Compound 035-B.

[0474] Example 10. Synthesis of Compound 042

[0475]

[0476] To a solution of 5-bromo-2,3-dihydro-1H-indene-1-carbonitrile (500 mg, 2.26 mmol) in THF (10 ml) was added NaH (181 mg, 4.52 mmol, 60%) at 0 oC, stirred for 0.5 h. Then MeI (1.61 g, 11.32 mmol) was added, the mixture was warmed up to 25 oC and stirred for 2 h. The reaction mixture was diluted with aq. NH4Cl and extracted with EtOAc. Organic layer dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Combi Flash to give compound 042-1 (431 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3) ppm: 7.45-7.38 (m, 2 H), 7.24 (s, 1 H), 3.15-2.93 (m, 2 H), 2.80-2.60 (m, 1 H), 2.25-2.10 (m, 1 H), 1.64 (s, 3H).

[0477] To a solution of compound 042-1 (430 mg, 1.83 mmol) in DMSO (5 mL) was added potassium carbonate (506 mg, 3,67 mmol) at 25 °C and stirred for 20 min. The mixture was then cooled to 0°C and H2O2 (488 mg, 7.32 mmol, 30%) was added dropwise. The reaction mixture was stirred for 3h and allowed to warm to room temperature. Water was added and extracted with EtOAc. Organic layer was concentrated and purified by Combi Flash to give compound 042-2 (393 mg) as a white solid. 1H NMR (400 MHz, CDCl3) ppm: 7.42 (s, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 1H), 5.48 (brs, 1H), 5.29 (brs, 1H), 3.03-2.93 (m, 2H), 2.66-2.55 (m, 1H), 2.10-2.00 (m, 1H), 1.54 (s, 3H). LCMS (ESI): m / z, 254.0 [M+H]+.

[0478] To a solution of compound 042-2 (390 mg, 1.54 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (468 mg, 1.85 mmol) in dioxane (5 mL) were added KOAc (456 mg, 4.62 mmol) and Pd(dppf)Cl2 (113 mg, 0.15 mmol) under N2. The mixture was stirred at 100℃ for 4h. The mixture was concentrated to give a residue and purified by Combi-flash to give compound 042-3 (312mg) as a yellow gum. 1H NMR (400 MHz, CDCl3) ppm: 7.75 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 1H), 5.36 (brs, 1H), 5.25 (brs, 1H), 3.13-2.88 (m, 2H), 2.66-2.55 (m, 1H), 2.10-2.00 (m, 1H), 1.57 (s, 3H), 1.35 (s, 12H).

[0479] To a solution of compound 042-3 (300 mg, 1.00 mmol) and Int-1 (315 mg, 1.05 mmol) in DMF (5 mL) were added K3PO4 (636 mg, 3.00 mmol) and Pd(dppf)Cl2 (65 mg, 0.20 mmol) under N2. The mixture was stirred at 100℃ for 2h. The mixture was concentrated to give a residue and purified by Combi-flash and then further purified by prep-HPLC (FA) to give compound 042 (15.6 mg) as a white solid. 1H NMR (400 MHz DMSO-d6,) ppm: 10.92 (s, 1H), 7.54 (d, J = 7.8Hz, 1H), 7.43-7.28 (m 5H), 5.76 (s, 1H), 4.35 (dd, J = 12.2, 5.0Hz, 1H), 3.06 (t, J = 7.2 Hz, 2H), 2.84-2.75 (m, 1H), 2.62 (td, J = 13.4, 6.8Hz, 2H),2.37-2.23(m, 2H), 2.11 -2.02 (m, 1H),1.69 (s, 3H). LCMS (ESI): m / z, 397.1[M+H]+.

[0480] Example 11. Synthesis of Compound 056

[0481]

[0482] To a solution of compound 042-1 (800 mg, 3.388 mmol) in EtOH (3 mL) and H2O (3 mL) was added KOH (1.14 g, 20.33 mmol). The reaction mixture was stirred at 100℃ for 12h. The mixture was treated with 1N HCl until pH ~7, concentrated to give a crude residue. The residue was purified by Combi-flash to give compound 056-1 (580 mg) as a yellow solid. LCMS (ESI): m / z, 255.0, 257.0 [M+H]+.

[0483] To a solution of compound 056-1 (150 mg, 0.588 mmol) in DMF (3 mL) was added HATU (107.32 mg, 0.282 mmol). The mixture was stirred at 20℃ for 15 min. To the mixture were added dimethylamine hydrochloride (71.92 mg, 0.882 mmol) and DIPEA (91.20 mg, 0.706 mmol). The mixture was stirred at 20℃ for 2 h. The organic layer was concentrated to give a residue and purified by Combi-flash to give compound 056-2 (138 mg) as a yellow solid. LCMS (ESI): m / z, 282.0, 284.0 [M+H]+.

[0484] To a solution of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (107.99 mg, 0.425 mmol) and compound 056-2 (100 mg, 0.354 mmol) in dioxane (3 mL) were added KOAc (104.34 mg, 1.063 mmol) and Pd(dppf)Cl2 (25.93  mg, 0.035 mmol) under N2. The mixture was stirred at 90℃ for 16h. The mixture was concentrated to give residue and purified by Combi-flash to give compound 056-3 (110 mg) as a yellow solid. LCMS (ESI): m / z, 330.2 [M+H]+.

[0485] To a solution of Int-1(91.89 mg, 0.304 mmol) and compound 056-3 (100 mg, 0.304 mmol) in DMF (3 mL) were added K3PO4 (193.40 mg, 0.911 mmol) and Pd(dppf)Cl2 (19.74 mg, 0.030 mmol) under N2. The mixture was stirred at 100oC for 2h. The mixture was concentrated to give a residue. The crude residue was purified by Combi-flash and then purified by prep-HPLC (FA) to give compound 056 (51 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 10.89 (s, 1H),7.45-7.07 (m, 6H),4.33 (dd. J= 12.1, 5.1 Hz. 1H), 3.19-3.10 (m, 2H), 2.85-2.62 (m, 7H), 2.59-2.54 (m,1H), 2.47 (d. J=9.2 Hz,1H), 2.33 (m, 1H), 2.11-1.98 (m, 1H), 1.39(s.3H). LCMS (ESI): m / z, 425.1 [M+H]+.

[0486] Example 12. Synthesis of Compound 057

[0487]

[0488] To a solution of compound 056-1 (130 mg, 0.510 mmol) in DMF (1 mL) was added HATU (107.32 mg, 0.282 mmol). The mixture was stirred at 20℃ for 15 min. To the mixture was added methanamine hydrochloride (41.29 mg, 0.611 mmol) and DIPEA (91.20 mg, 0.706 mmol). The mixture was stirred at 20℃ for 2h. Organic layer was concentrated to give a residue and purified by Combi-flash to give compound 057-1 (101.2 mg) as a yellow solid. LCMS (ESI): m / z, 268.0, 270.0[M+H]+.

[0489] To a solution of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (113.64 mg, 0.448 mmol) and compound 057-1 (100 mg, 0.373 mmol) in dioxane (3 mL) were added KOAc (109.80 mg, 1.119 mmol) and Pd(dppf)Cl2 (27.29 mg, 0.037 mmol) under N2. The mixture was stirred at 90℃ for 16 h. The reaction mixture was concentrated to give residue and purified by Combi-flash to give compound 057-2 (92 mg) as a yellow solid. LCMS (ESI): m / z, 316.2 [M+H]+.

[0490] To a solution of Int-1 (76.78 mg, 0.254 mmol) and compound 057-2 (80 mg, 0.254 mmol) in DMF (2 mL) were added K3PO4 (161.61 mg, 0.761 mmol) and Pd(dppf)Cl2 (16.50 mg, 0.025 mmol) under N2. The mixture was stirred at 100℃ for 4 h, then concentrated to give a crude residue. The residue was purified by Combi-flash and then purified by prep-HPLC (FA) to give compound 057 (18.12 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) ppm 10.89 (s, 1H), 7.50-7.18 (m 7H), 4.33 (dd. J= 12.2, 5.0 Hz. 1H), 3.01-2.89 (m, 2H), 2.80-2.73 (m, 1H), 2.64-2.57 (m,5H), 2.37-2.26 (m 1H), 2.11-1.99 (m, 1H), 1.95-1.81 (m, 1H), 1.46 (s.3H). LCMS (ESI): m / z, 393.1[M+H]+.

[0491] Example 13. Synthesis of Compound 058

[0492]

[0493] To a solution of 5-bromo-2,3-dihydro-1H-indene-1-carboxylic acid (100 mg, 0.415 mmol) in DMF (1.5 mL) was added HATU (189 mg, 0.498 mmol). The mixture was stirred at 20oC for 15 min. To the mixture was added methanamine hydrochloride (42 mg, 0.622 mmol) and DIPEA (161 mg, 1.244 mmol) and stirred for another 2h. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated to give a residue and purified by Combi-flash to give compound 058-1 (100 mg) as a yellow gum. LCMS (ESI): m / z, 256.0 [M+H]+.

[0494] To a solution of compound 058-1 (100 mg, 0.394 mmol) in dioxane (1.5 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (110 mg, 0.433 mmol), Pd(dppf)Cl2 (29 mg, 0.039 mmol) and KOAc (116 mg, 1.181 mmol) under N2. The mixture was stirred at100℃ for 16 h. The mixture was concentrated to give a residue and purified by Combi-flash to give compound 058-2 (100 mg) as a yellow gum. LCMS (ESI): m / z, 302.2 [M+H]+.

[0495] To a solution of Int-1 (100 mg, 0.331 mmol) and compound 058-2 (100 mg, 0.331 mmol) in DMF (1 mL) was added K3PO4 (210 mg, 0.992 mmol) and Pd(dtbpf)Cl2 (22 mg, 0.033 mmol) under N2. The mixture was stirred at 100℃ for 2 h. The mixture was concentrated to give a crude residue. The residue was purified by Combi-flash and then further purified by prep-HPLC (FA) to give compound 058 (15 mg) as a white solid. LCMS (ESI): m / z, 397.1 [M+H]+.

[0496] Example 14. Synthesis of Compound 047 and Compound 048

[0497]

[0498] Compound 033-2 (2000 mg) was separated by SFC [Column: DAICEL CHIRALPAK®AS-3, 25*250 mm 10 um; Mobile Phase A: Supercritical CO2; Mobile Phase B: MeOH; A:B = 85:15; flow rate: 120 mL / min; wavelength:214 nm / 254 nm; column temperature: RT, injection: 1 mL (67 mg / mL); cycle time: 5 min] to obtained compound 033-2A (770 mg) as a yellow solid and compound 033-2B (1050 mg) as a yellow gum.

[0499] Additional separation. Column: DAICEL CHIRALPAK®AS-3, 3.0*100 mm 3 um; Mobile Phase A: Supercritical CO2; Mobile Phase B: MeOH; A:B = 95:5; flow: 1.5 mL / min; wavelength:214 nm / 254 nm; column temperature: 35oC, run time: 5min. The first eluted enantiomer, with a retention time of 2.637 minutes, was designated as compound 033-2A. The second eluted enantiomer, with a retention time of 2.942 minutes, was designated as compound 033-2B.

[0500] Compound 047 and Compound 048 were synthesized from 033-2A and 033-2B, respectively, according to the same procedure of Compound 033.

[0501] Compound 047 LCMS (ESI) m / z, 383.1[M+H]+.

[0502] Compound 048 LCMS (ESI) m / z, 383.1[M+H]+.

[0503] Example 15. Synthesis of Compound 052 and Compound 053

[0504]

[0505] To a solution of compound 033-2A (100 mg, 0.348 mmol) in DMF (1.3 mL) was added NaH (46 mg, 1.150 mmol, 60% in mineral oil) at 0℃. The mixture was stirred at 0℃ for 30 min under N2. To the mixture was added CH3I (198 mg, 1.393 mmol) and stirred at 20℃ for 16 h. The mixture was quenched with saturated aq. NH4Cl and extracted with EtOAc. The organic layer was concentrated to give a residue and purified by Combi-flash to give compound 052-1 (47 mg) as a yellow gum. LCMS (ESI): m / z, 316.1 [M+H]+.

[0506] To a solution of compound 033-2B (100 mg, 0.348 mmol) in DMF (1.3 mL) was added NaH (46 mg, 1.150 mmol, 60% in mineral oil) at 0℃. The mixture was stirred at 0℃ for 30 min under N2. To the mixture was added CH3I (198 mg, 1.393 mmol) and stirred at 20℃ for 16 h. The mixture was quenched with saturated aq. NH4Cl and extracted with EtOAc. The organic layer was concentrated to give a residue and purified by Combi-flash to give compound 053-1 (50 mg) as a yellow gum. LCMS (ESI): m / z, 316.2 [M+H]+.

[0507] Compound 052 and Compound 053 were synthesized from 052-1 and 053-1, respectively, according to the same procedure of Compound 032.

[0508] Compound 052 LCMS (ESI) m / z, 411.1[M+H]+.

[0509] Compound 053 LCMS (ESI) m / z, 411.1[M+H]+.

[0510] Example 16. Synthesis of Compound 061

[0511]

[0512] To a solution of 4,4,5,5-tetramethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3,2-dioxaborolane (8.76 g, 26.549 mmol) and 2-bromo-3-(trifluoromethyl)pyridine (3 g, 13.274 mmol) in dioxane (50 mL)  and H2O (10.0 mL) was added K3PO4 (6.20 g, 29.204 mmol) and Pd(dppf)Cl2 (0.97 g, 1.327 mmol) under N2. The mixture was stirred at 100℃ for 2h. The mixture was concentrated to give a residue and purified by Combi-flash to give compound 061-1 (3.8 g) as a brown solid. LCMS (ESI): m / z, 350.1 [M+H]+.

[0513] To a solution of compound 061-1 (550 mg, 1.575 mmol) and Int-1 (571.90 mg, 1.890 mmol) in DMF (6 mL) was added K3PO4 (1003.06 mg, 4.726 mmol) and Pd(dppf)Cl2 (115.26 mg, 0.158 mmol). The mixture was stirred at 100℃ for 2h under N2. The mixture was concentrated to give a residue and purified by Combi-flash to give compound 061-2 (516.2 mg) as a yellow solid. LCMS (ESI): m / z, 445.1 [M+H]+.

[0514] To a solution of compound 061-2 (150 mg, 0.337 mmol) in DCM (5 mL) was added m-CPBA (205.37 mg, 1.012 mmol), The mixture was stirred at 40℃ for 45min. The mixture was concentrated to remove the solvent. The residue was purified by pre-HPLC to give compound 061 (18 mg) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 8.65 (d, J = 6.7 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.72 (t, J = 7.4 Hz, 1H), 7.60 – 7.55 (m, 1H), 7.49 – 7.31 (m, 4H), 7.19 – 7.11 (m, 1H), 6.82 – 6.73 (m, 1H), 4.42 (dd, J = 12.0, 5.2 Hz, 1H), 2.85 – 2.67 (m, 2H), 2.44 (qd, J = 12.5, 4.7 Hz, 1H), 2.26 – 2.18 (m, 1H). LCMS (ESI): m / z, 461.1 [M+H]+.

[0515] Example 17. Synthesis of Compound 062

[0516]

[0517] To a solution of 4,4,5,5-tetramethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3,2-dioxaborolane (634.67 mg, 1.923 mmol) and 2-bromo-3-(trifluoromethyl)pyridine (200 mg, 0.962 mmol)  in dioxane (3 mL)  and H2O (1 mL) was added K3PO4 (449.0 mg, 2.115 mmol) and Pd(dppf)Cl2 (70.35  mg, 0.096 mmol) under N2. The mixture was stirred at 100℃ for 1h. The mixture was concentrated to give a residue and purified by Combi-flash to give compound 062-1 (190 mg) as a brown solid. LCMS (ESI): m / z, 332.2 [M+H]+.

[0518] To a solution of compound 062-1 (190 mg, 0.574 mmol) and Int-1 (173.58 mg, 0.574 mmol) in DMF (2.5 mL) was added K3PO4 (365.34 mg, 1.721 mmol) and Pd(dppf)Cl2 (37.39 mg, 0.057 mmol). The mixture was stirred at 100℃ for 2.5h under N2. The mixture was concentrated to give a residue and purified by Combi-flash to give compound 062-2 (110 mg) as a yellow solid. LCMS (ESI): m / z, 427.1 [M+H]+.

[0519] To a solution of compound 062-2 (110 mg, 0.258 mmol) in DCM (2 mL) was added m-CPBA (66.7 mg, 0.387 mmol), The mixture was stirred at 50℃ for 1.5h. The mixture was concentrated to remove the solvent. The residue was purified by pre-HPLC to give compound 062 (15.4 mg) as a white solid. 1HNMR (400 MHz, DMSO-d6) ppm 10.84 (brs, 1H), 8.48  (d, J = 6.8 Hz, 1H), 7.84-7.90 (m, 1H), 7.77  (d, J = 6.8 Hz, 1H), 7.63-7.67 (m, 1H), 7.54-7.57 (m, 2H), 7.43-7.47 (m, 2H), 7.35-7.40 (m, 2H), 6.60  (t, J = 56.0 Hz, 1H), 4.32  (dd, J = 12.4, 5.2 Hz, 1H), 2.72-2.82 (m, 1H), 2.54-2.63 (m, 1H), 2.26-2.40 (m, 1H), 2.02-2.12 (m, 1H). LCMS (ESI): m / z, 443.1 [M+H]+.

[0520] Those skilled in the art reading the present disclosure appreciate that other compounds, e.g., additional compounds in Table C1 to C4 can be prepared in accordance with the present disclosure. Among other things, provided compounds can inhibit cell proliferation and are useful for treating various conditions, disorders or diseases including cancer. Certain useful technologies for assessing and confirming properties and activities of provided compounds are presented below as examples.

[0521] Biological assay

[0522] Example B1. VAV1 degradation assay in Jurkat cell line.

[0523] The Jurkat cells were cultured in RPMI 1640 medium supplemented with 10% Fetal Bovine Serum and 1% penicillin / streptomycin. The cells were seeded on 6-well plates in a density of 1.5x106 cells / mL, then the series diluted compounds to be tested were added. The final DMSO concentration is 1%. After treated 6 hours at 37℃, the cells were collected and washed twice by cold PBS. Then the pellets were lysed by RIPA buffer. Total protein abundant for each sample was calculated by BCA assay kit to adjust the loaded sample volume in western blot. The samples were then loaded on the precast gel for the protein separation and followed by primary antibody incubation, secondary antibody incubation, chemiluminescence, and relative quantification using DMSO control. The % of protein reduction was calculated as follows:

[0524] The results of % of protein reduction for certain compounds are provided in Table 1 as examples, wherein “A” represents 85-100% VAV1 protein reduction; “B” represents 50-85% VAV1 protein reduction; “C” represents 10-50% VAV1 protein reduction; “D” represents below 10% VAV1 protein reduction. “*” indicates the compound is a reference compound, “1*” is compound 185 described in WO 2024 / 151547.

[0525] Table 1: The percentage (%) of protein reduction for the treatment with 133 nM, 15 nM and 5 nM of Certain compounds.

[0526]

[0527] As demonstrated herein, various provided compounds as described herein can significantly reduce protein. As illustrated in Table 1, various provided compounds can provide more reduction of VAV1 protein levels compared to reference compounds, e.g., 1*.  In some embodiments, a stereoisomer, e.g., an enantiomer, can provide more reduction of VAV1 protein levels compared to another stereoisomer, e.g., the other enantiomer. For example, Compound 054 can more potently reduce VAV1 protein levels compared to Compound 055 at various concentrations.

[0528] Example B2. Pharmacokinetic Evaluation of Compound 035 and Compound 1* in Sprague-Dawley Rats and Cynomolgus Monkeys.

[0529] Compound 035 and compound 1* was formulated in a vehicle consisting of 5% (v / v) dimethyl sulfoxide (DMSO), 10% (v / v) Solutol HS-15, and 85% (v / v) normal saline. Pharmacokinetic studies were conducted in male Sprague-Dawley rats and male cynomolgus monkeys, which were fasted overnight prior to dosing. Rats received an intravenous (IV) dose of 0.5 mg / kg and an oral gavage dose of 1 mg / kg, while monkeys received an intravenous (IV) dose of 0.2 mg / kg and an oral dose of 0.5 mg / kg. Blood samples were collected into K₂EDTA tubes at predetermined time points: for IV dosing at 0 (pre-dose), 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose, and for oral dosing at 0 (pre-dose), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose. Plasma was separated by centrifugation at 4 °C and stored at −80 °C until analysis. Compound concentrations in plasma were quantified using a validated LC-MS / MS assay. Pharmacokinetic parameters including Cmax, Tmax, AUC, elimination half-life (T1 / 2), clearance (CL), volume of distribution at steady state (Vss), and oral bioavailability (F%) were calculated using non-compartmental analysis with Phoenix® WinNonlin® (Version 8.2，Pharsight， Mountain View，CA). Oral bioavailability was calculated based on dose-normalized AUC values following the formula: F(%) = (AUC_PO × Dose_IV) / (AUC_IV × Dose_PO) × 100. Study results are presented in Table 2 and Table 3.

[0530] Table 2: PK parameters of Compound 035 and Compound 1*in SD Rats

[0531]

[0532] Among other things, Compound 035 exhibited low systemic clearance, excellent exposure and oral bioavailability in SD rats.

[0533] Table 3: PK parameters of Compound 035 and Compound 1*in Cynomolgus Monkeys

[0534]

[0535] Among other things, Compound 035 exhibited low systemic clearance, excellent exposure and oral bioavailability in cynomolgus monkeys.

[0536] Example B3. Measurement of racemization at the glutarimide chiral center in HEPES buffer.

[0537] A solution of Compound 054 (1 mg) was dissolved in 50 µL of DMSO, followed by the addition of 5 mL of 1 M HEPES buffer (pH 7.4). The resulting solution was incubated at 37 °C to study the racemization behavior at the chiral center of the glutarimide moiety. Aliquots were taken at designated time points (0 h, 2 h, 8 h, and 24 h) for analysis. The extent of racemization was evaluated by chiral chromatographic techniques such as chiral HPLC. The enantiomeric composition at each time point was determined to assess, e.g., the rate and degree of racemization under physiological-like conditions.

[0538] A similar procedure was applied to Compound 055 to evaluate racemization at its glutarimide chiral center. Certain results are presented in Table 4.

[0539] Table 4

[0540]

[0541] Among other things, the present disclosure demonstrates that in various circumstances, Compound 054 or Compound 055 can be stable enough with respect to the glutarimide chiral center such that selective uses, administrations, deliveries, etc., of one enantiomer (e.g., through compositions enriched for the enantiomer) may be preferred over the other enantiomer, or mixtures of the enantiomers (e.g., racemic compositions).  For example, in some embodiments, selective uses, administrations, deliveries, etc., of Compound 054, or compositions enriched therefor, can provide various advantages and benefits (e.g., see Table 1). In some embodiments, as illustrated in the Examples, provided compounds are utilized as mixtures of stereoisomers (e.g., racemic mixtures of enantiomers).  In some embodiments, provided compounds are stereochemically enriched (e.g., having various stereochemical purities as described herein). In some embodiments, provided compounds are enantiomerically enriched (e.g., having various enantiomeric purities as described herein). In some embodiments, a stereochemically enriched composition (e.g., enriched for an enantiomer) can provide various benefits and advantages (see, e.g., Table 1) over an un-enriched (e.g., racemic) composition or a composition enriched for other stereoisomer(s) (e.g., the other enantiomer).

[0542] While various embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described in the present disclosure, and each of such variations and / or modifications is deemed to be included. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be example and that the actual parameters, dimensions, materials, and / or configurations may depend upon the specific application or applications for which the teachings of the present disclosure is / are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the embodiments of the present disclosure. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, claimed technologies may be practiced otherwise than as specifically described and claimed. In addition, any combination of two or more features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the present disclosure.

Claims

A compound having a structure of formula I:；                              I；or a salt thereof, wherein:X3is independently -C(R3)- or N, wherein R3is hydrogen or F;R2is F, Cl, methyl, or C2alkynyl;L1is:1) a bond, with the provision that R1 is optionally substituted，，; or2) an optionally substituted C1-4 alkyl or C1-4 heteroalkyl having 1-4 heteroatoms; and2a) One atom of L1 taken together with X1 or X2 to form an additional ring fused with the ring containing X1 and X2, wherein the fused ring system includes 8 to 10 ring atoms, wherein the additional ring has 0 heteroatom, and is optionally further substituted with 1-4 substituents;R1 is independently selected from the group consisting of hydrogen, hydroxyl, halogen, -OR’, -S(O)0-2R’, -S(O)0-2N(R’)R’’, -C(O)OR’, -N(R’)R’’, -N(R0)C(O)N(R’)R’’, -OC(O)N(R’)R’’, -NR’C(O)R’’ and -C(O)NR’R’’; or:2b) One atom of L1 taken together with X1 or X2 to form an additional ring fused with the ring containing X1 and X2, wherein the fused ring system includes 10 ring atoms, wherein the additional ring has the moiety of , and is optionally further substituted with 1-4 substituents，wherein “*” indicates the attachment to the ring containing X1 and X2; R1 is empty; each of X1 and X2 is independently -C(R4)-, wherein R4 is hydrogen or F;each of R0, R’ or R’’ is independently selected from an optionally substituted group consisting of H, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, or R’ is optionally taken together with the carbon atom directly attached to R1 to form an additional 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;each substituent is independently selected from halogen, hydroxyl, cyano, oxo, C1-3 haloalkyl, or R#; andtwo substituents are optionally and independently taken together to form a covalent bond, or:two or more substituents on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-8 membered ring having, in addition to the atom, 0-4 heteroatoms; or:two or more substituents on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;R# is independently H, halogen, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, C5-8 aryl, 5-8 membered heteroaryl having 1-4 heteroatoms, and combinations thereof, wherein each combination independently has 1-8 carbon atoms and 0-4 heteroatoms.A compound having the structure of formula Ia:；                            Ia；or a salt thereof, wherein:X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F;R2 is F, Cl, methyl, or C2 alkynyl;L1 is:1) a bond, with the provision that R1 is optionally substituted，，; or2) an optionally substituted C1-4 alkyl or C1-4 heteroalkyl having 1-4 heteroatoms; and2a) One atom of L1 taken together with X1 or X2 to form an additional ring fused with the ring containing X1 and X2, wherein the fused ring system includes 8 or 10 ring atoms, wherein the additional ring has 0 heteroatom, and is optionally further substituted with 1-4 substituents;R1 is independently selected from the group consisting of hydrogen, hydroxyl, halogen, -OR’ , -S(O)0-2R’, -S(O)0-2N(R’)R’’, -C(O)OR’, -N(R’)R’’, -N(R0)C(O)N(R’)R’’, -OC(O)N(R’)R’’, -NR’C(O)R’’ and -C(O)NR’R’’. In some embodiments, X3 is -C(R3)-, wherein R3 is hydrogen or F. In some embodiments, R2 is Cl. In some embodiments, R2 is Cl; and X3 is -C(R3)-, wherein R3 is hydrogen or F.A compound having the structure of formula II-1d:；                            II-1d；or a salt thereof, wherein: X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F;x1 is 0-4;each of X1 and X2 is independently -C(R4)-, wherein R4 is hydrogen or F;each Rs is independently selected from halogen, hydroxyl, cyano, C1-3 haloalkyl, C1-3 aliphatic, or C1-3 heteroaliphatic having 1-3 heteroatoms.A compound having the structure of formula II-2:；                         II-2；or a salt thereof, wherein: X3 is independently -C(R3)- or N, wherein R3 is hydrogen or F;R2 is F, Cl, methyl, or C2 alkynyl;R1 is independently selected from the group consisting of hydrogen, hydroxyl, halogen, -OR’, -S(O)0-2R’, -S(O)0-2N(R’)R’’, -C(O)OR’, -N(R’)R’’, -N(R0)C(O)N(R’)R’’, -OC(O)N(R’)R’’, -NR’C(O)R’’ and -C(O)NR’R’’; or:R4 is hydrogen or F;q is 1-3;x is 0-4;each of R0, R’ or R’’ is independently selected from an optionally substituted group consisting of H, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, or R’ is optionally taken together with the carbon atom directly attached to R1 to form an additional 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;each Rs is independently selected from halogen, hydroxyl, cyano, oxo, C1-3 haloalkyl, or R#; andtwo Rs are optionally and independently taken together to form a covalent bond, or:two or more Rs on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-8 membered ring having, in addition to the atom, 0-4 heteroatoms; or:two or more Rs on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;R# is independently H, halogen, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, C5-8 aryl, 5-8 membered heteroaryl having 1-4 heteroatoms, and combinations thereof, wherein each combination independently has 1-8 carbon atoms and 0-4 heteroatoms. The compound of any one of the preceding claims, wherein X3 is -C(R3)-, wherein R3 is hydrogen or F.The compound of any one of the preceding claims, wherein X3 is N.The compound of any one of the preceding claims, wherein R2 is F.The compound of any one of the preceding claims, wherein R2 is Cl.A compound having the structure of formula II-2a-1:；                        II-2a-1；or a salt thereof.A compound having the structure of formula II-2a-2:；                   II-2a-2；or a salt thereof.A compound having the structure of formula II-2b-1and II-2b-2:，；                            II-2b-1                                                   II-2b-2；or a salt thereof.A compound having the structure of formula II-2c-1and II-2c-2:，；                                    II-2c-1                                       II-2c-2；or a salt thereof.The compound of any one of the preceding claims, wherein q is 1.The compound of any one of the preceding claims, wherein q is 2.The compound of any one of the preceding claims, wherein q is 3.The compound of any one of the preceding claims, wherein R1 is -OR’, -S(O)0-2R’, -S(O)0-2N(R’)R’’, -C(O)OR’, -N(R’)R’’, -N(R0)C(O)N(R’)R’’, -OC(O)N(R’)R’’, -NR’C(O)R’’ and -C(O)NR’R’’.The compound of any one of the preceding claims, wherein R1 is -C(O)NR’R’’.The compound of any one of the preceding claims, wherein R1 is -C(O)NR’R’’, wherein R’ or R’’ is independently C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms.The compound of any one of the preceding claims, wherein each of R’ or R’’ is independently H, C1-6 aliphatic (e.g., C1-3 alkyl, etc.）, C1-6 heteroaliphatic having 1-4 heteroatoms (e.g., C1-3 alkoxyl, etc.).The compound of any one of the preceding claims, wherein each of R’ or R’’ is independently C1-3 aliphatic.The compound of any one of the preceding claims, wherein each of R’ or R’’ is independently C1-6 heteroaliphatic having 1-4 heteroatoms (e.g., C1-3 alkoxyl, etc.).The compound of any one of the preceding claims, wherein each of R’ or R’’ is independently 3-6 membered cycloalkyl.The compound of any one of the preceding claims, wherein each of R’ or R’’ is independently 3-6 membered heterocyclyl having 1-4 heteroatoms.The compound of any one of claims 3 and 9-10, wherein each of R’ is optionally taken together with the carbon atom directly attached to R1 to form an additional 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms.The compound of claim 24, wherein the 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms, is.The compound of any one of the preceding claims, wherein R1 is -C(O)NH2. The compound of any one of the preceding claims, wherein R1 is -C(O)NH(CH3). The compound of any one of the preceding claims, wherein R1 is -C(O)N(CH3)2. The compound of any one of the preceding claims, wherein R1 is -C(O)N(H)-CH2-CF3, -C(O)N(H)-(3-6 membered cycloalkyl), -C(O)N(H)-(cyclopropyl), -C(O)N(CH3)H, -C(O)N(CH3)2, -C(O)N(H)-CH2-CF3, ,,,,,.The compound of any one of the preceding claims, wherein R3 is hydrogen.The compound of any one of the preceding claims, wherein R3 is F.The compound of any one of the preceding claims, wherein R4 is hydrogen.The compound of any one of the preceding claims, wherein each x, x1 is independently 0.The compound of any one of the preceding claims, wherein each x, x1 is independently 1.The compound of any one of the preceding claims, wherein each x, x1 is independently 2.The compound of any one of the preceding claims, wherein each x, x1 is independently 3.The compound of any one of the preceding claims, wherein each Rs is independently halogen.The compound of any one of the preceding claims, wherein each Rs is independently F.The compound of any one of the preceding claims, wherein each Rs is independently R#.The compound of claim 35 or 36, wherein only one Rs is hydrogen.The compound of claim 35 or 36, wherein each Rs is not hydrogen.The compound of any one of the preceding claims, wherein each Rs is independently selected from C1-3 haloalkyl, R#; andtwo Rs are optionally and independently taken together to form a covalent bond, or:two or more Rs on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-8 membered ring having, in addition to the atom, 0-4 heteroatoms; or:two or more Rs on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms;R# is independently H, halogen, C1-6 aliphatic, C1-6 heteroaliphatic having 1-4 heteroatoms, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl having 1-4 heteroatoms, C5-8 aryl, 5-8 membered heteroaryl having 1-4 heteroatoms, and combinations thereof, wherein each combination independently has 1-8 carbon atoms and 0-4 heteroatoms.The compound of any one of the preceding claims, wherein each Rs is independently C1-6 aliphatic.The compound of any one of the preceding claims, wherein each Rs is independently C1-6 heteroaliphatic having 1-3 heteroatoms.The compound of any one of the preceding claims, wherein each Rs is independently C1-6 straight-chain alkyl.The compound of any one of the preceding claims, wherein each Rs is independently methyl.The compound of any one of the preceding claims, wherein each Rs is independently C1-3 haloalkyl.The compound of any one of the preceding claims, wherein each Rs is independently C1-3 alkoxyl.The compound of any one of the preceding claims, wherein each Rs is independently a 3-6 membered carbocyclic ring.The compound of any one of the preceding claims, wherein each Rs is independently a 3-6 membered cycloalkyl.The compound of any one of the preceding claims, wherein each Rs is independently a 3-6 membered heterocyclyl having 1-4 heteroatoms.The compound of any one of the preceding claims, wherein two or more Rs on the same atom are optionally taken together with their intervening atoms to form an optionally substituted, 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms.The compound of any one of the preceding claims, wherein two or more Rs on two or more atoms are optionally taken together with their intervening atoms to form an optionally substituted, 3-8 membered ring having, in addition to the intervening atoms, 0-4 heteroatoms.The compound of claim 52 or 53, wherein the ring is a 3-6 membered carbocyclic ring.The compound of claim 52 or 53, wherein the ring is a 3-6 membered cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl).The compound of claim 52 or 53, wherein the ring is a 3-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, sulfur, nitrogen. The compound of claim 52 or 53, wherein the ring is a 3-6 membered saturated heterocyclic ring having 1-3 heteroatoms independently selected from oxygen, sulfur, nitrogen (e.g., tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, piperidinyl, pyrrolinyl, etc.).A compound of Table C1-C4, or a pharmaceutically acceptable salt thereof.A compound, wherein the compound isor a salt thereof.A compound, wherein the compound is or a salt thereof.A compound, wherein the compound is or a salt thereof.A compound, wherein the compound isor a salt thereof.A compound, wherein the compound is or a salt thereof.A compound, wherein the compound is or a salt thereof.A compound, wherein the compound isor , or a salt thereof.A compound, wherein the compound is or a salt thereof.A compound, wherein the compound is or a salt thereof.A compound, wherein the compound is Compound 054 or a salt thereof, wherein Compound 054 is an enantiomer of , and wherein when Compound 054 is characterized by chiral HPLC, it elutes earlier than the other enantiomer, wherein the chiral HPLC comprises the following parameters (“Parameter Set 1”):the column is DAICEL CHIRALCEL® OD, size 4.6*150 mm, particle size 5 um;the mobile phase is a 10:90 (v / v) mixture of Mobile Phase A and Mobile Phase B, wherein Mobile Phase A is n-Hexane with 0.05% (e.g., v / v) DEA, and Mobile Phase B is EtOH with 0.05% (e.g., v / v) DEA;the follow rate is about 1.0 mL / min; andthe column temperature is 35 °C.A compound, wherein the compound is Compound 055 or a salt thereof, wherein Compound 055 is an enantiomer of , and wherein when Compound 055 is characterized by chiral HPLC, it elutes later than the other enantiomer, wherein the chiral HPLC comprises the following parameters (“Parameter Set 1”):the column is DAICEL CHIRALCEL® OD, size 4.6*150 mm, particle size 5 um;the mobile phase is a 10:90 (v / v) mixture of Mobile Phase A and Mobile Phase B, wherein Mobile Phase A is n-Hexane with 0.05% (e.g., v / v) DEA, and Mobile Phase B is EtOH with 0.05% (e.g., v / v) DEA;the follow rate is about 1.0 mL / min; andthe column temperature is 35 °C.The compound of any one of claims 1-67, wherein the compound comprises ,and the configuration of the chiral carbon in it is the same as that in Compound 054.The compound of any one of claims 1-67, wherein the compound comprises,and the configuration of the chiral carbon in it is the same as that in Compound 055.A compound, wherein the compound isor a salt thereof.A compound, wherein the compound isor a salt thereof.The compound of any one of claims 1-67, wherein is .The compound of any one of claims 1-67, wherein is .The compound of any one of the preceding claims, wherein the stereochemical purity of the compound is about or at least about 90%.A pharmaceutical composition comprising or delivering a compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.The composition of claim 77, wherein the stereochemical purity of the compound is about or at least about 90%.A method of degrading Proto-oncogene vav1 protein (VAV1) in a subject, comprising administering to the subject an effective amount of the compound of any one of claims 1-76 or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 77-78.The method of claim 77, wherein the compound mediates the interaction of a VAV1 protein with an E3 ligase, thereby increasing degradation of the VAV1 protein.The method of any of claims 79-80, wherein VAV1 is a regulator of a lymphocyte.The method of claim 81, wherein the lymphocyte is a T-cell.The method of claim 81, wherein the lymphocyte is a B-cell.The method of any of claims 79-83, wherein the compound interacts with the E3 ligase prior to the interaction of VAV1 with the E3 ligase.The method of any one of claims 80-84, wherein the E3 ligase comprises cereblon.A method of degrading Proto-oncogene vav 1 protein (VAV 1), comprising:(i) contacting the compound of any one of claims 1-76 or a pharmaceutically acceptable salt thereof with an E3 ligase, or a composition of any one of claims 77-78; and(ii) interacting the contacted E3 ligase with VAV1, thereby degrading VAV1.A method of treating a disorder caused by or associated with dysregulation of lymphocyte development or activation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-76 or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 77-78.The method of claim 87, wherein the lymphocyte is T-cell.The method of claim 87, where in the lymphocyte is B-cell.A method of treating a disorder caused by or associated with dysregulation of T-cell receptor signaling in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-76 or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 77-78.The method of claim 90, wherein the T-cell receptor signaling is IFNy, CD69, and / or IL-2.A method of treating a disorder caused by or associated with VAV1 polymorphisms in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-76 or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 77-78.A method of treating a disorder caused by or associated with immunopathology in a subj ect in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-76 or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 77-78.The method of claim 92 or 93, wherein the disorder is autoimmune disorder.The method of claim 94, wherein the autoimmune disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus, erythematosus. Hashimoto's thyroiditis, myasthenia gravis, diabetes type I or II, and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying aberrant reactions (e.g., inflammatory bowel disease, Crohn’s disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.The method of claim 92 or 93, wherein the disorder is a cancer, tumour or other malignancy, optionally wherein the disorder is a hematologic malignancy (e.g. T and B cell malignancy).The method of claim 92 or 93, wherein the disorder is selected from the group consisting of: leukemia, lymphoma, Acute myeloid leukemia (AML), T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK cell leukemia, hairy-cell leukemia, nasal and nasal-type NK / T cell lymphoma, mycosis fungoides and Sezary syndrome, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma unspecified, adult T-cell leukemia / lymphoma (HTLV1+), anaplastic large cell lymphoma, primary' cutaneous CD-30 positive T-cell lymphoproliferative disorders, cutaneous T-cell lymphoma, subcutaneous panniculitis like T-cell lymphoma, intestinal T-cell lymphoma (+enteropathy), hepatosplenic gamma / delta T-cell lymphoma, and non-Hodgkin lymphomas (e.g., B-cell non-Hodgkin lymphomas; e.g., Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma).The method of claim 92 or 93, wherein the disorder is selected from the group consisting of diabetes Type I or II, pernicious anemia, uveitis, psoriasis, alopecia areata, ulcerative colitis, Chron’s disease, atherosclerosis, myocarditis, pericarditis, pulmonary fibrosis, systemic sclerosis, morphea, Alzheimer’s disease, Acute Graft-vs. Host Disease or T-cell mediated kidney disease. The method of claim 92 or 93, wherein the disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, myasthenia gravis, Sjogren’s syndrome, Grave’s disease, an allergic disorder, an autoimmune liver disease, chronic inflammatory demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto’s thyroiditis, amyloidosis, inflammatory eye diseases, pemphigus, systemic lupus erythematosus, Chronic Graft vs. Host Disease, lupus nephritis, pulmonary' arterial hypertension or vasculitis.The method of any one of claim 92 or 93 and 99, wherein the disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, myasthenia gravis, Sjogren’s syndrome, Grave’s disease, asthma, allergic contact dermatitis, rhinitis, contact dermatitis, biliary' sclerosis, sclerosing cholangitis, chronic inflammatory' demyelinating polyradiculoneuropathy, macular degeneration, systemic lupus erythematosus, Hashimoto’s thyroiditis, amyloidosis, inflammatory eye diseases, pemphigus, systemic lupus erythematosus, Chronic Graft vs. Host Disease, lupus nephritis, pulmonary' arterial hypertension or vasculitis.The method of claim 92 or 93, wherein the disorder is selected from the group consisting of ulcerative colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, cutaneous lupus or axial spondylarthritis.The method of claim 92 or 93, wherein the disorder is selected from the group consisting of B-cell lymphoma, B-cell leukemia, T-cell lymphoma, T-cell leukemia or acute myeloid leukemia.The method of claim 92 or 93, wherein the disorder is ulcerative colitis.The method of claim 92 or 93, wherein the disorder is chronic lymphocytic leukemia.A method of treating an transplantation setting disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-76 or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 77-78.The method of claim 105, wherein the transplantation setting disease is selected from the group consisting of graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, graft vessel disease, graft atherosclerosis, and transplant coronary disease.A method of degrading proto-oncogene vav1 protein (VAV1) in a subject suffering from an autoimmune disease, or a transplantation setting disease, comprising administering to the subject an effective amount of the compound of any one of claims 1-76 or a pharmaceutically acceptable salt thereof, or a composition of any one of claims 77-78.The method of claim 107, wherein the autoimmune disorder is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, systemic lupus, erythematosus, Hashimoto’s thyroiditis, myasthenia gravis, diabetes type I or II, and the disorders associated therewith, vasculitis, pernicious anemia, Sjogren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases (e.g., allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis), inflammatory diseases optionally with underlying aberrant reactions (e.g., inflammatory bowel disease, Crohn’s disease or ulcerative colitis, intrinsic asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury), atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitis, seborrheic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis.The method of claim 107, wherein the transplantation setting disease is selected from the group consisting of graft-versus-host disease, chronic graft rejection, acute graft rejection, transplant vasculopathy, graft vessel disease, graft atherosclerosis, and transplant coronary disease.A method for characterizing a compound or composition, comprising utilizing chiral HPLC comprising one or more parameters in Parameter Set 1.A method for confirming identity of a compound or composition, comprising utilizing chiral HPLC comprising one or more parameters in Parameter Set 1.A method for identifying a compound or composition, comprising utilizing chiral HPLC comprising one or more parameters in Parameter Set 1.The method of any one of claims 110-112, wherein the compound or composition is a compound or composition of any one of claims 1-78.The method of any one of claims 110-112, wherein the compound is Compound 054 or a salt thereof, or composition comprises Compound 054 or a salt thereof.The method of any one of claims 110-112, wherein the compound is Compound 055 or a salt thereof, or composition comprises Compound 055 or a salt thereof.A method for assessing a composition, comprising utilizing chiral HPLC one or more parameters in Parameter Set 1.The method of claim 116, wherein enantiomeric purity of a compound is assessed.The method of claim 117, comprising releasing the composition if the enantiomeric purity is about or above a threshold (e.g., about 90%).The method of any one of claims 117-118, comprising rejecting the composition if the enantiomeric purity is below a threshold (e.g., about 90%).The method of any one of claims 117-119, wherein the composition is or comprises a preparation of a compound of any one of claims 1-75.The method of any one of claims 117-119, wherein the composition is or comprises a commercial batch of a compound of any one of claims 1-75.The method of any one of claims 120-121, wherein the compound is Compound 054 or a salt thereof.The method of any one of claims 120-121, wherein the compound is Compound 055 or a salt thereof.

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