Formulations for treating cancer

Abstract

The present disclosure relates to methods and compositions for the treatment of cancer.

Description

[0001] FORMULATIONS FOR TREATING CANCER

[0002] Background

[0003] The von Hippel-Lindau (VHL) protein is a subunit of the E3 ubiquitin ligase complexes. VHL is a popular E3 ligase being recruited by bifunctional compounds to induce ubiquitination and subsequent proteasomal degradation of a target protein. The present invention relates to useful formulations and methods for treatment of cancer using bifunctional compounds that comprise a VHL binding moiety.

[0004] Summary The present disclosure features solid dispersions of a compound and carrier, pharmaceutical compositions, and methods useful for treating cancer.

[0005] In one aspect, the present disclosure provides a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I:

[0006] A-L-B

[0007] Formula I, or a pharmaceutical salt thereof, wherein

[0008] A is a protein binding moiety;

[0009] B is the degradation moiety;

[0010] L is a linker;

[0011] A1is a bond between the linker and A; A2is a bond between B and the linker;

[0012] A has the structure of Formula II: optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alky ny I, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C6-C12 aryl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C1-C10 heteroalkyl, optionally wherein are C2-C10 heterocyclyl, C2-C6 heteroaryl, C6-C12 aryl, C3- © ( D ) may be joined to through one or more atoms;

[0013] (77 (77 optionally wherein if and ' are C2-C10 heterocyclyl, C2-C6 heteroaryl, C6-C12 aryl, C3-C10 cycloalkyl,

[0014] (77 ( 7 or C3-C10 carbocyclyl, then may be joined to ' — ' through one or more atoms; optionally wherein if are C2-C10 heterocyclyl, C2-C6 heteroaryl, C6-C12 aryl, C3-C10 cycloalkyl, or C3-C10

[0015] (77 (77 carbocyclyl, then ' — ' may be joined to ' — ' through one or more atoms; B has the structure of Formula III:

[0016] Formula III, wherein

[0017] Q is NR1R2, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, or optionally substituted C2-C6 heteroaryl, wherein the carbocyclyl, aryl, or heteroaryl is optionally substituted with A2and / or C1-C4 alkyl;

[0018] R1is, independently, H, A2, C(O)A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, or C(O)R1a, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;

[0019] R2is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, or C(O)R1a, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;

[0020] R3is, independently, A2, C(O)A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted Ce-C-io aryl;

[0021] R4is, independently, H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted Ce-C-io aryl;

[0022] R5is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[0023] R6is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce alkyl Ce-C-io aryl, or optionally substituted Ci-Ce alkyl C3-C10 heteroaryl; each R1ais, independently, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen, CN, or C1-C4 alkyl; and wherein one and only one of Q, R1, R2, R3, or R6comprises A2or C(O)A2; and wherein one and only one of ®, ® , ®, or ® comprises A1.

[0024] In some embodiments of any of the aspects described herein, the amorphous form of a compound of Formula I is substantially amorphous.

[0025] In some embodiments of any of the aspects described herein, a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I is an “amorphous solid dispersion” (ASD). In some embodiments of any of the aspects described herein, an amorphous solid dispersion (ASD) is a dispersion of an amorphous form of compound of Formula I , in a matrix that consists of at least one carrier. The matrix may also comprise polymers, surfactants or mixtures thereof.

[0026] In another aspect, the present disclosure provides a pharmaceutical composition comprising the solid dispersion of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0027] In another aspect, the present disclosure provides a pharmaceutical composition of a pharmaceutically acceptable carrier and a compound of Formula I:

[0028] A-L-B

[0029] Formula I, or a pharmaceutical salt thereof, wherein

[0030] A is a protein binding moiety;

[0031] B is the degradation moiety;

[0032] L is a linker;

[0033] A1is a bond between the linker and A;

[0034] A2is a bond between B and the linker;

[0035] A has the structure of Formula II: optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alky ny I, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C6-C12 aryl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C1-C10 heteroalkyl, optionally wherein if are C2-C10 heterocyclyl, C2-C6 heteroaryl, C6-C12 aryl, C3- ycloalkyl, or C3-C10 carbocyclyl, then may be joined to through one or more atoms; optionally wherein if are C2-C10 heterocyclyl, C2-C6 heteroaryl, C6-C12 aryl, C3-C10 cycloalkyl, or C3-C10

[0036] (T) ( ) carbocyclyl, then ' — ' may be joined to ' — ' through one or more atoms;

[0037] B has the structure of Formula III:

[0038] Formula III, wherein

[0039] Q is NR1R2, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, or optionally substituted C2-C6 heteroaryl, wherein the carbocyclyl, aryl, or heteroaryl is optionally substituted with A2and / or C1-C4 alkyl;

[0040] R1is, independently, H, A2, C(O)A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, or C(O)R1a, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;

[0041] R2is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, or C(O)R1a, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;

[0042] R3is, independently, A2, C(O)A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted Ce-C-io aryl;

[0043] R4is, independently, H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted Ce-C-io aryl;

[0044] R5is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[0045] R6is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce alkyl Ce-C-io aryl, or optionally substituted Ci-Ce alkyl C3-C10 heteroaryl; each R1ais, independently, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen, CN, or C1-C4 alkyl; and wherein one and only one of Q, R1, R2, R3, or R6comprises A2or C(O)A2; and wherein one and only one of ®, ® , ®, or ® comprises A1.

[0046] In another aspect, pharmaceutical composition of a pharmaceutically acceptable carrier and a compound of Formula I further comprises a pharmaceutically acceptable salt thereof.

[0047] In some embodiments of any of the aspects described herein, R9is H, optionally substituted Ci-Ce alkyl, or A2;

[0048] R10is H, optionally substituted Ci-Ce alkyl, or A2; each R11is, independently, halogen, A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, hydroxy, thiol; c is 0, 1 , 2, 3, or 4; and wherein if R6comprises A2or C(O)A2, then one and only one of R9, R10, or R11comprises A2.

[0049] In some embodiments, A is wherein each E1is, independently, CRE1, O, or NRE2; each F1is, independently, CRF1, O, or NRF2; each RE1is, independently, H, A1, halogen, CN, NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, amino, hydroxy, thiol, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A1and / or halogen or C1-C4 alkyl; each RE2is, independently, absent, H, A1, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A1and / or halogen or C1-C4 alkyl; each RF1is, independently, H, A1, halogen, CN, NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, amino, hydroxy, thiol, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A1and / or halogen or C1-C4 alkyl; each RF2is, independently, absent, H, A1, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A1 and / or halogen or C1-C4 alkyl; d is 0, 1 , 2, or 3; e is 0, 1 , 2, or 3; wherein one and only one of E1, F1, RE1, RE2, RF1, or RF2comprises A1.

[0050] In some embodiments of any of the aspects described herein,

[0051] In some embodiments of any of the aspects described herein, A is

[0052] In some embodiments of any of the aspects described herein, In some embodiments of any of the aspects described herein, A is In some embodiments of any of the aspects described herein, A is

[0053] In some embodiments of any of the aspects described herein, A is In some embodiments of any of the aspects described herein,

[0054] In some embodiments of any of the aspects described herein,

[0055] In some embodiments of any of the aspects described herein,

[0056] In some embodiments of any of the aspects described herein,

[0057] In some embodiments of any of the aspects described herein, A is

[0058] In some embodiments of any of the aspects described herein, A is In some embodiments of any of the aspects described herein, A is wherein each E2is, independently, CRE3, O, or NRE4; each F1is, independently, CRF3, O, or NRF4; each RE3is, independently, H, halogen, CN, NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, amino, hydroxy, thiol, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with halogen or C1-C4 alkyl; each RE4is, independently, absent, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with halogen or C1-C4 alkyl; each RF3is, independently, H, halogen, CN, NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, amino, hydroxy, thiol, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with halogen or C1-C4 alkyl; each RF4is, independently, absent, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A1 and / or halogen or C1-C4 alkyl;

[0059] RF3bis optionally substituted Ci-Ce heteroalkyl;

[0060] RF3cis H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, or optionally substituted C2-C9 heteroaryl;

[0061] RF3dis optionally substituted Ci-Ce alkyl;

[0062] RF3eis H or optionally substituted Ci-Ce alkyl; and

[0063] RF3fis H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, or optionally substituted C2-C9 heteroaryl; and

[0064] K is C or N; and q is 0, 1 , 2, 3, 4, or 5; r is O, 1 , or 2. In some embodiments of any of the aspects described herein, A is

[0065] In some embodiments of any of the aspects described herein, A is wherein

[0066] C1is CRC3or N;

[0067] C2is CRC3or N;

[0068] D1is optionally substituted C2-C9 heteroaryl;

[0069] E3is optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl;

[0070] RC1is hydrogen, A1, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[0071] RC2is hydrogen, A1, NH2, optionally substituted Ci-Ce alkyl; each RC3is, independently, A1, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci- Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, or optionally substituted C2-C9 heteroaryl;

[0072] RD1is A1, hydrogen, acyl, oxo, thiol, CN, acyl, hydroxy, amino, thiol, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, or optionally substituted C2-C9 heteroaryl;

[0073] RE5is A1, hydrogen, acyl, oxo, thiol, CN, acyl, hydroxy, amino, thiol, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted C2-C9 heteroaryl; each s is, independently 0, 1 , 2, or 3.

[0074] In some embodiments of any of the aspects described herein, A is wherein each RD4is, independently, absent, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with halogen or C1-C4 alkyl; and

[0075] RE6is, independently, H, halogen, CN, NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, amino, hydroxy, thiol, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with halogen or C1-C4 alkyl. In some embodiments of any of the aspects described herein, A is

[0076] In some embodiments of any of the aspects described herein,

[0077] In some embodiments of any of the aspects described herein, A is

[0078] In some embodiments of any of the aspects described herein, A is In some embodiments of any of the aspects described herein,

[0079] 5 In some embodiments of any of the aspects described herein,

[0080] In some embodiments of any of the aspects described herein,

[0081] In some embodiments of any of the aspects described herein,

[0082]

[0083] In some embodiments of any of the aspects described herein, B is

[0084] derivative or analog thereof. In some embodiments of any of the aspects described herein, B is In some embodiments of any of the aspects described herein, B is

[0085] In some embodiments of any of the aspects described herein, L has the structure of

[0086] Formula IV:

[0087] A1-(B1)f-(C1a)g-(B2)h-(D1a)-(B3)r(C2a)r(B4)k-A2,

[0088] Formula IV or a pharmaceutically acceptable salt thereof, wherein

[0089] A1is a bond between the linker and A;

[0090] A2is a bond between Formula III and the linker; each of B1, B2, B3, and B4is, independently, optionally substituted C1-C4 alkyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C6-12 aryl, O, S, S(O)2, or NRN; each RNis, independently, H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alky ny I, optionally substituted C2-10 heterocyclyl, optionally substituted C2-6 heteroaryl, or optionally substituted C1-7 heteroalkyl; each of C1aand C2ais, independently, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; each of f, g, h, i, j, and k is, independently, 0 or 1 ; and

[0091] D1ais optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alky ny I, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C6-C12 aryl, optionally substituted C2-C10 polyethylene glycol, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C1-C10 heteroalkyl; or D is absent, and the linker is A1-(B1)f-(C1a)g-(B2)h-(B3)r(C2a)r(B4)k-A2.

[0092] In some embodiments of any of the aspects described herein, L has the structure of Formula V: A1-G-(H)-(J)i-G-A2,

[0093] Formula V wherein

[0094] A1is a bond between the linker and A;

[0095] A2is a bond between Formula III and the linker; I is 0 or 1 ; each G is, independently, absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl;

[0096] J is absent, O, S, NRN, optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C2-C10 polyethylene glycol, optionally substituted C1-C10 heteroalkylene, optionally substituted C2-io carboocyclylene, or optionally substituted C2-C10 heterocyclylene; each RNis, independently, H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alky ny I, optionally substituted C2-6 heterocyclylene, optionally substituted C6-12 aryl, or optionally substituted C1-7 heteroalkyl; and H is optionally substituted C3-C10 carbocyclylene, optionally substituted C2-12 heterocyclylene, optionally substituted Ce-C-io arylene, or optionally substituted C2-C9 heteroarylene.

[0097] In some embodiments of any of the aspects described herein, L is absent.

[0098] In some embodiments of any of the aspects described herein, the compound of Formula I is a compound of Table 1. Table 1 . Compounds

[0099]

[0100]

[0101]

[0102]

[0103] In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is a compound having the structure of Formula IA:

[0104] Formula IA wherein

[0105] Xi is absent, H, or OH (H and OH only when m is 0);

[0106] X2 is absent or O;

[0107] X3is O or CR4bR5b;

[0108] R2bis H or R2band R3bcombine to form C=O;

[0109] R3bis H, hydroxy, or optionally substituted heterocycle;

[0110] R4bis H, methyl, or OH;

[0111] R5band R6bis H or methyl, or R5band R6bare C=O;

[0112] R7bis absent, H, or OH; m is 0 or 1 ; n is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15;

[0113] 0 is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20; and p is 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or 28.

[0114] In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is a compound having the structure of Formula Ila:

[0115] each of R8b, R9b, and R10bis, individually, H or

[0116] 5 In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is a compound having the structure of Formula lib: each of R8b, R9b, and R10bis, individually, H or

[0117] In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is a compound having the structure of Formula He: each of R8b, R9b, and R10bis, individually,

[0118] In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is a polymer. Polymers include, but are not limited to: polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, and hydroxypropyl cellulose. Examples of polymers include ethylene vinyl acetate, poly(meth) acrylic acid, polyamides, copolymers and mixtures thereof. Examples of polymers include synthetic polymers such as polymers of lactic acid and glycolic acid, poly-anhydrides, polyurethanes, and natural polymers such as alginate and other polysaccharides including dextran and cellulose, collagen, albumin and other proteins, copolymers and mixtures thereof. These polymers may be used alone, as physical mixtures (blends), or as co-polymers.

[0119] In some embodiments, the pharmaceutically acceptable carrier is polyethylene glycol,

[0120] Polyvinylpyrrolidone, poly lactic-co-glycolic acid, poly vinyl alcohol, phospholipids, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, 1 ,2-Distearoyl-sn-glycero-3- phosphocholine, polymethacrylates, polyvinyl acetate, cellulose derivatives, glyceryl behenate, polyethyleneglycol derivatives of a mono-glyceride, vitamin E, polyethylene or polyoxyethylene esters of hydroxyl stearic acid, polyoxylglycerides, polyethoxylated castor oil or combinations thereof. In some embodiments of any of the aspects described herein, the carrier is a polymer. In some embodiments of any of the aspects described herein, the polymer is poly (urethane), poly(siloxane), poly(silicone), poly(methyl methacrylate), poly(vinyl alcohol), poly(ethylene), poly(vinyl pyrrolidone), poly(2-hydroxy ethyl methacrylate), poly(N-vinyl pyrrolidone), poly(methyl methacrylate), poly(vinyl alcohol), poly(acrylic acid), polyacrylamide, poly(ethylene-co-vinyl acetate), poly(ethylene glycol), poly(methacrylic acid), polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), polyanhydrides, polyorthoester, and / or a combination thereof.

[0121] In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is poly(vinyl alcohol) (PVA). In some embodiments of any of the aspects described herein, the formulation comprises in situ PLGA gel. In some embodiments of any of the aspects described herein, the formulation comprises a PLGA ratio of lactic acid to glycolic acid. In some embodiments of any of the aspects described herein, the PLGA ratio is 50% lactic acid to 50% glycolic acid. In some embodiments of any of the aspects described herein, the PLGA ratio is 65% lactic acid to 35% glycolic acid. In some embodiments of any of the aspects described herein, the PLGA ratio is 75% lactic acid to 25% glycolic acid. In some embodiments of any of the aspects described herein, the PLGA ratio is 85% lactic acid to 15% glycolic acid. In some embodiments of any of the aspects described herein, the formulation comprises between about 80 mg and about 900 mg of PLGA per g of formulation. In some embodiments of any of the aspects described herein, the formulation comprises between about 80 mg and about 200 mg of PLGA per g of formulation. In some embodiments of any of the aspects described herein, the PLGA has an ester N-terminus. In some embodiments of any of the aspects described herein, the PLGA has an acid N-terminus. In some embodiments of any of the aspects described herein, the formulation comprises between about 1 mg and about 250 mg of PLGA per g of formulation. In some embodiments of any of the aspects described herein, the formulation comprises between about 1 mg and about 100 mg of PLGA per g of formulation. In some embodiments of any of the aspects described herein, the formulation comprises between about 1 mg and about 75 mg of PLGA per g of formulation. In some embodiments of any of the aspects described herein, the formulation comprises between about 1 mg and about 50 mg of PLGA per g of formulation.

[0122] In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is a polymer. In some embodiments of any of the aspects described herein, the polymer is poly(urethane), poly(siloxane), poly(silicone), poly(methyl methacrylate), poly(vinyl alcohol), poly(ethylene), poly(vinyl pyrrolidone), poly(2-hydroxy ethyl methacrylate), poly(N-vinyl pyrrolidone), poly(methyl methacrylate), poly(vinyl alcohol), poly(acrylic acid), polyacrylamide, poly(ethylene-co-vinyl acetate), poly(ethylene glycol), poly(methacrylic acid), polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), polyanhydrides, polyorthoester, and / or a combination thereof.

[0123] In some embodiments of any of the aspects described herein, the formulation comprises poly (lactic-co-glycolic) acid (PLGA) microspheres. In some embodiments of any of the aspects described herein, the PLGA microspheres are between about 1 and about 100 pm in size. In some embodiments of any of the aspects described herein, the PLGA microspheres are between about 5 and about 100 pm in size. In some embodiments of any of the aspects described herein, the PLGA microspheres are between about 5 and about 10 pm in size. In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is polyethylene glycol (PEG). In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is Polyvinylpyrrolidone. In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is alpha cyclodextrin. In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is beta cyclodextrin. In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is gamma cyclodextrin. In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is sulfobutylether-p-cyclodextrin.

[0124] In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is poly(lactic-co-glycolic) acid (PLGA). In some embodiments, the poly(lactic-co-glycolic) acid (PLGA) is PLGA 85:15. In some embodiments, the poly(lactic-co-glycolic) acid (PLGA) is PLGA 75:25. In some embodiments, the poly(lactic-co-glycolic) acid (PLGA) is PLGA 60:40. In some embodiments, the poly(lactic-co-glycolic) acid (PLGA) is PLGA 50:50. In some embodiments, poly(lactic-co-glycolic) acid (PLGA) is PLGA 10:90.

[0125] In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is Polyvinylpyrrolidone PVP K30. Iln some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is Polyvinylpyrrolidone PVP K13. Iln some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is Polyvinylpyrrolidone PVP K25. In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is Polyvinylpyrrolidone PVP K15. In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is Polyvinylpyrrolidone PVP K12.ln some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is albumin. In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is polyvinyl alcohol (PVA).ln some embodiments, the pharmaceutically acceptable carrier is a mixture of Polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG). In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is dipalmitoylphosphatidylcholine (DPPC). In some embodiments, the pharmaceutically acceptable carrier is 1 ,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC).

[0126] In some embodiments of any of the aspects described herein, the pharmaceutically acceptable carrier is a mixture of any two of the following carriers: polyethylene glycol, Polyvinylpyrrolidone, poly lactic-co-glycolic acid, poly vinyl alcohol, phospholipids, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, 1 ,2-Distearoyl-sn-glycero-3-phosphocholine, polymethacrylates, polyvinyl acetate, cellulose derivatives, glyceryl behenate, polyethyleneglycol derivatives of a mono-glyceride, vitamin E, polyethylene or polyoxyethylene esters of hydroxyl stearic acid, polyoxylglycerides, or polyethoxylated castor oil. In some embodiments, the pharmaceutically acceptable carrier is a mixture of polyethylene glycol, and poly lactic-co-glycolic acid. In some embodiments, the pharmaceutically acceptable carrier is a mixture of Polyvinylpyrrolidone, and poly lactic-co-glycolic acid. In some embodiments, the pharmaceutically acceptable carrier is a mixture of poly vinyl alcohol, and polyethoxylated castor oil. In some embodiments, the pharmaceutically acceptable carrier is a mixture of polyethylene glycol (PEG), and polyethoxylated castor oil.

[0127] In some embodiments of any of the aspects described herein, the solid dispersion of a pharmaceutically acceptable carrier and the amorphous form of a compound of Formula I or a pharmaceutical salt thereof, further comprises an excipient. In some embodiments of any of the aspects described herein, the excipient includes a solvent, a diluent, a granulating agent, a dispersing agent, a surfactant, an emulsifier, a stabilizer, a polymer, a binding agent, a preservative, a cryoprotectant, a buffering agent, a lubricating agent, an oil, or a combination thereof. In some embodiments of any of the aspects described herein, the surfactant is polysorbate (e.g., polysorbate 20, or polysorbate 80), polaxamer (e.g., Poloxamer 188, or Poloxamer 407 / Pluronic 127), TWEEN (e.g., TWEEN 20, TWEEN 80). In some embodiments of any of the aspects described herein, the excipient is a solvent. In some embodiments of any of the aspects described herein, the solvent is water, dichloromethane, dimethyl sulfoxide, dimethyl formamide, ethyl acetate, methyl ethyl ketone, tetrahydrofuran, ethyl benzoate, chlorobenzene, benzyl alcohol, methyl n-propyl ketone, n-butyl acetate, trichloroethylene, ethyl-L-lactate, 2-methyl tetra hydrofuran, 1 ,2-dichlorobenzene, toluene, methyl isobutyl ketone, butyl lactate, p-xylene, acetone, methanol, dichloromethane, or a combination thereof. In some embodiments of any of the aspects described herein, the excipient is a diluent. In some embodiments of any of the aspects described herein, the diluent is calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, or a combination thereof.

[0128] In another aspect, a solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 15 percent to about 85 percent by weight of the solid dispersion; and a pharmaceutically acceptable carrier in an amount of about 15 percent to about 85 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 25 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 15 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 49 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 40 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 45 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 60 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 75 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 85 percent by weight of the solid dispersion. In certain embodiments, the solid dispersion comprises the amorphous form of a compound of Formula I in an amount of about 15 percent to about 85 percent (e.g., about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, or about 85%) by weight of the solid dispersion. In certain embodiments, the solid dispersion comprises the pharmaceutically acceptable carrier in an amount of about 15 percent to about 85 percent (e.g., about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, or about 85%) by weight of the solid dispersion. For example, in one embodiment, the solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the solid dispersion, and the pharmaceutically acceptable carrier in an amount of about 50 percent by weight of the solid dispersion. For example, in one embodiment, the solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the solid dispersion, and PVP K12, the pharmaceutically acceptable carrier, in an amount of about 50 percent by weight of the solid dispersion.

[0129] In some embodiments, the pharmaceutical composition is suspended in a vehicle prior to administration. In some embodiments, the vehicle further comprises a surfactant. In some embodiments, the vehicle comprises the surfactant in an amount of about 0.1 to about 25 percent (e.g., about 0.1%, about 0.2%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%) by weight of the pharmaceutical composition. In some embodiments, the vehicle comprises the surfactant in an amount of about 0.2 percent by weight of the pharmaceutical composition. In some embodiments, the vehicle comprises the surfactant in an amount of about 0.5 percent by weight of the pharmaceutical composition. In some embodiments, the vehicle comprises the surfactant in an amount of about 20 percent by weight of the pharmaceutical composition. In some embodiments, the vehicle is saline. In some embodiments, the vehicle is saline and TWEEN. In some embodiments, the vehicle is saline and 0.2% TWEEN 20. In some embodiments of any of the aspects described herein, saline is normal saline.

[0130] In another aspect, a pharmaceutical composition comprises an amorphous form of a compound of Formula I , in an amount of about 15 percent to about 85 percent by weight of the pharmaceutical composition; and a pharmaceutically acceptable carrier in an amount of about 15 percent to about 85 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises an amorphous form of a compound of Formula I, in an amount of about 25 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises an amorphous form of a compound of Formula I, in an amount of about 15 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises an amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises an amorphous form of a compound of Formula I, in an amount of about 49 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises an amorphous form of a compound of Formula I, in an amount of about 40 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises an amorphous form of a compound of Formula I, in an amount of about 45 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises an amorphous form of a compound of Formula I, in an amount of about 60 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises an amorphous form of a compound of Formula I, in an amount of about 75 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises an amorphous form of a compound of Formula I, in an amount of about 85 percent by weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises the amorphous form of a compound of Formula I in an amount of about 15 percent to about 85 percent (e.g., about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, or about 85%) by weight of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises the pharmaceutically acceptable carrier in an amount of about 15 percent to about 85 percent (e.g., about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, or about 85%) by weight of the pharmaceutical composition. For example, in one embodiment, the pharmaceutical composition comprises an amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the pharmaceutical composition, and the pharmaceutically acceptable carrier in an amount of about 50 percent by weight of the pharmaceutical composition. For example, in one embodiment, the pharmaceutical composition comprises an amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the pharmaceutical composition, and PVP K12, the pharmaceutically acceptable carrier, in an amount of about 50 percent by weight of the pharmaceutical composition.

[0131] In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, in an amount of about 25 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, in an amount of about 15 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, in an amount of about 50 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, in an amount of about 49 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, in an amount of about 40 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, in an amount of about 45 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, in an amount of about 60 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, in an amount of about 75 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, in an amount of about 85 percent by weight of the pharmaceutical composition.

[0132] In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 1 pm and 25 pm. In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 5 pm and 25 pm. In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 10 pm and 25 pm. In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 15 pm and 25 pm. In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 20 pm and 25 pm. In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 1 pm and 5 pm. In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 1 pm and 10 pm. In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 1 pm and 15 pm. In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 1 pm and 20 pm. In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 5 pm and 20 pm. In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 5 pm and 15 pm. In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 5 pm and 10 pm. In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 10 pm and 15 pm. In some embodiments of any of the aspects described herein, the pharmaceutical composition further comprises a particle size of between 10 pm and 20 pm.

[0133] In some embodiments, the solid dispersion of a pharmaceutically acceptable carrier and the amorphous form of a compound of Formula I or a pharmaceutical salt thereof, further comprises a surfactant. In some embodiments, the solid dispersion of a pharmaceutically acceptable carrier and the amorphous form of a compound of Formula I or a pharmaceutical salt thereof, further comprises a surfactant. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprising the solid dispersion of a pharmaceutically acceptable carrier and a compound of Formula I or a pharmaceutically acceptable salt thereof, further comprises a surfactant. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula I or a pharmaceutically acceptable salt thereof, further comprises a surfactant. In some embodiments of any of the aspects described herein, the surfactant is sodium dodecyl sulfate, phospholipids (e.g., lecithin), quaternary ammonium salts (e.g., cetrimonium bromide), pyridinium salts (e.g., cetylpyridinium chloride), fatty acid salts, poloxamers, poloxamines, polysorbates, fatty acid esters of sorbitan, polyethylene glycol alkyl ethers, fatty acid esters of polyethylene glycol, alkyl polyglycosides (e.g., alkyl polyglucosides), cyclodextrins, and fatty acid monoglycerides (e.g., monolaurin). In some embodiments of any of the aspects described herein, the surfactant is polysorbate (e.g., polysorbate 20, or polysorbate 80), polaxamer (e.g., Poloxamer 188, or Poloxamer 407 / Pluronic 127), TWEEN (e.g., TWEEN 20, TWEEN 80). In another aspect, a solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 15 percent to about 85 percent by weight of the solid dispersion; a pharmaceutically acceptable carrier in an amount of about 15 percent to about 85 percent by weight of the solid dispersion, and a surfactant in an amount of about 0.1 percent to about 25 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises the surfactant, in an amount of about 2.5 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises the surfactant, in an amount of about 1.5 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises the surfactant, in an amount of about 5 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises the surfactant, in an amount of about 2 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises the surfactant in an amount of about 4 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises the surfactant, in an amount of about 4.5 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises the surfactant, in an amount of about 6 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises the surfactant, in an amount of about 7.5 percent by weight of the solid dispersion. In some embodiments of any of the aspects described herein, the solid dispersion comprises the surfactant, in an amount of about 85 percent by weight of the solid dispersion. In certain embodiments, the solid dispersion comprises the amorphous form of a compound of Formula I in an amount of about 15 percent to about 85 percent (e.g., about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, or about 85%) by weight of the solid dispersion. In certain embodiments, the solid dispersion comprises the pharmaceutically acceptable carrier in an amount of about 15 percent to about 85 percent (e.g., about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, or about 85%) by weight of the solid dispersion. In certain embodiments, the solid dispersion comprises the surfactant, in an amount of about 0.1 percent to about 25 percent (e.g., about 0.1%, about 0.2%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%,) by weight of the solid dispersion. For example, in one embodiment, the solid dispersion comprises an amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the solid dispersion, and the pharmaceutically acceptable carrier in an amount of about 50 percent by weight of the solid dispersion. For example, in one embodiment, the solid dispersion comprises the amorphous form of a compound of Formula I, in an amount of about 49 percent by weight of the solid dispersion, and the pharmaceutically acceptable carrier in an amount of about 49 percent by weight of the solid dispersion, and the surfactant in an amount of about 2 percent by weight of the solid dispersion. For example, in one embodiment, the solid dispersion comprises the amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the solid dispersion, PVP K12, the pharmaceutically acceptable carrier, in an amount of about 50 percent by weight of the solid dispersion, and polysorbate 20, the surfactant, in an amount of about 2 percent by weight of the solid dispersion.

[0134] In some embodiments of any of the aspects described herein, the surfactant is a compound having the structure: wherein each of t, u, v, and w are, independently, a whole number from 1 to 17, wherein the sum of t, u, v, and w = 20;

[0135] R11 b= (CH2)x(CH = CH)y(CH2)zCH3; x = 1 , 2, 3, 4, or 5; y = 0 or 1 ; and z = 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12.

[0136] In some embodiments of any of the aspects described herein, the surfactant is a compound having the structure: wherein a = 2-130; and b = 15-67.

[0137] In some embodiments of any of the aspects described herein, the surfactant is a compound having the structure:

[0138] In some embodiments of any of the aspects described herein, the surfactant is polysorbate. In some embodiments of any of the aspects described herein, the surfactant is polysorbate 20. In some embodiments of any of the aspects described herein, the surfactant is polysorbate 80. In some embodiments of any of the aspects described herein, the surfactant is poloxamer. In some embodiments of any of the aspects described herein, the poloxamer is Poloxamer 188. In some embodiments of any of the aspects described herein, the poloxamer is Poloxamer 407 / Pluronic 127. In some embodiments of any of the aspects described herein, the pharmaceutically acceptable surfactant is POLOXAMERO188 (P-188). In some embodiments of any of the aspects described herein, the pharmaceutically acceptable surfactant is POLOXAMERO407 (P-407). In some embodiments of any of the aspects described herein, the surfactant is TWEEN. In some embodiments of any of the aspects described herein, the surfactant is TWEEN 20. In some embodiments of any of the aspects described herein, the surfactant is TWEEN 80. In some embodiments of any of the aspects described herein, the surfactant is solutol. In some embodiments of any of the aspects described herein, the surfactant is Kolliphor EL. In some embodiments of any of the aspects described herein, the surfactant is Cremphor EL. In some embodiments of any of the aspects described herein, the surfactant is Sodium taurocholate. In some embodiments of any of the aspects described herein, the surfactant is Brij 97. In some embodiments of any of the aspects described herein, the surfactant is Tyloxapol.

[0139] In another aspect, a pharmaceutical composition comprises an amorphous form of a compound of Formula I, in an amount of about 15 percent to about 85 percent (e.g., about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, or about 85%) by weight of the pharmaceutical composition; a pharmaceutically acceptable carrier in an amount of about 15 percent to about 85 percent (e.g., about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, or about 85%) by weight of the pharmaceutical composition, and a surfactant in an amount of about 0.1 percent to about 25 percent (e.g., about 0.1%, about 0.2%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%) by weight of the pharmaceutical composition. For example, in one embodiment, the pharmaceutical composition comprises an amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the pharmaceutical composition, and the pharmaceutically acceptable carrier in an amount of about 50 percent by weight of the pharmaceutical composition. For example, in one embodiment, the pharmaceutical composition comprises the amorphous form of a compound of Formula I, in an amount of about 49 percent by weight of the pharmaceutical composition, and the pharmaceutically acceptable carrier in an amount of about 49 percent by weight of the pharmaceutical composition, and the surfactant in an amount of about 2 percent by weight of the pharmaceutical composition. For example, in one embodiment, the pharmaceutical composition comprises the amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the pharmaceutical composition, PVP K12, the pharmaceutically acceptable carrier, in an amount of about 50 percent by weight of the pharmaceutical composition, and polysorbate 20, the surfactant, in an amount of about 2 percent by weight of the pharmaceutical composition.

[0140] In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises the surfactant in an amount of about 0.1 to about 25 percent (e.g., about 0.1%, about 0.2%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1 .5%, about 2.0%, about 2.5%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%,) by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises the surfactant in an amount of about 1 to about 5 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises the surfactant in an amount of about 1 to about 2 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises the surfactant in an amount of about 5 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises the surfactant in an amount of about 7.5 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises the surfactant in an amount of about 2.5 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises the surfactant in an amount of about 1 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises the surfactant in an amount of about 1 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises the surfactant in an amount of about 2 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises the surfactant in an amount of about 10 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises the surfactant in an amount of about 15 percent by weight of the pharmaceutical composition. In some embodiments of any of the aspects described herein, the pharmaceutical composition comprises the surfactant in an amount of about 12.5 percent by weight of the pharmaceutical composition.

[0141] In some embodiments of any of the aspects described herein, the compound of Formula I reduces the level and / or activity of a protein.

[0142] In some embodiments of any of the aspects described herein, the pharmaceutical composition reduces the level and / or activity of a protein.

[0143] In another aspect, the present disclosure provides a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier, and an amorphous form of a compound of Formula I and a surfactant. In some embodiments of any of the aspects described herein, the amorphous form of a compound of Formula I and a surfactant are combined prior to spray-drying. In some embodiments of any of the aspects described herein, the surfactant-inclusive pharmaceutical composition reduces the level and / or activity of a protein.

[0144] In another aspect, the present disclosure provides a surfactant-inclusive pharmaceutical composition of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, and a surfactant. In some embodiments of any of the aspects described herein, the surfactant-inclusive pharmaceutical composition reduces the level and / or activity of a protein.

[0145] In another aspect, the present disclosure provides a surfactant-inclusive pharmaceutical composition of a pharmaceutically acceptable carrier and a compound of Formula I, and a surfactant. In some embodiments of any of the aspects described herein, the surfactant-inclusive pharmaceutical composition reduces the level and / or activity of a protein.

[0146] In some embodiments of any of the aspects described herein, the surfactant-inclusive pharmaceutical composition comprises a surfactant. In some embodiments, the surfactant is sodium dodecyl sulfate, phospholipids (e.g., lecithin), quaternary ammonium salts (e.g., cetrimonium bromide), pyridinium salts (e.g., cetylpyridinium chloride), fatty acid salts, poloxamers, poloxamines, polysorbates, fatty acid esters of sorbitan, polyethylene glycol alkyl ethers, fatty acid esters of polyethylene glycol, alkyl polyglycosides (e.g., alkyl polyglucosides), cyclodextrins, and fatty acid monoglycerides (e.g., monolaurin). In some embodiments of any of the aspects described herein, the surfactant is polysorbate. In some embodiments of any of the aspects described herein, the surfactant is polysorbate 20. In some embodiments of any of the aspects described herein, the surfactant is polysorbate 80. In some embodiments of any of the aspects described herein, the surfactant is poloxamer. In some embodiments of any of the aspects described herein, the poloxamer is Poloxamer 188. In some embodiments of any of the aspects described herein, the poloxamer is Poloxamer 407 / Pluronic 127. In some embodiments of any of the aspects described herein, the surfactant is TWEEN. In some embodiments of any of the aspects described herein, the surfactant is TWEEN 20. In some embodiments of any of the aspects described herein, the surfactant is TWEEN 80. In some embodiments of any of the aspects described herein, the surfactant is solutol. In some embodiments of any of the aspects described herein, the surfactant is cyclodextrin. In some embodiments of any of the aspects described herein, the surfactant is alpha cyclodextrin. In some embodiments of any of the aspects described herein, the surfactant is beta cyclodextrin. In some embodiments of any of the aspects described herein, the surfactant is gamma cyclodextrin. In some embodiments of any of the aspects described herein, the surfactant is sulfobutylether-p-cyclodextrin.

[0147] In some embodiments of any of the aspects described herein, the surfactant-inclusive pharmaceutical composition further comprises PVP K12. In some embodiments of any of the aspects described herein, the amorphous form of a compound of Formula I is suspended in a vehicle prior to administration. In some embodiments, the vehicle is saline and TWEEN 20. In some embodiments of any of the aspects described herein, the surfactant-inclusive pharmaceutical composition is administered intramuscularly. In some embodiments of any of the aspects described herein, the surfactant-inclusive pharmaceutical composition is administered subcutaneously.

[0148] In another aspect, the present disclosure provides a kit comprising: a) the surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, and a surfactant in one vial, and b) a vehicle in a separate vial. In some embodiments, the vehicle is saline and TWEEN 20. In some embodiments, the surfactant- inclusive pharmaceutical composition and the vehicle are mixed to form a solution, and administering the resulting solution. In some embodiments, the resulting solution from the kit is administered intramuscularly. In some embodiments, the resulting solution from the kit is administered subcutaneously.

[0149] In another aspect, the invention features a method of decreasing the levels and / or activity of BRG1 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof. In another aspect, the invention features a method of decreasing the levels and / or activity of BRM in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0150] In another aspect, the invention features a method of decreasing the levels and / or activity of BRG1 and / or BRM in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof. In another aspect, the invention features a method of decreasing the levels of or activity of a MYC in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical composition thereof.

[0151] In another aspect, the invention features a method of decreasing the levels of or activity of an AR, i.e. androgen receptor, in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical composition thereof.

[0152] In some embodiments, the cell is a cancer cell.

[0153] In another aspect, the invention features a method of decreasing the levels and / or activity of a CBP in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0154] In another aspect, the invention features a method of decreasing the levels and / or activity of a EP300 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0155] In another aspect, the invention features a method of decreasing the levels and / or activity of a BRD9 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0156] In another aspect, the invention features a method of decreasing the levels and / or activity of an estrogen receptor in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0157] In another aspect, the invention features a method of decreasing the levels and / or activity of a IRAK4 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0158] In another aspect, the invention features a method of decreasing the levels and / or activity of IRAK4 and / or IMiD in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0159] In another aspect, the invention features a method of decreasing the levels and / or activity of a STAT3 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0160] In another aspect, the invention features a method of decreasing the levels and / or activity of a MDM2 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0161] In another aspect, the invention features a method of decreasing the levels and / or activity of a BCLXL in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof. In another aspect, the invention features a method of decreasing the levels and / or activity of a BTK in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0162] In another aspect, the invention features a method of decreasing the levels and / or activity of BTK and / or IMiD in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0163] In another aspect, the invention features a method of decreasing the levels and / or activity of a TRK in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0164] In another aspect, the invention features a method of decreasing the levels and / or activity of a IKZF1 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0165] In another aspect, the invention features a method of decreasing the levels and / or activity of a IKZF3 in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0166] In another aspect, the invention features a method of decreasing the levels and / or activity of a BRAF V600x in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0167] In another aspect, the invention features a method of decreasing the levels and / or activity of an EGFR L858R in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof. In another aspect, the invention features a method of inducing apoptosis in a cell, the method involving contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical composition thereof.

[0168] In a further aspect, the invention features a method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical composition thereof.

[0169] In some embodiments of any of the aspects described herein, the method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, and a surfactant, that reduces the level and / or activity of a protein.

[0170] In some embodiments of any of the aspects described herein, the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myelofibrosis, lymphoma, leukemia, esophageal, stomach, or lung cancer. In some embodiments of any of the aspects described herein, the cancer is gastric cancer. In some embodiments of any of the aspects described herein, the cancer is metastatic. In some embodiments of any of the aspects described herein, the method further comprises administering to the subject an anticancer therapy. In some embodiments of any of the aspects described herein, the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof.

[0171] In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, head and neck cancer, gastric cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, neuroblastoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma). In some embodiments, the sarcoma is synovial sarcoma.

[0172] In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, head and neck cancer, prostate cancer, acute leukemia, gastric cancer, or breast cancer.

[0173] In some embodiments, the cancer is gastric cancer.

[0174] In some embodiments, the breast cancer is found to be ER positive i.e. the cancer cells contain estrogen receptors.

[0175] In some embodiments, the breast cancer is found to be ER negative i.e. cancer cells do not contain estrogen receptors.

[0176] In some embodiments, the prostate cancer is found to be AR positive i.e. cancer cells contain androgen receptors.

[0177] In some embodiments, the prostate cancer is CRPC i.e. castration-resistant prostate cancer.

[0178] In some embodiments, the prostate cancer is CRPC i.e. castration-sensitive prostate cancer. In one aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of CBP, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myelofibrosis, lymphoma, leukemia, esophogeal, stomach, or lung cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is bladder cancer.

[0179] In one aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound that reduces the level and / or activity of EP300, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments of any of the aspects described herein, the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myeloma, skin, endometrial, esophageal, cervical, gastric, lymphoma, leukemia, esophogeal, stomach, lung cancer, or non-small cell lung cancer. In some embodiments, the cancer is prostate cancer.

[0180] In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepatic bile duct cancer, invasive / i nfiltrati ng breast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma metastatic breast cancer, metastatic melanoma metastatic squamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, Diffuse large B cell lymphoma (DLBCL), testicular cancer, throat cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T- cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, Adult T-cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis;; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, unclassifiable, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicle center lymphoma, T cell / histocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric, Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0181] In some embodiments of any of the foregoing methods, the cancer is a drug resistant cancer or has failed to respond to a prior therapy (e.g., vemurafenib, dacarbazine, a CTLA4 inhibitor, a PD1 inhibitor, interferon therapy, a BRAF inhibitor, a MEK inhibitor, radiotherapy, temozolimide, irinotecan, a CAR-T therapy, herceptin, perjeta, tamoxifen, xeloda, docetaxol, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inihibitors, alimta, abraxane, Adriamycin®, gemcitabine, avastin, halaven, neratinib, a PARP inhibitor, ARN810, an mTOR inhibitor, topotecan, gemzar, a VEGFR2 inhibitor, a folate receptor antagonist, demcizumab, fosbretabulin, or a PDL1 inhibitor).

[0182] In some embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepatic bile duct cancer, invasive / infiltrating breast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma metastatic breast cancer, metastatic melanoma metastatic squamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, Adult T- cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); Diffuse large B cell lymphoma (DLBCL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis;; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, unclassifiable, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicle center lymphoma, T cell / histocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric, Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0183] In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma (e.g., a soft tissue sarcoma, synovial sarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, low-grade rhabdomyosarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is a malignant, rhabdoid tumor, a CD8+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, or colorectal cancer. In some embodiments, the cancer is a sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma), non-small cell lung cancer (e.g., squamous or adenocarcinoma), stomach cancer, or breast cancer. In some embodiments, the cancer is sarcoma (e.g., synovial sarcoma or Ewing’s sarcoma). In some embodiments, the sarcoma is synovial sarcoma.

[0184] In some embodiments of any of the aspects described herein, the method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, and a surfactant, that reduces the level and / or activity of a protein.

[0185] In some embodiments of any of the aspects described herein, the method of treating inflammatory and / or autoimmune disorders in a subject in need thereof, the method comprising administering to the subject an effective amount of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating inflammatory and / or autoimmune disorders in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating inflammatory and / or autoimmune disorders in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating inflammatory and / or autoimmune disorders in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, and a surfactant, that reduces the level and / or activity of a protein.

[0186] In some embodiments of any of the aspects described herein, the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis. In some embodiments, the method further comprises administering to the subject a JAK inhibitor. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.

[0187] In some embodiments, treating an inflammatory disorder and / or autoimmune disorder can result in a reduction in inflammation. In some embodiments, for example, after treatment, inflammation is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment.

[0188] In some embodiments, treating an inflammatory disorder and / or autoimmune disorder can result in a change in cytokine signaling, typically when phosphorylation within the JAK-STAT pathway is altered (e.g., by JAK inhibition). In some embodiments, inhibiting JAK2 may affect phosphorylation of EPO, TPO, GM-CSF, IL-3, IL-5, IL-12, IL-23, INF-y, IL-6, IL-11 , IL-13, IL-25, IL-27, and / or IL-31 , which in turn can affect the immune system response. Other cytokines that interact with JAK1 , JAK3, and / or TYK2 include IL-10, IL-22, type 1 IFNs (a / p), IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.

[0189] In some embodiments of any of the aspects described herein, the method of treating disease, disorder, or medical condition mediated by member of the JAK-STAT pathway in a subject in need thereof, the method comprising administering to the subject an effective amount of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating disease, disorder, or medical condition mediated by member of the JAK-STAT pathway in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating disease, disorder, or medical condition mediated by member of the JAK-STAT pathway in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating disease, disorder, or medical condition mediated by member of the JAK-STAT pathway in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant- inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, and a surfactant, that reduces the level and / or activity of a protein. In some embdoiments, the member of the JAK-STAT pathway is a janus kinase (JAK). In some embodiments, the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT). In some embodiments, the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.

[0190] In some embodiments, the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, Crohn’s disease, refractory, moderate-to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 109 / L, polycythemia vera, steroid- refractory acute graft-versus-host disease, chronic graft-versus-host disease, or particular course juvenile idiopathic arthritis.

[0191] In some embodiments, the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is non-infectious non-anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, sjorgren’s syndrome, or systemic lupus erythematosus.

[0192] In some embodiments, the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis.

[0193] In some embodiments of any of the aspects described herein, the method of inducing immune tolerance in a subject in need thereof, the method comprising administering to the subject an effective amount of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of inducing immune tolerance in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of inducing immune tolerance in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of inducing immune tolerance in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, and a surfactant, that reduces the level and / or activity of a protein.

[0194] In some embodiments of any of the aspects described herein, the method of inhibiting an inflammatory or autoimmune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of inhibiting an inflammatory or autoimmune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of inhibiting an inflammatory or autoimmune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of inhibiting an inflammatory or autoimmune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, and a surfactant, that reduces the level and / or activity of a protein.

[0195] In some embodiments, the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis.

[0196] In some embodiments, the inflammatory and / or autoimmune disorder is moderate-to-severe rheumatoid arthritis, psoriatic arthritis (e.g., active), ankylosing spondylitis (e.g., active), non-radiographic axial spondyloarthritis, moderate-to-severe active ulcerative colitis, Crohn’s disease, refractory, moderate- to-severe atopic dermatitis, intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, intermediate- or high-risk primary or secondary (postpolycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 109 / L, polycythemia vera, steroid-refractory acute graft-versus-host disease, chronic graft-versus-host disease, or particular course juvenile idiopathic arthritis.

[0197] In some embodiments, the inflammatory and / or autoimmune disorder is non-infectious non- anterior uveitis, dermatomyositis, cicatricial alopecia, alopecia areata, rheumatoid arthritis, nonsegmental vitiligo, pyoderma gangrenosum, nail psoriasis, lichen planopilaris, inflammatory genodermatoses, palmoplantar pustulosis, moderate-to severe plaque psoriasis, alopecia areata, Sjogren’s syndrome, or systemic lupus erythematosus.

[0198] In some embodiments, the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, and plaque psoriasis.

[0199] In some embodiments of any of the aspects described herein, the method of suppressing a memory CD8+T cell response in a subject in need thereof, the method comprising administering to the subject an effective amount of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of suppressing a memory CD8+T cell response in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of suppressing a memory CD8+T cell response in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of suppressing a memory CD8+T cell response in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, and a surfactant, that reduces the level and / or activity of a protein.

[0200] In some embodiments of any of the aspects described herein, the method of treating an infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating an infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating an infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating an infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant- inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, and a surfactant, that reduces the level and / or activity of a protein. In some embodiments, the infection is Herpesvirus K*.

[0201] In some embodiments, the infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvirus K*, CMV, varicellazoster virus), Papillomaviridae family (e.g., Human Papillomavirus (HPV, HPV E1)), Parvoviridae family (e.g., Parvovirus B19), Polyomaviridae family (e.g., JC virus and BK virus), Paramyxoviridae family (e.g., Measles virus), Togaviridae family (e.g., Rubella virus). In some embodiments, the disorder is Coffin Siris, Neurofibromatosis (e.g., NF-1 , NF-2, or Schwannomatosis), or Multiple Meningioma.

[0202] In some embodiments of any of the aspects described herein, the method of treating Rubinstein Taybi syndrome in a subject in need thereof, the method comprising administering to the subject an effective amount of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating Rubinstein Taybi syndrome in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating Rubinstein Taybi syndrome in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein. In some embodiments of any of the aspects described herein, the method of treating Rubinstein Taybi syndrome in a subject in need thereof, the method comprising administering to the subject an effective amount of a surfactant-inclusive pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, and a surfactant, that reduces the level and / or activity of a protein. In another aspect, the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0203] In another aspect, the invention features a method of reducing tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0204] In another aspect, the invention features a method of suppressing metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0205] In another aspect, the invention features a method of suppressing metastatic colonization of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing pharmaceutical compositions or spray-dried pharmaceutical compositions thereof.

[0206] In another aspect, the invention features a method of reducing the level and / or activity of a protein in a melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, osteosarcoma, neuroblastoma, esophageal, stomach, or hematologic cancer cell, the method including contacting the cell with an effective amount of any of the foregoing pharmaceutical compositions or spray -dried pharmaceutical compositions thereof.

[0207] In some embodiments of any of the above aspects, the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, osteosarcoma, neuroblastoma, esophageal, stomach, or hematologic cell is in a subject.

[0208] In some embodiments of any of the above aspects, the effective amount of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I , reduces the level and / or activity of a protein by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of EP300 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of a protein by at least 90% (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0209] In some embodiments of any of the above aspects, the effective amount of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, and a surfactant, reduces the level and / or activity of a protein by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of EP300 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of a protein by at least 90% (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%). In some embodiments of any of the above aspects, the effective amount of the pharmaceutical composition reduces the level and / or activity of a protein by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of EP300 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of a protein by at least 90% (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0210] In some embodiments of any ofthe above aspects, the effective amount of The surfactant-inclusive pharmaceutical composition reduces the level and / or activity of a protein by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of EP300 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and / or activity of a protein by at least 90% (e.g., 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0211] In some embodiments, the subject has cancer. In some embodiments, the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a hematologic cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin’s lymphoma. In some embodiments, the cancer is breast cancer (e.g., an ER positive breast cancer, an ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer). In some embodiments, the cancer is a bone cancer (e.g., Ewing’s sarcoma). In some embodiments, the cancer is a renal cell carcinoma (e.g., a Microphthalmia Transcription Factor (MITF) family translocation renal cell carcinoma (tRCC)). In some embodiments, the cancer is metastatic (e.g., the cancer has spread to the liver). The metastatic cancer can include cells exhibiting migration and / or invasion of migrating cells and / or include cells exhibiting endothelial recruitment and / or angiogenesis. In other embodiments, the migrating cancer is a cell migration cancer. In still other embodiments, the cell migration cancer is a non-metastatic cell migration cancer. The metastatic cancer can be a cancer spread via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces. Alternatively, the metastatic cancer can be a cancer spread via the lymphatic system, or a cancer spread hematogenously. In some embodiments, the effective amount of an agent that reduces the level and / or activity of a protein is an amount effective to inhibit metastatic colonization of the cancer to the liver.

[0212] In some embodiments, the method further includes administering to the subject or contacting the cell with an anticancer therapy, e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation. In some embodiments, the anticancer therapy is a chemotherapeutic or cytotoxic agent, e.g., an antimetabolite, antimitotic, antitumor antibiotic, asparaginespecific enzyme, bisphosphonates, antineoplastic, alkylating agent, DNA-Repair enzyme inhibitor, histone deacetylase inhibitor, corticosteroid, demethylating agent, immunomodulatory, janus-associated kinase inhibitor, phosphinositide 3-kinase inhibitor, proteasome inhibitor, or tyrosine kinase inhibitor. Chemotherapeutic and cytotoxic agents include, but are not limited to, alkylating agents, cytotoxic antibiotics, antimetabolites, vinca alkaloids, etoposides, and others (e.g., paclitaxel, taxol, docetaxel, taxotere, cis-platinum). A list of additional compounds having anticancer activity can be found in L. Brunton, B. Chabner and B. Knollman (eds). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition, 2011 , McGraw Hill Companies, New York, NY.

[0213] In some embodiments, the anticancer therapy and the compound of the invention are administered within 28 days of each other and each in an amount that together are effective to treat the subject.

[0214] In some embodiments, the cancer is resistant to one or more chemotherapeutic or cytotoxic agents (e.g., the cancer has been determined to be resistant to chemotherapeutic or cytotoxic agents such as by genetic markers, or is likely to be resistant, to chemotherapeutic or cytotoxic agents such as a cancer that has failed to respond to a chemotherapeutic or cytotoxic agent). In some embodiments, the cancer has failed to respond to one or more chemotherapeutic or cytotoxic agents. In some embodiments, the cancer is resistant or has failed to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgpl OO, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., Nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or tametinib), and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).

[0215] In some embodiments of any of the aspects described herein, the administering comprises combining the amorphous form of a compound of Formula I is suspended in a vehicle prior to administration.

[0216] In some embodiments of any of the aspects described herein, the administering comprises coupling a vial comprising the pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I and a vial comprising a vehicle, transferring the contents of the syringe into the vial, mixing to form a solution, and administering the resulting solution.

[0217] In some embodiments of any of the aspects described herein, the administering comprises coupling a vial comprising the pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I and a syringe comprising PLGA and a carrier, transferring the contents of the syringe into the vial, mixing to form a solution, and administering the resulting solution.

[0218] In some embodiments of any of the aspects described herein, the administering comprises coupling a syringe comprising the pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I and a syringe comprising PLGA and another carrier, mixing to form a solution, and administering the resulting solution.

[0219] In some embodiments of any of the aspects described herein, the effective amount of the compound is administered at a dose of between about 0.1 mg / kg and about 1000 mg / kg. In some embodiments of any of the aspects described herein, the effective amount of the compound is administered at a dose of between about 0.1 mg / mL and about 1000 mg / mL. In some embodiments of any of the aspects described herein, the effective amount of the compound is administered at a dose of between about 0.1 mg and about 1000 mg. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered in a dose of between about 0.25 mL and about 3 mL. In some embodiments of any of the aspects described herein, the formulation is administered in a dose of between about 0.50 mL and about 3 mL. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered in a dose of between about 0.75 mL and about 3 mL. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered in a dose of between about 1 mL and about 3 mL. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered in a dose of between about 1 mL and about 2 mL. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered in a dose of between about 1 .5 mL and about 3 mL. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered in a dose of between about 2 mL and about 3 mL. In some embodiments of any of the aspects described herein, the effective amount of the compound is administered in a dose of between about 0.1 mg / m2 and about 1000 mg / m2.

[0220] In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered at least once every week. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered at least once every two weeks. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered at least once every three weeks. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered at least once every four weeks. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered at least once every month. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered at least once every six weeks. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered at least once every eight weeks. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered at least once every 2 months.

[0221] In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered to the subject in a one-week dosing cycle. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered to the subject in a two-week dosing cycle. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered to the subject in a three-week dosing cycle. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered to the subject in a four-week dosing cycle. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered to the subject in a one-month dosing cycle. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered to the subject in a six-week dosing cycle. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered to the subject in an eight-week dosing cycle. In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered to the subject in a two-month dosing cycle.

[0222] In some embodiments of any of the aspects described herein, a pharmaceutical composition of the present disclosure is administered in an amount sufficient to maintain a concentration of between about 1 ng / mL and about 10 ng / mL over a dosing cycle. In some embodiments of any of the aspects described herein, a pharmaceutical composition of the present disclosure is administered in an amount sufficient to maintain a concentration of between about 1 ng / mL and about 5 ng / mL over a dosing cycle. In some embodiments of any of the aspects described herein, a pharmaceutical composition of the present disclosure is administered in an amount sufficient to maintain a concentration of between about 1 ng / mL and about 3 ng / mL over a dosing cycle.

[0223] In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered subcutaneously.

[0224] In some embodiments of any of the aspects described herein, the pharmaceutical composition is administered intramuscularly.

[0225] Chemical Terms

[0226] The terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0227] For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be understood, other atoms, such as hydrogen atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with the groups defined herein, a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.

[0228] The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms). An alkylene is a divalent alkyl group.

[0229] The term “alkenyl,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[0230] The term “alky ny I,” as used herein, alone or in combination with other groups, refers to a straight chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).

[0231] The term “amino,” as used herein, represents -N(RN1)2, wherein each RN1 is, independently, H, OH, NO2, N(RN2)2, SO2ORN2, SO2RN2, SORN2, an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited RN1 groups can be optionally substituted; or two RN1 combine to form an alkylene or heteroalkylene, and wherein each RN2 is, independently, H, alkyl, or aryl. The amino groups of the compounds described herein can be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e. , -N(RN1)2).

[0232] The term “aryl,” as used herein, refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,2-dihydronaphthyl, indanyl, and 1 H-indenyl.

[0233] The term “arylalkyl,” as used herein, represents an alkyl group substituted with an aryl group. Unsubstituted arylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-C6 alkyl C6-C10 aryl, C1-C10 alkyl C6-C10 aryl, or C1-C20 alkyl C6-C10 aryl), such as, benzyl and phenethyl. In some embodiments, the alkyl and the aryl each are further substituted with 1 , 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups.

[0234] The term “carbocyclyl,” as used herein, refers to a non-aromatic C3-C12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals. A carbocyclylene is a divalent carbocyclyl group.

[0235] The term “cycloalkyl,” as used herein, refers to a saturated, non-aromatic, and monovalent mono- di-, or tricyclic radical of 3 to 10, preferably 3 to 6 carbon atoms. The cycloalkyl group may be fully saturated or contain 1 or more double or triple bonds, provided that no ring is aromatic. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. The term “cycloalkoxy” as used herein, refers to cycloalkyl-O- groups (e.g., cyclopropoxy and cyclobutoxy).

[0236] The term “halo,” as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0237] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an “alkoxy” which, as used herein, refers alkyl-O- (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl group.

[0238] The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkenyl groups. Examples of heteroalkenyl groups are an “alkenoxy” which, as used herein, refers alkenyl-O- A heteroalkenylene is a divalent heteroalkenyl group.

[0239] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkynyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkynyl groups. Examples of heteroalkynyl groups are an “alkynoxy” which, as used herein, refers alkynyl-O- A heteroalkynylene is a divalent heteroalkynyl group.

[0240] The term “heteroaryl,” as used herein, refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing 1 , 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.

[0241] The term “heteroarylalkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group. Unsubstituted heteroarylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-C6 alkyl C2-C9 heteroaryl, C1-C10 alkyl C2-C9 heteroaryl, or C1-C20 alkyl C2- C9 heteroaryl). In some embodiments, the alkyl and the heteroaryl each are further substituted with 1 , 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups.

[0242] The term “heterocyclyl,” as used herein, refers a mono- or polycyclic radical having 3 to 12 atoms having at least one ring containing 1 , 2, 3, or 4 ring atoms selected from N, O or S, wherein no ring is aromatic. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetra hydrofuranyl, and 1 ,3-dioxanyl. A heterocyclylene is a divalent heteroocyclyl group.

[0243] The term “hydroxyl,” as used herein, represents an -OH group.

[0244] The term “thiol,” as used herein, represents an -SH group.

[0245] The term “carbonyl,” as used herein, represents an -C(O)- group.

[0246] The term “thiocarbonyl,” as used herein, represents an -C(S)- group.

[0247] The term “sulfonyl,” as used herein, represents an -S(O)2- group.

[0248] The alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified. Substituents include, for example: alkyl (e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl (e.g., substituted and unsubstituted thiazole, substituted and unsubstituted pyridine, substituted and unsubstituted benzothiazole, substituted and unsubstituted furan, substituted and unsubstituted pyrazole, etc.), heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)).

[0249] Compounds described herein can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. The appropriate technique and / or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art. "Racemate" or "racemic mixture" means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light. “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds described herein may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer. Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s), or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.

[0250] Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium.

[0251] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36CI,123l and125L Isotopically-labeled compounds (e.g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by2H or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,11C, and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labelled compounds are known to those of skill in the art. For example, isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present disclosure described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0252] As is known in the art, many chemical entities can adopt a variety of different solid forms such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvate). In some embodiments, compounds of the present disclosure may be utilized in any such form, including in any solid form. In some embodiments, compounds described or depicted herein may be provided or utilized in hydrate or solvate form.

[0253] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0254] Definitions

[0255] In this application, unless otherwise clear from context, (i) the term “a” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; and (iii) the terms “including” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps.

[0256] As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 to 5.5 nM.

[0257] As used herein, the term “administration” refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.

[0258] The term “cancer” refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0259] As used herein, the term “CBP” refers to the Creb-binding protein in a human cell.

[0260] As used herein, the term “CBP-related disorder” refers to a disorder that is caused or affected by the level of activity of CBP.

[0261] As used herein, the term “CBP loss of function mutation” refers to a mutation in CBP that leads to the protein having diminished activity (e.g., at least 1% reduction in CBP activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP activity). Exemplary CBP loss of function mutations include, but are not limited to, a homozygous CBP mutation and chromosomal translocations.

[0262] As used herein, the term “CBP loss of function disorder” refers to a disorder (e.g., cancer) that exhibits a reduction in CBP activity (e.g., at least 1% reduction in CBP activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP activity).

[0263] By “reducing the activity of CBP” is meant reducing the level of an activity related to CBP, or a related downstream effect. The activity level of a CBP may be measured using any method known in the art, e.g., HiBit assay. By “reducing the level of CBP,” is meant decreasing the level of CBP in a cell or subject. The level of CBP may be measured using any method known in the art.

[0264] As used herein, a “combination therapy” or “administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be affected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally.

[0265] A “compound of the present disclosure” and similar terms as used herein, whether explicitly noted or not, refers to compounds useful for treating cancer described herein, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof. Those skilled in the art will appreciate that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, and tautomers) or isotopic (e.g., in which one or more atoms has been substituted with a different isotope of the atom, such as hydrogen substituted for deuterium) forms. Unless otherwise indicated or clear from context, a depicted structure can be understood to represent any such isomeric or isotopic form, individually or in combination. Compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, one or more compounds depicted herein may exist in different tautomeric forms. As will be clear from context, unless explicitly excluded, references to such compounds encompass all such tautomeric forms. In some embodiments, tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form. Examples of moieties with prototropic tautomeric forms are ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1 H- and 3H-imidazole, 1 H-, 2H- and 4H-1 ,2,4-triazole, 1 H- and

[0266] 2H- isoindole, and 1 H- and 2H-pyrazole. In some embodiments, tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversion.

[0267] As used herein, the term “degrader” refers to a small molecule compound including a degradation moiety, wherein the compound interacts with a protein (e.g., BRD9) in a way which results in degradation of the protein, e.g., binding of the compound results in at least 5% reduction of the level of the protein, e.g., in a cell or subject.

[0268] As used herein, the term “degradation moiety” refers to a moiety whose binding results in degradation of a protein, e.g., BRG1 , BRM, CBP, EP300, BRD9, estrogen receptop, IRAK4, IRAK4 and / or IMiD, STAT3, MDM2, BCLXL, BTK, TRK, IKZF1 , IKZF3, BRAF V600x, or EGFR L858R. In one example, the moiety binds to a protease or a ubiquitin ligase that metabolizes the protein, e.g., BRG1 , BRM, CBP, EP300, BRD9, estrogen receptop, IRAK4, IRAK4 and / or IMiD, STAT3, MDM2, BCLXL, BTK, TRK, IKZF1 , IKZF3, BRAF V600x, or EGFR L858R.

[0269] As used herein, the term “determining the level of a protein” refers to the detection of a protein, or an mRNA encoding the protein, by methods known in the art either directly or indirectly. “Directly determining” means performing a process (e.g., performing an assay or test on a sample or “analyzing a sample” as that term is defined herein) to obtain the physical entity or value. “Indirectly determining” refers to receiving the physical entity or value from another party or source (e.g., a third-party laboratory that directly acquired the physical entity or value). Methods to measure protein level generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix- assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other protein partners. Methods to measure mRNA levels are known in the art.

[0270] As used herein, the terms “effective amount,” “therapeutically effective amount,” and “a “sufficient amount” of an agent that reduces the level and / or activity of a protein (e.g., in a cell or a subject) described herein, unless specified otherwise, refer to a quantity sufficient to, when administered to the subject, including a human, decrease a protein immunohistochemistry score of the subject or an amount sufficient to reduce the level of protein expression in the subject, as described herein. An “effective amount” may also refer to a quantity sufficient to, when administered to the subject, including a human, effect beneficial or desired results, including clinical results, and, as such, an “effective amount” or synonym thereto depends on the context in which it is being applied. For example, in the context of treating cancer, it is an amount of the agent that reduces the level and / or activity of a protein sufficient to achieve a treatment response as compared to the response obtained without administration of the agent that reduces the level and / or activity of a protein. The amount of a given agent that reduces the level and / or activity of a protein described herein that will correspond to such an amount will vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, and / or weight) or host being treated, and the like, but can nevertheless be routinely determined by one of skill in the art. Also, as used herein, a “therapeutically effective amount” of an agent that reduces the level and / or activity of a protein of the present disclosure is an amount which results in a beneficial or desired result in a subject, e.g., as compared to a control. As defined herein, a therapeutically effective amount of an agent that reduces the level and / or activity of a protein of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response.

[0271] As used herein, the term “EP300” refers to the EP300 protein in a human cell.

[0272] As used herein, the term “EP300-related disorder” refers to a disorder that is caused or affected by the level of activity of CBP.

[0273] As used herein, the term “EP300 loss of function mutation” refers to a mutation in EP300 that leads to the protein having diminished activity (e.g., at least 1 % reduction in EP300 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in CBP activity). Exemplary EP300 loss of function mutations include, but are not limited to, a homozygous EP300 mutation and chromosomal translocations.

[0274] As used herein, the term “EP300 loss of function disorder” refers to a disorder (e.g., cancer) that exhibits a reduction in EP300 activity (e.g., at least 1% reduction in EP300 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in EP300 activity). By “reducing the activity of EP300” is meant reducing the level of an activity related to EP300, or a related downstream effect. The activity level of a EP300 may be measured using any method known in the art, e.g., HiBit assay.

[0275] By “reducing the level of EP300,” is meant decreasing the level of EP300 in a cell or subject. The level of EP300 may be measured using any method known in the art.

[0276] As used herein, the term “inhibitor” refers to any agent which reduces the level and / or activity of a protein (e.g., BRD9). Non-limiting examples of inhibitors include small molecule inhibitors, degraders, antibodies, enzymes, or polynucleotides (e.g., siRNA).

[0277] By “level” refers to a level of a protein, or mRNA encoding the protein, as compared to a reference. The reference can be any useful reference, as defined herein. By a “decreased level” or an “increased level” of a protein refers to a decrease or increase in protein level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by less than about 0.01 -fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less; or an increase by more than about 1 .2-fold, about 1 .4-fold, about 1 .5-fold, about 1 .8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold, or more). A level of a protein may be expressed in mass / vol (e.g., g / dL, mg / mL, pg / mL, ng / mL) or percentage relative to total protein or mRNA in a sample.

[0278] As used herein, “matrix” refers to the background material or material environment in which a compound of Formula I is present.

[0279] As used herein, “microparticle” refers to a to particle ranging from about 1 pm and about 25 pm in size (e.g., diameter), for example, about 1 pm, about 2 pm, about 3 pm, about 4 pm, about 5 pm, about 6 pm, about 7 pm, about 8 pm, about 9 pm, about 10 pm, about 11 pm, about 12 pm, about 13 pm, about 14 pm, about 15 pm, about 16 pm, about 17 pm, about 18 pm, about 19 pm, about 20 pm, about 21 pm, about 22 pm, about 23 pm, about 24 pm, about 25 pm, including all values and ranges in between.

[0280] As used herein, “metastatic nodule” refers to an aggregation of tumor cells in the body at a site other than the site of the original tumor.

[0281] As used herein, “normal saline” refers to solutions comprising varying concentrations of sodium chloride (NaCI) in water that are compatible with fluids in the body (e.g. solutions comprising 0.9% NaCI that compatible with the salinity found in most mammalian cells and in human blood). Normal saline will range in pH depending upon the pH of the water used in preparation (e.g. pH of water ranging from 5.5- 8.5).

[0282] A “pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0283] As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of the compound of any of the compounds described herein. For example, pharmaceutically acceptable salts of any of the compounds described herein include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid.

[0284] The compounds described herein may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds described herein, be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable nontoxic acids and bases including inorganic and organic acids and bases.

[0285] The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); for intravenous administration (e.g., as a sterile syringe suitable for intramuscular use); for subcutaneous administration; or in any other pharmaceutically acceptable formulation.

[0286] By a “reference” is meant any useful reference used to compare protein or mRNA levels. The reference can be any sample, standard, standard curve, or level that is used for comparison purposes. The reference can be a normal reference sample or a reference standard or level. A “reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a subject that is diagnosed with a disease, but not yet treated with a compound described herein; a sample from a subject that has been treated by a compound described herein; or a sample of a purified protein (e.g., any described herein) at a known normal concentration. By “reference standard or level” is meant a value or number derived from a reference sample. A “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound described herein. In preferred embodiments, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of a purified protein, e.g., any described herein, within the normal reference range can also be used as a reference.

[0287] As used herein, the term “subject” refers to any organism to which a compound of the disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.

[0288] As used herein, the term “substantially amorphous” refers to a formulation in which less than 20% (w / w) of the active compound, or a pharmaceutically acceptable salt thereof, is present in a crystalline form (e.g., less than 15%, 12%, 10%, 8%, 5%, 3%, or 1% (w / w) is present in a crystalline form, such as between 0.01 % and 20%, 0.01% and 15%, 0.01% and 12%, 0.01% and 10%, 0.01 % and 8%, 0.01 % and 5%, 0.01% and 3%, and 0.01% and 1% (w / w) in crystalline form), and the remainder is in amorphous form as determined using the X-ray powder diffraction.

[0289] As used herein, the term “solid dispersion” refers to a solid composition, in which one or more active ingredients, e.g., a compound of Formula I in the amorphous state, is dispersed in an inert carrier or in a matrix. The matrix or carrier may comprise polymers, surfactants or mixtures thereof.

[0290] As used herein, the term “surfactant-inclusive” refers to refers to a solid composition of a compound of Formula I, in which the compound of Formula I and a surfactant are mixed and then processed by spray-drying.

[0291] As used herein, the terms "treat," "treated," or "treating" mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Compounds of the invention may also be used to “prophylactically treat” or “prevent” a disorder, for example, in a subject at increased risk of developing the disorder.

[0292] As used herein, the terms “variant” and “derivative” are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other substance described herein. A variant or derivative of a compound, peptide, protein, or other substance described herein may retain or improve upon the biological activity of the original material.

[0293] As used herein the term “D50” is defined as the median for a volume distribution (as opposed to a mass, number, or surface distribution) of the particles. The particle size can be measured by conventional particle size measuring techniques well known to those skilled in the art. Such techniques include, for example, optical microscopy, electron microscopy, sedimentation, field flow fractionation, photon correlation spectroscopy, light scattering (e.g., with a Microtrac UPA 150, Malvern Mastersizer), laser diffraction, and centrifugation. D50 values are commonly derived of particle size distributions of particles suspended in a non-solvent, the distributions measured by light scattering.

[0294] As used herein, the term “drug particle” refers to solid particles including a drug. The drug particles can be included in the pharmaceutical compositions of the invention. For example, the pharmaceutical composition can contain particulates containing or formed from an amorphous form of a compound of Formula I.

[0295] As used herein, the term “ester saccharide” refers to a sugar ester of a hydrophobic alkyl group (e.g., typically from 8 to 24 carbon atoms in length). Ester saccharides include ester glycosides and ester glucosides. Ester glycosides that can be used in the pharmaceutical compositions of the invention include, without limitation, Cs-14 alkyl (e.g., octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, or tetradecyl-) esters of a or 0 -D-maltoside, -glucoside or -sucroside. For example, the pharmaceutical compositions can include a surfactant selected from sucrose mono-dodecanoate, sucrose monotridecanoate, or sucrose mono-tetradecanoate.

[0296] As used herein, the term “alkyl saccharide” refers to a sugar ether of a hydrophobic alkyl group (e.g., typically from 9 to 24 carbon atoms in length). Alkyl saccharides include alkyl glycosides and alkyl glucosides. Alkyl glycosides that can be used in the pharmaceutical compositions of the invention include, without limitation, Cs-14 alkyl (e.g., octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, or tetradecyl-) ethers of a or 0 -D-maltoside, -glucoside or -sucroside, alkyl thiomaltosides, such as heptyl, octyl, dodecyl-, tridecyl-, and tetradecyl-0-D-thiomaltoside; alkyl thioglucosides, such as heptyl- or octyl 1 -thio a- or 0-D- glucopyranoside; alkyl thiosucroses; and alkyl maltotriosides. For example, the pharmaceutical composition can include a surfactant selected from octyl maltoside, dodecyl maltoside, tridecyl maltoside, and tetradecyl maltoside. Alkyl glucosides that can be used in the pharmaceutical compositions of the invention include, without limitation, Cs-14 alkyl (e.g., octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, or tetradecyl-) ethers of glucoside, such as dodecyl glucoside or decyl glucoside.

[0297] As used herein, the term “PEG” refers to polyethylene glycol. Polyethylene glycol (PEG), also known as poly(oxyethylene) glycol, is a condensation polymer of ethylene oxide and water. PEG refers to a compound that includes repeating ethylene glycol units. The structure of PEG may be expressed as -(O-CH2-CH2)n-O. PEG is a hydrophilic compound that is biologically inert (i.e., non-immunogenic) and generally considered safe for administration to humans.

[0298] As used herein, the term “polyglycolized glyceride” refers to a polyethylene glycol glyceride monoester, a polyethylene glycol glyceride diester, a polyethylene glycol glyceride triester, or a mixture thereof containing a variable amount of free polyethylene glycol, such as a polyethylene glycol-oil transesterification product. The polyglycolized glyceride can include either monodisperse (i.e., single molecular weight) or polydisperse polyethylene glycol moieties of a predetermined size or size range (e.g., PEG2 to PEG 40). Polyethylene glycol glycerides include, for example: PEG glyceryl caprate, PEG glyceryl caprylate, PEG-20 glyceryl laurate (Tagat® L, Goldschmidt), PEG-30 glyceryl laurate (Tagat® L2, Goldschmidt), PEG-15 glyceryl laurate (Glycerox L series, Croda), PEG-40 glyceryl laurate (Glycerox L series, Croda), PEG-20 glyceryl stearate (Capmul® EMG, ABITEC), and Aldo® MS-20 KFG, Lonza), PEG-20 glyceryl oleate (Tagat® O, Goldschmidt), and PEG-30 glyceryl oleate (Tagat® 02, Goldschmidt). Caprylocapryl PEG glycerides include, for example, caprylic / capric PEG-8 glyceride (Labrasol®, Gattefosse), caprylic / capric PEG-4 glyceride (Labrafac® Hydro, Gattefosse), and caprylic / capric PEG-6 glyceride (SOFTIGEN®767, Huis). Oleoyl PEG glyceride include, for example oleoyl PEG-6 glyceride, (Labrafil M1944 OS, Gattefosee). Lauroyl PEG glycerides includes, for example, lauroyl PEG-32 glyceride (Gelucire® ELUCIRE 44 / 14, Gattefosse). Stearoyl PEG glycerides include, for example stearoyl PEG-32 glyceride (Gelucrire 50 / 13, Gelucire 53 / 10, Gattefosse). PEG castor oils include PEG-3 castor oil (Nikkol CO-3, Nikko), PEG-5, 9, and 16 castor oil (ACCONON CA series, ABITEC), PEG-20 castor oil, (Emalex C-20, Nihon Emulsion), PEG-23 castor oil (Emulgante EL23), PEG-30 castor oil (Incrocas 30, Croda), PEG-35 castor oil (lncrocas-35, Croda), PEG-38 castor oil (Emulgante EL 65, Condea), PEG-40 castor oil (Emalex C-40, Nihon Emulsion), PEG-50 castor oil (Emalex C-50, Nihon Emulsion), PEG-56 castor oil (Eumulgin® PRT 56, Pulcra SA), PEG-60 castor oil (Nikkol CO-60TX, Nikko), PEG-100 castor oil, PEG- 200 castor oil (Eumulgin® PRT 200, Pulcra SA), PEG-5 hydrogenated castor oil (Nikkol HCO-5, Nikko), PEG-7 hydrogenated castor oil (Cremophor WO7, BASF), PEG-10 hydrogenated castor oil (Nikkol HCO- 10, Nikko), PEG-20 hydrogenated castor oil (Nikkol HCO-20, Nikko), PEG-25 hydrogenated castor oil (Simulsol® 1292, Seppic), PEG-30 hydrogenated castor oil (Nikkol HCO-30, Nikko), PEG-40 hydrogenated castor oil (Cremophor RH 40, BASF), PEG-45 hydrogenated castor oil (Cerex ELS 450, Auschem Spa), PEG-50 hydrogenated castor oil (Emalex HC-50, Nihon Emulsion), PEG-60 hydrogenated castor oil (Nikkol HCO-60, Nikko), PEG-80 hydrogenated castor oil (Nikkol HCO-80, Nikko), and PEG-100 hydrogenated castor oil (Nikkol HCG-100, Nikko). Additional polyethylene glycol-oil transesterification products include, for example, stearoyl PEG glyceride (Gelucire® 50 / 13, Gattefosse). The polyglycolized glycerides useful in the pharmaceutical compositions of the invention can include polyethylene glycol glyceride monoesters, diesters, and / or tri esters of hexanoic, heptanoic, caprylic, nonanoic, capric, lauric, myristic, palmitic, heptadecanoic, stearic, arachidic, behenic, lignoceric, a- linolenic, stearidonic, eicosapentaenoic, docosahexaenoic, linoleic, y-linolenic, dihomo-y-linolenic, arachidonic, oleic, elaidic, eicosenoic, erucic, or nervonic acid, or mixtures thereof. The polyglycol moiety in a polyglycolized glyceride can be polydisperse; that is, they can have a variety of molecular weights.

[0299] As used herein, the term “polysorbate surfactant” refers to an oily liquid derived from pegylated sorbitan esterified with fatty acids. Common brand names for polysorbate surfactant include Alkest™, Canarcel™ and Tween™. Polysorbate surfactants include, without limitation, polyoxyethylene 20 sorbitan monolaurate (TWEEN™ 20), polyoxyethylene (4) sorbitan monolaurate (TWEEN™ 21), polyoxyethylene 20 sorbitan monopalmitate (TWEEN™ 40), polyoxyethylene 20 sorbitan monostearate (TWEEN™ 60); and polyoxyethylene 20 sorbitan monooleate (TWEEN™ 80).

[0300] As used herein, the term “poloxamer” refers to an ethoxylated propoxylated block copolymers having formula H(OCH2CH2)a(OCHCH3CH2)b(OCH2CH2)aOH, wherein a and b are integers. For example, the poloxamer can be a block copolymer in which a is 12 and b is 20 (Poloxamer® 124), where a is 38 and b is 29, where a is 80 and b is 27 (Poloxamer® 188), where a is 64 and b is 37 (Poloxamer® 237), where a is 141 and b is 44 (Poloxamer® 338), where a is 49 and b is 57, or where a is 101 and b is 56 (Poloxamer® 407).

[0301] As used herein, the term “Polyvinyl alcohol” or “PVA” is a polymer prepared from polyvinyl acetates by replacement of the acetate groups with hydroxyl groups and has the chemical formula (CH2CHOH)[n]. Most polyvinyl alcohols are soluble in water.

[0302] As used herein, the term “polyvinylpyrrolidone” or “PVP” refers to water-soluble made of monomer N- vinylpyrrolidone Polymer. The term and abbreviation PVP, povidone (povidone), povidone (plasdone), povidone (polyvidone), Crospovidone, kollidon are used interchangeably.

[0303] As used herein, the term “poly lactic-co-glycolic acid” or “PLGA” refers to a polylactic acid-glycolic acid copolymer, is formed by random polymerization of two monomers (lactic acid and glycolic acid).

[0304] As used herein, the term “phospholipids” refers to a glycerol phosphate with an organic headgroup such as choline, serine, ethanolamine or inositol and either one or two fatty acids esterified to the glycerol backbone. See FIG. 1. Phospholipids include, but are not limited to, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol as well as corresponding lysophospholipids. For example, a “phospholipid” can refer to an organic compound of Formula I: wherein Rais a fatty acid residue or H, Rbis a fatty acid residue or H, Rcis H or a nitrogen containing compound such as choline (HOCH2CH2N+(CH3)3OH-), ethanolamine (HOCH2CH2NH2), inositol, or serine, and Rdis a negative charge, H, or a cation such as an alkali metal cation (for example, Li+, Na+, or K+). Raand Rbare not simultaneously H. When Rcis H, the compound is a diacylglycerophosphate (also known as phosphatidic acid), while when Rcis a nitrogen-containing compound, the compound is a phosphatide such as lecithin, cephalin, phosphatidyl serine, or plasmalogen. The Rasite is referred to as position 1 of the phospholipid (per the stereospecific [sn] system of nomenclature), the Rbsite is referred to as position 2 of the phospholipid (the sn2 position), and the Rcsite is referred to as position 3 of the phospholipid (the sn3 position). Phospholipids also include phosphatidic acid and / or lysophosphatidic acid. Sphingolipids containing a phosphorus group are grossly classified as phospholipids; they contain a sphingosine base rather than a glycerol base.

[0305] As used herein, the term “dipalmitoylphosphatidylcholine” or “DPPC” refers to a phospholipid consisting of two C16palmitic acid groups attached to a phosphatidylcholine head-group.

[0306] As used herein, the term “distearoylphosphatidylcholine” or “DSPC” refers to a phosphatidylcholine with stearoyl (octadecanoyl) acyl groups. As used herein, the term “polymethacrylates” refers to polymer prepared from cationic and anionic polymers of dimethylaminoethyl methacrylates, methacrylic acid, and methacrylic acid esters in varying ratios from methyl methacrylate.

[0307] As used herein, the term “cellulose derivatives” refers to polysaccharides composed of linear chains of p (1-4) glucosidic units with methyl, hydroxypropyl or carboxyl substituents.

[0308] As used herein, the term “glyceryl behenate” refers to monoester of glycerin and behenic acid

[0309] As used herein, the term “castor oil” or “polyethoxylated castor oil” refers to a compound formed from the ethoxylation of castor oil, wherein at least one chain of polyethylene glycol is covalently bound to the castor oil. The castor oil may be hydrogenated or unhydrogenated. Synonyms for polyethoxylated castor oil include, but are not limited to polyoxyl castor oil, hydrogenated polyoxyl castor oil, mcrogolglyceroli ricinoleas, macrogolglyceroli hydroxystearas, polyoxyl 35 castor oil, and polyoxyl 40 hydrogenated castor oil. Suitable polyethoxylated castor oils include, but are not limited to, the Nikkol™ HCO series (available from Nikko Chemicals Co. Ltd.), such as Nikkol HCO-30, HC-40, HC-50, and HC- 60 (polyethylene glycol-30 hydrogenated castor oil, polyethylene glycol-40 hydrogenated castor oil, polyethylene glycol-50 hydrogenated castor oil, and polyethylene glycol-60 hydrogenated castor oil, Emulphor™ EL-719 (castor oil 40 mole-ethoxylate, available from Stepan Products), the Cremophore™ series (available from BASF), which includes Cremophore RH40, RH60, and EL35 (polyethylene glycol- 40 hydrogenated castor oil, polyethylene glycol-60 hydrogenated castor oil, and polyethylene glycol-35 hydrogenated castor oil, respectively), and the Emulgin® RO and HRE series (available from Cognis PharmaLine). Other suitable polyoxyethylene castor oil derivatives include those listed in R. C. Rowe and P. J. Shesky, Handbook of Pharmaceutical Excipients, (2006), 5th ed., which is incorporated herein by reference in its entirety.

[0310] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

[0311] Brief Description of the Drawings

[0312] Figure 1A: Pharmacokinetic and pharmacodynamic profiles (Plasma concentration, CBP and c-MYC degradation) of a single dose of an amorphous solid dispersion150 mg / kg dose formulation administered intramuscularly (IM).

[0313] Figure 1 B: Pharmacokinetic and pharmacodynamic profiles (Plasma concentration, CBP and c-MYC degradation) of a single dose of an amorphous solid dispersion 150 mg / kg dose formulation administered subcutaneously (SC).

[0314] Figure 1C: Pharmacokinetic and pharmacodynamic profiles (Plasma concentration, CBP and c-MYC degradation) of a single dose of an amorphous solid dispersion 60 mg / kg dose formulation administered subcutaneously (SC).

[0315] Figure 2A: Tumor sizes across different treatment groups measured at various time points during the 3- week study of Compound A efficacy and its target degradation (CBP) in female BALB / c Nude mice. Figure 2B: Body weight changes observed in the mice throughout the 3-week study of Compound A efficacy and its target degradation (CBP) in female BALB / c Nude mice. Figure 2C: Plasma concentration of Compound A and levels of CBP degradation in samples collected at the end of the 3-week study of Compound A efficacy and its target degradation (CBP) in female BALB / c Nude mice.

[0316] Figure 3A: Tumor sizes in different treatment groups over a 3-week study of A efficacy and CBP target degradation in Female NOG SCID mice.

[0317] Figure 3B: Body weight changes observed during a 3-week study of A efficacy and CBP target degradation in Female NOG SCID mice.

[0318] Figure 3C: Plasma concentration of Compound A and levels of CBP degradation at various timepoints over a 3-week study of efficacy and CBP target degradation in Female NOG SCID mice.

[0319] Figure 4A: Plot of plasma concentration of Compound B as a function of time demonstrating sustained exposure is obtained for at least two weeks with the amorphous microsuspension dosed subcutaneously (SC) in mice. Both Formulation 1 (legend: •) and Formulation 2 (legend: O) provided similar exposures, when dosed via subcutaneous route.

[0320] Figure 4B: Plot of plasma concentration of Compound B as a function of time demonstrating sustained exposure is obtained for at least two weeks with the amorphous microsuspension dosed intramuscularly in mice. Formulation 2 (legend: □), made with ASD B2, provided higher exposure than observed in Formulation 1 (legend: ■) when given via intramuscular route.

[0321] Detailed Description

[0322] The present disclosure features compositions and methods useful for the treatment of cancer.

[0323] The disclosure further features compositions and methods useful for reducing the level and / or activity of a protein, e.g., for the treatment of disorders such as cancer in a subject in need thereof.

[0324] Compounds

[0325] The present disclosure provides a compound of Formula I:

[0326] A-L-B

[0327] Formula I, or a pharmaceutical salt thereof, wherein

[0328] A is a protein binding moiety;

[0329] B is the degradation moiety;

[0330] L is a linker;

[0331] A1is a bond between the linker and A;

[0332] A2is a bond between B and the linker;

[0333] A has the structure of Formula II: pendently, absent, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alky ny I, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C6 heteroarvl. ootionallv substituted C6-C12 aryl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C1-C10 heteroalkyl, optionally wherein if are C2-C10 heterocyclyl, C2-C6 heteroaryl, C6-C12 aryl, C3-

[0334] C10 cycloalkyl, or C3-C10 carbocyclyl, then may be joined to through one or more atoms; optionally wherein if are C2-C10 heterocyclyl, C2-C6 heteroaryl, C6-C12 aryl, C3-C10 cycloalkyl, or C3-C10 carbocyclyl, then may be joined to through one or more atoms; optionally wherein if C10 heterocyclyl, C2-C6 heteroaryl, C6-C12 aryl, C3-C10 cycloalkyl, or C3-C10 , may be joined to through one or more atoms;

[0335] B has the structure of Formula III:

[0336] Formula III, wherein

[0337] Q is NR1R2, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, or optionally substituted C2-C6 heteroaryl, wherein the carbocyclyl, aryl, or heteroaryl is optionally substituted with A2and / or C1-C4 alkyl;

[0338] R1is, independently, H, A2, C(O)A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, or C(O)R1a, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;

[0339] R2is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, or C(O)R1a, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;

[0340] R3is, independently, A2, C(O)A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted Ce-C-io aryl;

[0341] R4is, independently, H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted Ce-C-io aryl;

[0342] R5is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;

[0343] R6is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce alkyl Ce-C-io aryl, or optionally substituted Ci-Ce alkyl C3-C10 heteroaryl; each R1ais, independently, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen, CN, or C1-C4 alkyl; and wherein one and only one of Q, R1, R2, R3, or R6comprises A2or C(O)A2; and wherein one and only one of ©, ® , ®, or ® comprises A1.

[0344] In some embodiments of any of the aspects described herein, L has the structure of

[0345] Formula IV:

[0346] A1-(B1)f-(C1a)g-(B2)h-(D1a)-(B3)r(C2a)r(B4)k-A2,

[0347] Formula IV or a pharmaceutically acceptable salt thereof, wherein

[0348] A1is a bond between the linker and A;

[0349] A2is a bond between Formula III and the linker; each of B1, B2, B3, and B4is, independently, optionally substituted C1-C4 alkyl, optionally substituted Ce-C-io aryl, optionally substituted Ce-C-io aryl C1-4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C6-12 aryl, O, S, S(O)2, or NRN; each RNis, independently, H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alky ny I, optionally substituted C2-10 heterocyclyl, optionally substituted C2-6 heteroaryl, or optionally substituted C1-7 heteroalkyl; each of C1aand C2ais, independently, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; each of f, g, h, i, j, and k is, independently, 0 or 1 ; and

[0350] D1ais optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alky ny I, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C6-C12 aryl, optionally substituted C2-C10 polyethylene glycol, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C1-C10 heteroalkyl; or D is absent, and the linker is A1-(B1)f-(C1a)g-(B2)h-(B3)r(C2a)r(B4)k-A2.

[0351] In some embodiments of any of the aspects described herein, L has the structure of Formula V: A1-G-(H)-(J)i-G-A2,

[0352] Formula V wherein

[0353] A1is a bond between the linker and A;

[0354] A2is a bond between Formula III and the linker;

[0355] I is 0 or 1 ; each G is, independently, absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl;

[0356] J is absent, O, S, NRN, optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C2-C10 polyethylene glycol, optionally substituted C1-C10 heteroalkylene, optionally substituted C2-io carboocyclylene, or optionally substituted C2-C10 heterocyclylene; each RNis, independently, H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alky ny I, optionally substituted C2-6 heterocyclylene, optionally substituted C6-12 aryl, or optionally substituted C1-7 heteroalkyl; and

[0357] H is optionally substituted C3-C10 carbocyclylene, optionally substituted C2-12 heterocyclylene, optionally substituted Ce-C-io arylene, or optionally substituted C2-C9 heteroarylene.

[0358] In some embodiments of any of the aspects described herein, L is absent.

[0359] In some embodiments of any of the aspects described herein, the compound of Formula I is a compound of Table 1.

[0360] Pharmaceutical Uses

[0361] The compounds described herein are useful in the methods of the disclosure and, while not bound by theory, are believed to exert their desirable effects through their ability to modulate the level, status, and / or activity of a protein, e.g., by reducing the level of an activity related to a protein (e.g., BRG1 , BRM, CBP, EP300, BRD9, estrogen receptop, IRAK4, IRAK4 and / or IMiD, STAT3, MDM2, BCLXL, BTK, TRK, IKZF1 , IKZF3, BRAF V600x, or EGFR L858R) in a cell in a mammal.

[0362] An aspect of the present disclosure relates to methods of treating cancer such as cancer in a subject in need thereof. In some embodiments, the pharmaceutical composition is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, and (i) increased progression free survival of a subject.

[0363] T reating cancer can result in a reduction in size or volume of a tumor. For example, after treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. For example, the size of a tumor may be measured as a diameter of the tumor.

[0364] Treating cancer may further result in a decrease in number of tumors. For example, after treatment, tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

[0365] Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x).

[0366] Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present disclosure in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[0367] Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[0368] In some embodiments of any of the aspects described herein, the cancer is a malignant rhabdoid tumor, a CDS+ T-cell lymphoma, endometrial carcinoma, ovarian carcinoma, bladder cancer, stomach cancer, pancreatic cancer, esophageal cancer, prostate cancer, renal cell carcinoma, melanoma, colorectal cancer, a sarcoma, non-small cell lung cancer, stomach cancer, breast cancer, or SMARCAB1- loss cancer.

[0369] In some embodiments, the cancer is a malignant rhabdoid tumor.

[0370] In some embodiments, the cancer is a CDS+ T-cell lymphoma.

[0371] In some embodiments, the cancer is endometrial carcinoma.

[0372] In some embodiments, the cancer is ovarian carcinoma.

[0373] In some embodiments, the cancer is bladder cancer.

[0374] In some embodiments, the cancer is stomach cancer.

[0375] In some embodiments, the cancer is pancreatic cancer.

[0376] In some embodiments, the cancer is esophageal cancer.

[0377] In some embodiments, the cancer is prostate cancer.

[0378] In some embodiments, the cancer is renal cell carcinoma.

[0379] In some embodiments, the cancer is melanoma.

[0380] In some embodiments, the cancer is colorectal cancer.

[0381] In some embodiments, the cancer is a sarcoma, e.g., a soft tissue sarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adult fibrosarcoma, alveolar soft-part sarcoma, angiosarcoma, clear cell sarcoma, desmoplastic small round cell tumor, epithelioid sarcoma, fibromyxoid sarcoma, gastrointestinal stromal tumor, Kaposi sarcoma, liposarcoma, leiomyosarcoma, malignant mesenchymoma malignant peripheral nerve sheath tumors, myxofibrosarcoma, or low-grade rhabdomyosarcoma. In particular embodiments, the sarcoma is synovial sarcoma.

[0382] In some embodiments, the cancer is non-small cell lung cancer.

[0383] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is a SMARCAB1-loss cancer, e.g., high grade ovarian serous adenocarcinoma, epithelioid sarcoma, atypical teratoid / rhabdoid tumor, malignant rhabdoid tumor (MRT), prostate adenocarcinoma, conventional glioblastoma multiforme, breast invasive ductal carcinoma, sarcoma (NOS), gastrointestinal stromal tumor, kidney / renal medullary carcinoma, pancreatic neuroendocrine neoplasm, sinonasal adenocarcinoma, adrenal cortex carcinoma, proximal-type epithelioid sarcoma, head and neck carcinoma, invasive breast carcinoma, rhabdoid tumor of the kidney, dedifferentiated liposarcoma, pancreatic adenocarcinoma, chordoma, testicular yolk sac tumor, small cell lung carcinoma, squamous cell lung carcinoma, acral lentiginous melanoma, peripheral T-cell lymphoma, nasal cavity and paranasal sinus squamous cell carcinoma, myoepithelial carcinoma, malignant peripheral nerve sheath tumor, breast invasive lobular carcinoma, chordoma, a SMARCB1 -mutant cancer, or lung adenocarcinoma. In particular embodiments, the SMARCAB1-loss cancer is chordoma.

[0384] In one aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that reduces the level and / or activity of a protein, or a pharmaceutically acceptable salt thereof.

[0385] In some embodiments of any of the aspects described herein, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered intramuscularly. In some embodiments of any of the aspects described herein, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I , or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered subcutaneously.

[0386] In some embodiments of any of the aspects described herein, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a pharmaceutically acceptable carrier and a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered intramuscularly. In some embodiments of any of the aspects described herein, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a pharmaceutically acceptable carrier and a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered subcutaneously.

[0387] In one aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0388] In one aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a pharmaceutically acceptable carrier and a compound of Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is gastric cancer.

[0389] In one aspect, the present disclosure provides a method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0390] An aspect of the present invention relates to methods of treating inflammation and / or autoimmune disorders in a subject in need thereof. In some embodiments, the pharmaceutical composition is administered in an amount and for a time effective to result in one of (or more, e.g., two or more, three or more, four or more of): (a) reduced T cell (e.g., CD8+memory T cells) activity, (b) reduced inflammation, (c) reduced thrombopoiesis, (d) reduced B cell proliferation, (e) increased survival of subject, and (f) increased progression free survival of a subject.

[0391] Treating inflammatory disorders and / or autoimmune disorders can result in a reduction in T cell (e.g., CD8+memory T cells) activity. For example, after treatment, T cell (e.g., CD8+memory T cells) activity is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. T cell activity may be measured by any reproducible means of measurement.

[0392] Treating inflammatory disorders and / or autoimmune disorders can result in a reduction in inflammation. For example, after treatment, inflammation is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. T cell activity may be measured by any reproducible means of measurement.

[0393] Treating inflammatory disorders and / or autoimmune disorders can result in a change in cytokine signaling, typically when phosphorylation within the JAK-STAT pathway is altered (e.g., by JAK inhibition). Specifically, each cytokine receptor is paired with a JAK pair. When the JAK pair is cross-linked by its cytokine, the JAKs phosphorylate each other and also phosphorylate the cytokine receptor, which creates a STAT binding site for a STAT to then also become phosphorylated. In some embodiments, inhibiting JAK2 may affect phosphorylation of EPO, TPO, GM-CSF, IL-3, IL-5, IL-12, IL-23, INF-y, IL-6, IL-11 , IL-13, IL-25, IL-27, and / or IL-31 , which in turn can affect the immune system response. Other cytokines that interact with JAK1 , JAK3, and / or TYK2 include IL-10, IL-22, type 1 IFNs (a / p), IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 .Treating cancer, infection, inflammatory disorders, and / or autoimmune disorders can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound described herein. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[0394] Treating cancer, infection, inflammatory disorders, and / or autoimmune disorders can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of a compound described herein. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of a compound described herein.

[0395] Amorphous Solid Dispersion

[0396] The term “amorphous solid dispersion” (ASD) as used herein refers to a dispersion of an amorphous form of compound of Formula I , in a matrix that consists of at least one carrier. The matrix may also comprise polymers, surfactants or mixtures thereof. In certain embodiments, the “amorphous solid dispersion” (ASD) is a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I. In certain dosage forms of the invention, the amorphous solid dispersion is a form having homogenously dispersed compounds of Formula I throughout the polymer in a manner that results in a single glass transition temperature Tg. In other dosage forms of the invention, the compound of Formula I is heterogeneously dispersed throughout the polymer in a manner that results in multiple glass transition temperatures Tg. Various methods exist for the preparation of an amorphous solid dispersion, for example, spray drying, melt extrusion, and solution evaporation, particularly hot melt extrusion and spray drying.

[0397] Pharmaceutically acceptable polymers for making amorphous solid dispersions

[0398] Pharmaceutically acceptable carriers include one or more polymers capable of forming an amorphous solid dispersion with an amorphous form of a compound of Formula I. Two or more polymers can be used together and can optionally include one or more surfactants. Generally, optimal Tgvalues include from 50°C to 180°C, which is higher than the melting temperature of a compound of Formula I but lower than the temperature at which a compound of Formula I decomposes.

[0399] Exemplary polymers are one or more of PVP K12 (Tg= 105°C), ethyl cellulose (Tg= 133°C), cellulose acetate phthalate (CAP, Tg= 171 °C), hydroxypropylmethyl cellulose acetate (Tg= 177°C), hydroxypropylmethyl cellulose acetate succinate (HPMCAS, Tg= 1 15°C), hydroxypropylmethyl cellulose phthalate (HPMCP, Tg= 133°C), polyvinyl pyrrolidone (Tg= 174°C), crospovidone (Tg= 190°C to 195°C), polyvinyl alcohol (Tg= 75°C), and polyvinyl acetate phthalate (Tg= 55°C).

[0400] Examples of carriers which can be used in the formulations of the invention are, without limitation, polyethylene glycol, Polyvinylpyrrolidone, poly lactic-co-glycolic acid, poly vinyl alcohol, phospholipids, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, 1 ,2-Distearoyl-sn-glycero-3- phosphocholine, polymethacrylates, polyvinyl acetate, cellulose derivatives, glyceryl behenate, polyethyleneglycol derivatives of a mono-glyceride, vitamin E, polyethylene or polyoxyethylene esters of hydroxyl stearic acid, polyoxylglycerides, polyethoxylated castor oil or combinations thereof.

[0401] Methods of making solid dispersion systems The pharmaceutical composition including the solid dispersion (e.g., a spray dried dispersion (SDD) can be made using any useful method. Generally, one or more carriers and a compound of Formula I, are combined either with or without a solvent (e.g., one or more of dimethyl acetamide, dimethyl formamide, pyrrolidone, methyl pyrrolidone, methanol, ethyl acetate, dichloromethane, ethanol, and acetone) to form a mixture (e.g., a liquid mixture) or a solution. Optionally, the carrier and a compound of Formula I , either with or without additional excipients, can be heated near or past the glass transition temperature Tgor melting temperature Tmto form a liquid mixture. Then, the resultant solution can be spray dried to form a solid dispersion.

[0402] Spray dried processes for making microparticles

[0403] The compositions of the invention can be prepared by any useful process, such as spray drying to form, for example, a spray dried amorphous solid dispersion. In one example, one or more carriers and a compound of Formula I, with or without a surfactant and are combined with one or more solvents (e.g., acetone, ethyl acetate, 1 :1 MeOH / DCM) to form a solution having about 4% (w / w) to about 80% (w / w) of total solids. If no surfactant is present, then percentage (w / w) total solids is determined by dividing the total mass of the compound and one or more carriers by the total mass of the compound, one or more carriers, and one or more solvents. If a surfactant is present, then percentage (w / w) total solids is determined by dividing the total mass of the compound and one or more carriers, and one or more surfactants by the total mass of the compound, one or more carriers, one or more surfactants, and one or more solvents. The solution can then be spray dried to form a spray dried dispersion (SDD), which can optionally undergo further drying steps. In particular embodiments, the SDD includes about 50% (w / w) of a compound of Formula I with the one or more carriers (i.e. , the weight ratio of a compound of Formula I to the polymer is about 50:50). In particular embodiments, the SDD includes about 49% (w / w) of a compound of Formula I with the one or more carriers and one or more surfactants (i.e., the weight ratio of a compound of Formula I to the polymer to the surfactant is about 49:49:2).

[0404] For example, to produce an 50% (w / w) a compound of Formula I in an SDD, a solution was prepared having about 50% (w / w) a compound of Formula I and about 50% (w / w) of a pharmaceutically acceptable carrier or a combination of a pharmaceutically acceptable carrier in ethyl acetate or 1 :1 MeOH / DCM. The solution was then spray dried at the appropriate temperature.

[0405] For example, to produce an 50% (w / w) a compound of Formula I in an SDD, a solution was prepared having about 50% (w / w) a compound of Formula I and about 50% (w / w) of PVP K12 in ethyl acetate or 1 :1 MeOH / DCM. The solution was then spray dried at the appropriate temperature.

[0406] In some examples, the solid dispersion comprises the amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the solid dispersion, and the pharmaceutically acceptable carrier in an amount of about 50 percent by weight of the solid dispersion. For example, in certain embodiments, solid dispersion comprises the amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the solid dispersion, and PVP K12 in an amount of about 50 percent by weight of the solid dispersion, the solid dispersion comprises the amorphous form of a compound of Formula I, in an amount of about 49 percent by weight of the solid dispersion, and the pharmaceutically acceptable carrier in an amount of about 49 percent by weight of the solid dispersion, and the surfactant in an amount of about 2 percent by weight of the solid dispersion. For example, in certain embodiments, solid dispersion comprises the amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the solid dispersion, and PVP K12 in an amount of about 50 percent by weight of the solid dispersion and Polysorbate 20 in an amount of about 2 percent by weight of the solid dispersion.

[0407] The resultant SDD can be blended with one or more excipients, as described herein, and then granulated and / or compacted to produce a final blend for encapsulating or tableting. In particular embodiments, the one or more excipients include a binding agent, a filler, a disintegrating agent, a wetting agent, a glidant, and a lubricant.

[0408] Other Pharmaceutically acceptable excipients

[0409] Pharmaceutically acceptable excipients useful in the pharmaceutical compositions of the invention can further include one or more other ingredients capable of maintaining a compound of Formula I in a substantially amorphous form. In particular embodiments, the excipient is a pharmaceutically acceptable carrier, as described herein.

[0410] The pharmaceutical compositions can include an amorphous solid dispersion of a compound of Formula I described herein, in any pharmaceutically acceptable carrier. In one embodiment an amorphous solid dispersion as described herein is administered to a patient in need thereof as a spray dried dispersion (SDD). In another embodiment the present invention provides a spray dried dispersion (SDD) including a compound of Formula I and one or more pharmaceutically acceptable excipients as defined herein. In a further embodiment the SDD includes a compound of Formula I and one or more pharmaceutically acceptable excipients.

[0411] Amorphous Solid Dispersion Pharmaceutical Compositions

[0412] Pharmaceutically acceptable polymers include one or more carriers capable of forming an amorphous solid dispersion with an amorphous form of a compound of Formula I. Two or more carriers can be used together and can optionally include one or more surfactants. Exemplary carriers are PVP K12. Exemplary amorphous solid dispersions are those having about 50% by weight of an amorphous form of a compound of Formula I or a pharmaceutically acceptable salt thereof, and between about 50% of a pharmaceutically acceptable carrier. Exemplary amorphous solid dispersions are those having about 49% by weight of an amorphous form of a compound of Formula I or a pharmaceutically acceptable salt thereof, and between about 49% of a pharmaceutically acceptable carrier, and between about 2% by weight of a surfactant.

[0413] Pharmaceutical Compositions

[0414] The pharmaceutical compositions described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.

[0415] The compounds described herein may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the methods described herein. In accordance with the methods of the disclosure, the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds described herein may be administered, for example, by parenteral administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. In particular embodiments, a compound of the present disclosure or a pharmaceutically acceptable salt thereof is formulated for intramuscular and / or subcutaneous administration. In some embodiments, a pharmaceutical composition of the present disclosure is administered to a subject in need thereof intramuscularly. In some embodiments, a pharmaceutical composition of the present disclosure is administered to a subject in need thereof subcutaneously.

[0416] Pharmaceutical compositions of a compound of Formula I described herein can be prepared in combination with a suitable excipient, such as surfactant, such as a solvent, a diluent, a granulating agent, a dispersing agent, a surfactant, an emulsifier, a stabilizer, a polymer, a binding agent, a preservative, a cryoprotectant, a buffering agent, a lubricating agent, an oil, or a combination thereof. Dispersions can be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable pharmaceutical compositions are described, for example, in Remington’s Pharmaceutical Sciences (2012, 22nd ed.) and in The United States Pharmacopeia: The National Formulary (USP 41 NF36), published in 2018. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe.

[0417] In some examples, the pharmaceutical composition comprises the amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the pharmaceutical composition, and the pharmaceutically acceptable carrier in an amount of about 50 percent by weight of the pharmaceutical composition. For example, in certain embodiments, pharmaceutical composition comprises the amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the pharmaceutical composition, and PVP K12 in an amount of about 50 percent by weight of the pharmaceutical composition, the pharmaceutical composition comprises the amorphous form of a compound of Formula I, in an amount of about 49 percent by weight of the pharmaceutical composition, and the pharmaceutically acceptable carrier in an amount of about 49 percent by weight of the pharmaceutical composition, and the surfactant in an amount of about 2 percent by weight of the pharmaceutical composition. For example, in certain embodiments, pharmaceutical composition comprises the amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the pharmaceutical composition, and PVP K12 in an amount of about 50 percent by weight of the pharmaceutical composition and Polysorbate 20 in an amount of about 2 percent by weight of the pharmaceutical composition.

[0418] In some examples, the pharmaceutical composition comprises a solid dispersion of the amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the pharmaceutical composition, and the pharmaceutically acceptable carrier in an amount of about 50 percent by weight of the pharmaceutical composition. For example, in certain embodiments, pharmaceutical composition comprises a solid dispersion of the amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the pharmaceutical composition, and PVP K12 in an amount of about 50 percent by weight of the pharmaceutical composition, the pharmaceutical composition comprises a solid dispersion of the amorphous form of a compound of Formula I, in an amount of about 49 percent by weight of the pharmaceutical composition, and the pharmaceutically acceptable carrier in an amount of about 49 percent by weight of the pharmaceutical composition, and the surfactant in an amount of about 2 percent by weight of the pharmaceutical composition. For example, in certain embodiments, pharmaceutical composition comprises a solid dispersion ofthe amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the pharmaceutical composition, and PVP K12 in an amount of about 50 percent by weight of the pharmaceutical composition and Polysorbate 20 in an amount of about 2 percent by weight of the pharmaceutical composition. In some examples, the pharmaceutical composition comprises in situ PLGA gel. Preferably, the pharmaceutical composition comprises a PLGA ratio of lactic acid to glycolic acid. Preferably, the PLGA ratio is 50% lactic acid to 50% glycolic acid. Preferably, the PLGA ratio is 65% lactic acid to 35% glycolic acid. Preferably, the PLGA ratio is 75% lactic acid to 25% glycolic acid. Preferably, the PLGA ratio is 85% lactic acid to 15% glycolic acid. Preferably, the pharmaceutical composition comprises between about 80 mg and about 900 mg of PLGA per g of pharmaceutical composition. Preferably, the pharmaceutical composition comprises between about 80 mg and about 200 mg of PLGA per g of pharmaceutical composition.

[0419] Preferably, the PLGA has an ester N-terminus. Preferably, the PLGA has an acid N-terminus. Preferably, the pharmaceutical composition comprises between about 1 mg and about 250 mg of PLGA per g of pharmaceutical composition. Preferably, the pharmaceutical composition comprises between about 1 mg and about 100 mg of PLGA per g of pharmaceutical composition. Preferably, the pharmaceutical composition comprises between about 1 mg and about 75 mg of PLGA per g of pharmaceutical composition. Preferably, the pharmaceutical composition comprises between about 1 mg and about 50 mg of PLGA per g of pharmaceutical composition.

[0420] Particle size distribution (PSD) is represented as Dio, D50, and D90 values. D10 indicates the size below which 10% of all particles in the pharmaceutical composition are found. D50 indicates the size below which 50% of all particles in the pharmaceutical composition are found. D90 indicates the size below which 90% of all particles in the pharmaceutical composition are found. In some embodiments, particle size is represented as D10 of the pharmaceutical composition. In some embodiments, particle size is represented as D50 of the pharmaceutical composition. In some embodiments, particle size is represented as D90 of the pharmaceutical composition. In some embodiments, particle size is represented as particle size distribution (PSD). In some embodiments, the size of particles in a pharmaceutical composition is measured as an average particle size (e.g., D50). In some embodiments, the size of particles of a pharmaceutical composition of the present disclosure is measured as an average particle size.

[0421] In some embodiments, a pharmaceutical composition of the present disclosure is a pharmaceutical composition. In some embodiments, the size of particles of a pharmaceutical composition of the present disclosure is measured as an average particle size (e.g., D50). In some embodiments, a pharmaceutical composition comprises an average particle size (e.g., D50) of between about 1 pm and about 50 pm. In some embodiments, a pharmaceutical composition comprises an average particle size of between about 1 pm and about 25 pm. In some embodiments, a pharmaceutical composition comprises an average particle size of between about 1 pm and about 10 pm. In some embodiments, a pharmaceutical composition comprises an average particle size of between about 1 pm and about 5 pm. In some embodiments, a pharmaceutical composition comprises an average particle size of between about 1 pm and about 3 pm.

[0422] In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 30 mg and about 200 mg (e.g., 30-50 mg, 30-100 mg, 30- 150 mg, 50-100 mg, 50-150 mg, 50-200 mg, 100-200 mg) of compound per g of pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 30 mg and about 50 mg of compound per g of pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 30 mg and about 100 mg of compound per g of pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 30 mg and about 150 mg of compound per g of pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 50 mg and about 100 mg of compound per g of pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 50 mg and about 150 mg of compound per g of pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 50 mg and about 200 mg of compound per g of pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 100 mg and about 200 mg of compound per g of pharmaceutical composition.

[0423] A pharmaceutical composition and / or pharmaceutical composition can be described by identifying weight percentages of the total mass of the pharmaceutical composition of each component of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition as described herein comprises a compound of the present disclosure, water and / or oil, and one or more further excipients.

[0424] In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises a weight percentage of a compound of Formula I of the present disclosure of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 1 % compound by weight and about 20% of compound by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 3% compound by weight and about 20% of compound by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 3% compound by weight and about 15% of compound by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 3% compound by weight and about 10% of compound by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 4% compound by weight and about 20% of compound by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 4% compound by weight and about 15% of compound by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 4% compound by weight and about 10% of compound by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 3% compound by weight and about 5% by weight of the total mass of the pharmaceutical composition.

[0425] In further embodiments, a pharmaceutical composition and / or pharmaceutical composition comprises a percentage by weight of one or more excipients of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 0.1% excipient by weight and about 5% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 0.2% excipient by weight and about 0.5% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 0.5% excipient by weight and about 3% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 0.5% excipient by weight and about 2.25% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 0.5% excipient by weight and about 2% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 0.5% excipient by weight and about 4% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises between about 0.1% excipient by weight and about 2% excipient by weight of the total mass of the pharmaceutical composition.

[0426] In further embodiments, the remainder of the pharmaceutical composition and / or pharmaceutical composition comprises water and / or oil, sufficient to make the total weight percent of the pharmaceutical composition equal to 100%. In some embodiments, the percentage by weight of water and / or oil of the total mass of the pharmaceutical composition is 100% minus the sum of the percentage of compound by weight and the percentage of one of more excipients by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition comprises between about 75% water and / or oil by weight and about 97% water and / or oil by weight of the total mass of the pharmaceutical composition.

[0427] A liquid pharmaceutical composition and / or pharmaceutical composition can have different measurable properties that alter drug availability, one of which is viscosity. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure has a viscosity of between about 1 and about 25 cp. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure has a viscosity of between about 1 and about 5 cp. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure has a viscosity of between about 1 and about 10 cp. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure has a viscosity of between about 1 and about 15 cp. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure has a viscosity of between about 1 and about 20 cp.

[0428] A pharmaceutical composition and / or pharmaceutical composition of the present disclosure may be lyophilized, frozen, spray dried, powdered, aqueous, or oil-based. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure is lyophilized. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure comprises a cryoprotectant. In some embodiments, the cryoprotectant is trehalose, sucrose, mannitol, PVP, PVA, PEG, amino acids such as glycine or a combination thereof. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure is frozen. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure is spray dried. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure is powdered. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure is crystalline. In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure is partially crystalline (mixture of crystalline and amorphous) In some embodiments, a pharmaceutical composition and / or pharmaceutical composition of the present disclosure is amorphous (e.g., the amorphous pharmaceutical composition is media milled in oil).

[0429] In some embodiments, a pharmaceutical composition of the present disclosure is administered using an 18 gauge needle. In some embodiments, a pharmaceutical composition of the present disclosure is administered using a 19 gauge needle. In some embodiments, a pharmaceutical composition of the present disclosure is administered using a 20 gauge needle. In some embodiments, a pharmaceutical composition of the present disclosure is administered using a 21 gauge needle. In some embodiments, a pharmaceutical composition of the present disclosure is administered using a 22 gauge needle. In some embodiments, a pharmaceutical composition of the present disclosure is administered using a 23 gauge needle. In some embodiments, a pharmaceutical composition of the present disclosure is administered using a 24 gauge needle. In some embodiments, a pharmaceutical composition of the present disclosure is administered using a 25 gauge needle. In some embodiments, a pharmaceutical composition of the present disclosure is administered using a 26 gauge needle. In some embodiments, a pharmaceutical composition of the present disclosure is administered using a 27 gauge needle. In some embodiments, a pharmaceutical composition of the present disclosure is administered using a 28 gauge needle. In some embodiments, the weight of a subject in need thereof determines the needle gauge used for administration. The compounds described herein may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice. Carrier

[0430] Solid dispersions of the invention include a carrier.

[0431] Suitable carriers are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., ct al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.

[0432] Non-limiting examples of pharmaceutically acceptable carriers include, but are not limited to: polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, ethylene vinyl acetate, poly(meth) acrylic acid, polyamides, copolymers and mixtures thereof. Non-limiting examples of pharmaceutically acceptable carriers include, but are not limited to, synthetic polymers such as polymers of lactic acid and glycolic acid, poly-anhydrides, polyurethanes, and natural polymers such as alginate and other polysaccharides including dextran and cellulose, collagen, albumin and other proteins, copolymers and mixtures thereof. In general, these biodegradable polymers degrade either by enzymatic hydrolysis or exposure to water in vivo, by surface or bulk erosion. These biodegradable polymers may be used alone, as physical mixtures (blends), or as co-polymers.

[0433] Preferably, the pharmaceutically acceptable carrier is polyethylene glycol, Polyvinylpyrrolidone, poly lactic-co-glycolic acid, poly vinyl alcohol, phospholipids, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, 1 ,2-Distearoyl-sn-glycero-3-phosphocholine, polymethacrylates, polyvinyl acetate, cellulose derivatives, glyceryl behenate, polyethyleneglycol derivatives of a mono-glyceride, vitamin E, polyethylene or polyoxyethylene esters of hydroxyl stearic acid, polyoxylglycerides, polyethoxylated castor oil or combinations thereof.

[0434] Preferably, the pharmaceutically acceptable carrier is poly(vinyl alcohol) (PVA). Preferably, the pharmaceutically acceptable carrier is PEG. When polyethylene glycol (PEG) is used, it is preferably PEG-200-800, more preferably PEG-400. When polyethylene glycol (PEG) is used, it is preferably PEG- 2000-8000, more preferably PEG-4000. Preferably, the pharmaceutically acceptable carrier is a mixture of PEG and PVP. Preferably, the pharmaceutically acceptable carrier is PVP. Preferably, the pharmaceutically acceptable carrier is p-cyclodextrin. Preferably, the pharmaceutically acceptable carrier is sulfobutylether-p-cyclodextrin. Preferably, the pharmaceutically acceptable carrier is PLGA 85:15. Preferably, the pharmaceutically acceptable carrier is PLGA 75:25. Preferably, the pharmaceutically acceptable carrier is PLGA 60:40. Preferably, the pharmaceutically acceptable carrier is PLGA 50:50. Preferably, the pharmaceutically acceptable carrier is PLGA 10:90. Preferably, the pharmaceutically acceptable carrier is Polyvinylpyrrolidone PVP K12. Preferably, the pharmaceutically acceptable carrier is albumin. Preferably, the pharmaceutically acceptable carrier is polyvinyl alcohol (PVA). Preferably, the pharmaceutically acceptable carrier is a mixture of Polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG). Preferably, the pharmaceutically acceptable carrier is dipalmitoylphosphatidylcholine (DPPC). Preferably, the pharmaceutically acceptable carrier is 1 ,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC). Poly (lactic-co-glycolic) acid (PLGA)-based Microspheres and In Situ Gels

[0435] Poly (lactic-so-glycolic) acid (PLGA) formulations have been used for over 30 years to deliver small molecules, peptides, and proteins for periods ranging from 1 week to 6 months. Around 20 PLGA formulated drugs have been approved by the FDA. Most commonly, PLGA formulations are microspheres, but they can also be in the form of in situ gels and solid implants. As used herein, the terms microparticle and microsphere are interchangeable. PLGA is typically defined by its molecular weight, its lactic acid to glycolic acid (L:G) ratio, by the end group attached, and also by the molecular shape (e.g., linear or branched).

[0436] In some embodiments, a pharmaceutical composition of the present disclosure comprises PLGA microspheres. In some embodiments, a pharmaceutical composition of the present disclosure comprises in situ PLGA gels. In some embodiments, a pharmaceutical composition of the present disclosure comprises solid PLGA implants. In some embodiments, the PLGA is linear. In some embodiments, the PLGA is branched. In some embodiments, the PLGA has an ester N-terminus (e.g., RG502). In some embodiments, the PLGA has an acid N-terminus (e.g., RG502H).

[0437] In one aspect, the present disclosure provides a pharmaceutically acceptable composition comprising a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I that reduces the level and / or activity of a protein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0438] In some embodiments, a PLGA microsphere and / or PLGA gel formulation of the present disclosure comprises one or more excipients. In some embodiments, a PLGA microsphere and / or PLGA gel formulation of the present disclosure comprises a solvent, a diluent, a granulating agent, a dispersing agent, a surfactant, an emulsifier, a stabilizer, a polymer, a binding agent, a preservative, a cryoprotectant, a buffering agent, a lubricating agent, an oil, or a combination thereof. In some embodiments, the excipient is used to reconstitute a lyophilized, frozen, spray dried, or powdered PLGA microsphere formulations prior to administration. In some embodiments, a PLGA microsphere and / or PLGA gel formulation of the present disclosure is suspended and dispersed in an excipient. In some embodiments, a PLGA microsphere and / or PLGA gel formulation of the present disclosure comprises a solvent, diluent, surfactant, or a combination thereof. In some embodiments, a PLGA microsphere and / or PLGA gel formulation of the present disclosure is suspended and dispersed in poly(vinyl alcohol) (PVA). In some embodiments, a PLGA microsphere and / or PLGA gel formulation of the present disclosure is suspended and dispersed in POLOXAMERO188 (P-188). In some embodiments, a PLGA microsphere and / or PLGA gel formulation of the present disclosure is suspended and dispersed in POLOXAMERO407 (P-407).

[0439] In situ forming PLGA gel implants / depots are formed by mixing drug powder with PLGA dissolved in an excipient (e.g., a solvent) just before injection. After injection, the excipient, which is generally a water-miscible solvent, is diluted with water at the injection site, leading to gel formation and solidification of the drug / PLGA mixture. In some embodiments, a PLGA in situ gel formulation of the present disclosure comprises one or more excipients. In some embodiments, the excipient comprises a solvent. In some embodiments, the solvent is dichloromethane (DCM), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), ethyl acetate, N-methyl-2-pyrrolidone (NMP), methyl ethyl ketone, tetra hydrofuran, ethyl benzoate, chlorobenzene, benzyl alcohol, methyl n-propyl ketone, n-butyl acetate, trichloroethylene, ethyl-L-lactate, 2-methyl tetra hydrofuran, 1 ,2-dichlorobenzene, toluene, methyl isobutyl ketone, butyl lactate, p-xylene, acetone, methanol, dichloromethane, or combinations thereof. In some embodiments, the solvent is dimethyl sulfoxide (DMSO). In some embodiments, the solvent is dimethyl formamide (DMF). In some embodiments the solvent is ethyl acetate. In some embodiments the solvent is N-methyl-2-pyrrolidone (NMP). In some embodiments the solvent is 1 :1 MeOH / DCM.

[0440] Microparticles or microspheres are a common form of PLGA formulation. Particle size distribution (PSD) is represented as D10, D50, and D90 values. D10 indicates the size below which 10% of all particles in the pharmaceutical composition are found. D50 indicates the size below which 50% of all particles in the pharmaceutical composition are found. D90 indicates the size below which 90% of all particles in the pharmaceutical composition are found. In some embodiments, particle size is represented as D10 of the pharmaceutical composition. In some embodiments, particle size is represented as D50 of the pharmaceutical composition. In some embodiments, particle size is represented as D90 of the pharmaceutical composition. In some embodiments, particle size is represented as particle size distribution (PSD). In some embodiments, the size of particles in a pharmaceutical composition is measured as an average particle size (e.g., D50). In some embodiments, the size of a PLGA microsphere is measured as an average particle size.

[0441] In some embodiments, the average size of a PLGA microsphere is about 100 pm. In some embodiments, the average size of a PLGA microsphere is between about 90 pm and about 100 pm. In some embodiments, the average size of a PLGA microsphere is between about 80 pm and about 90 pm. In some embodiments, the average size of a PLGA microsphere is between about 70 pm and about 80 pm. In some embodiments, the average size of a PLGA microsphere is between about 60 pm and about 70 pm. In some embodiments, the average size of a PLGA microsphere is between about 50 pm and about 60 pm. In some embodiments, the average size of a PLGA microsphere is between about 40 pm and about 50 pm. In some embodiments, the average size of a PLGA microsphere is between about 30 pm and about 40 pm. In some embodiments, the average size of a PLGA microsphere is between about 20 pm and about 30 pm. In some embodiments, the average size of a PLGA microsphere is between about 10 pm and about 20 pm. In some embodiments, the average size of a PLGA microsphere is between about 1 pm and about 10 pm. In some embodiments, the average size of a PLGA microsphere is between about 5 pm and about 10 pm. In some embodiments, the average size of a PLGA microsphere is between about 5 pm and about 100 pm. In some embodiments, the average size of a PLGA microsphere is between about 1 pm and about 100 pm.

[0442] In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 50 mg and about 800 mg (e.g., 50-100 mg, 50-200 mg, 80-200 mg, 50-300 mg, 50-400 mg, 50-500 mg, 50-600 mg, 50-700 mg, 100-200 mg, 100-400 mg, 100-500 mg, 100- 700 mg, 100-800 mg, 200-400 mg, 200-500 mg, 200-800 mg, 500-800 mg) of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 50 mg and about 100 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 50 mg and about 200 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 80 mg and about 200 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 50 mg and about 300 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 50 mg and about 400 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 50 mg and about 500 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 50 mg and about 600 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 50 mg and about 700 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 100 mg and about 200 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 100 mg and about 400 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 100 mg and about 500 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 100 mg and about 700 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 100 mg and about 800 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 200 mg and about 400 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 200 mg and about 500 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 200 mg and about 800 mg of compound per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 500 mg and about 800 mg of compound per g of formulation.

[0443] In some embodiments, a PLGA microsphere formulation and / or in situ PLGA gel formulation of the present disclosure comprises between about 80 mg and about 900 mg (e.g., 80-200 mg, 100-200 mg, 100-400 mg, 100-500 mg, 100-700 mg, 200-400 mg, 200-500 mg, 200-900 mg, 500-900 mg) of PLGA per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 80 mg and about 200 mg of PLGA per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 100 mg and about 200 mg of PLGA per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 100 mg and about 400 mg of PLGA per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 100 mg and about 500 mg of PLGA per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 100 mg and about 700 mg of PLGA per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 200 mg and about 400 mg of PLGA per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 200 mg and about 500 mg of PLGA per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 200 mg and about 900 mg of PLGA per g of formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 500 mg and about 900 mg of PLGA per g of formulation.

[0444] A PLGA microsphere formulation and / or PLGA gel formulation can be described by identifying weight percentages of the total mass of the formulation of each component ofthe formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation as described herein comprises a compound of the present disclosure, PLGA, and one or more excipients. In some embodiments, one or more excipients is evaporated from a PLGA microsphere formulation during formulation processing. The weight percentages for all components of a formulation should add up to 100%.

[0445] In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation can comprise a percentage of a compound of the present disclosure, of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or PLGA in situ gel formulation of the present disclosure comprises between about 5% compound by weight and about 70% compound by weight of the total mass of the formulation. In some embodiments, a PLGA microsphere formulation of the present disclosure comprises between about 10% compound by weight and about 70% compound by weight of the total mass of the formulation. In some embodiments, a PLGA microsphere formulation of the present disclosure comprises between about 20% compound by weight and about 30% compound by weight of the total mass of the formulation. In some embodiments, a PLGA in situ gel formulation of the present disclosure comprises between about 5% compound by weight and about 20% compound by weight of the total mass of the formulation. In some embodiments, a PLGA in situ gel formulation of the present disclosure comprises between about 8% compound by weight and about 20% compound by weight of the total mass of the formulation. In some embodiments, a PLGA in situ gel formulation of the present disclosure comprises between about 8% compound by weight and about 10% compound by weight of the total mass of the formulation. In some embodiments, a PLGA in situ gel formulation of the present disclosure comprises between about 10% compound by weight and about 20% compound by weight of the total mass of the formulation.

[0446] In further embodiments, a PLGA microsphere and / or in situ PLGA gel formulation comprises a weight percentage of PLGA of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 10% by weight of PLGA and about 90% by weight of PLGA of the total mass ofthe formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 20% by weight of PLGA and about 90% by weight of PLGA of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 30% by weight of PLGA and about 90% by weight of PLGA of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 30% by weight of PLGA and about 80% by weight of PLGA of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 30% by weight of PLGA and about 70% by weight of PLGA of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 30% by weight of PLGA and about 60% by weight of PLGA of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 30% by weight of PLGA and about 50% by weight of PLGA of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 30% by weight of PLGA and about 40% by weight of PLGA of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 10% by weight of PLGA and about 40% by weight of PLGA of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 10% by weight of PLGA and about 30% by weight of PLGA of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 20% by weight of PLGA and about 30% by weight of PLGA of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 10% by weight of PLGA and about 20% by weight of PLGA of the total mass of the formulation.

[0447] In further embodiments, a PLGA microsphere and / or in situ PLGA gel formulation can comprise a percentage of one or more excipients (e.g., polymer), of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 50% excipient by weight and about 75% excipient by weight of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 50% excipient by weight and about 70% excipient by weight of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 60% excipient by weight and about 70% excipient by weight of the total mass of the formulation. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure comprises between about 50% excipient by weight and about 60% excipient by weight of the total mass of the formulation.

[0448] In further embodiments, an excipient may be evaporated from a PLGA microsphere formulation as part of formulation processing. In some embodiments, a PLGA microsphere formulation of the present disclosure comprises between about 50% excipient by weight and about 75% excipient by weight of the total mass of the formulation. In some embodiments, a PLGA microsphere formulation of the present disclosure comprises between about 50% excipient by weight and about 70% excipient by weight of the total mass of the formulation that is evaporated during formulation processing. In some embodiments, a PLGA microsphere formulation of the present disclosure comprises between about 60% excipient by weight and about 70% excipient by weight of the total mass of the formulation that is evaporated during formulation processing. In some embodiments, a PLGA microsphere formulation of the present disclosure comprises between about 50% excipient by weight and about 60% excipient by weight of the total mass of the formulation that is evaporated during formulation processing.

[0449] PLGA properties such as molecular weight and / or L:G ratios can affect final structures of microspheres, as they influence other events during microparticle formation, such as PLGA coalescence, shell formation, and solidification. This, in turn, impacts formation of pores throughout the microspheres, ultimately determining the initial burst and subsequent drug release kinetics. PLGAs with different L:G ratios dissolve in different solvents, making the L:G ratio even more important. As the L:G ratio increases, i.e., as the lactide portion increases, PLGA dissolves in a larger number of solvents. When the L:G ratio is smaller than 50:50 (i.e., more glycolide), the PLGA dissolves generally in only in highly fluorinated solvents, such as hexafluoroisopropanol. In some embodiments, a PLGA microsphere formulation of the present disclosure comprises a PLGA ratio of lactic acid to glycolic acid. In some embodiments, an in situ PLGA gel formulation of the present disclosure comprises a PLGA ratio of lactic acid to glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 95% lactic acid to 5% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 90% lactic acid to 10% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 85% lactic acid to 15% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 80% lactic acid to 20% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 75% lactic acid to 25% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 70% lactic acid to 30% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 65% lactic acid to 35% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 60% lactic acid to 40% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 55% lactic acid to 45% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 50% lactic acid to 50% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 45% lactic acid to 55% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 40% lactic acid to 60% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 35% lactic acid to 65% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 30% lactic acid to 70% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 25% lactic acid to 75% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 20% lactic acid to 80% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 15% lactic acid to 85% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 10% lactic acid to 90% glycolic acid. In some embodiments, the PLGA ratio of lactic acid to glycolic acid is 5% lactic acid to 95% glycolic acid. In some embodiments, the formulation comprises a mixture of one or more PLGA ratios of lactic acid to glycolic acid. In some embodiments, the PLGA has an ester N-terminus (e.g., RG502). In some embodiments, the PLGA has an acid N-terminus (e.g., RG502H).

[0450] Excipient-dependent PLGA solubility affects molecular dimensions and ultimately the solution viscosity. The solution viscosity in turn significantly impacts the droplet breakage and resultant emulsion microdroplet size distribution. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure has a viscosity of between about 1 and about 25 cp. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure has a viscosity of between about 1 and about 5 cp. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure has a viscosity of between about 1 and about 10 cp. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure has a viscosity of between about 1 and about 15 cp. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure has a viscosity of between about 1 and about 20 cp.

[0451] In some embodiments, a PLGA microsphere formulation and / or in situ PLGA gel formulation of the present disclosure is lyophilized. In some embodiments, a PLGA microsphere formulation and / or in situ PLGA gel formulation of the present disclosure is frozen. In some embodiments, a PLGA microsphere formulation and / or in situ PLGA gel formulation of the present disclosure is spray dried. In some embodiments, a PLGA microsphere formulation and / or in situ PLGA gel formulation of the present disclosure is powdered. In some embodiments, a PLGA microsphere formulation and / or in situ PLGA gel formulation of the present disclosure is aqueous. In some embodiments, a PLGA microsphere formulation and / or in situ PLGA gel formulation of the present disclosure is oil-based. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure is crystalline. In some embodiments, a PLGA microsphere and / or in situ PLGA gel formulation of the present disclosure is amorphous.

[0452] Surfactants

[0453] The suspensions of the invention can contain a surfactant in an amount sufficient to provide amorphous dispersions of injectable particulates that form the pharmaceutical composition of the invention. The surfactant can be selected based on its hydrophilic-lipophilic balance (HLB) to match the surface properties of drug particles and the continuous phase (e.g., of water). The surfactant can be an ionic or a neutral surfactant. In general, non-ionic surfactants are preferred and surfactants where the hydrophilic function includes polyethylene oxide are especially preferred.

[0454] Non-limiting examples of ionic surfactants are sodium dodecyl sulfate (SDS), phospholipids (e.g., lecithin), quaternary ammonium salts (e.g., cetrimonium bromide), pyridinium salts (e.g., cetylpyridinium chloride), and fatty acid salts. Non-limiting examples of non-ionic surfactants are poloxamers (also known under tradenames Cremophor®, Kolliphor®, Lutrol®, Pluronic®, and Synperonic®), poloxamines, polysorbates (also known under tradename Tween®), fatty acid esters of sorbitan (also known under tradename Span®), polyethylene glycol alkyl ethers (also known under tradename Brij®), fatty acid esters of polyethylene glycol (also known under tradenames Solutol® and Myrj®), alkyl polyglycosides (e.g., alkyl polyglucosides (also known under tradenames Triton® and Ecoteric®)), and fatty acid monoglycerides (e.g., monolaurin). Preferably, the surfactant is POLOXAMER®188 (P-188). Preferably, the surfactant is POLOXAMER®407 (P-407). Preferably, the surfactant is polysorbate. Preferably, the surfactant is polysorbate 20. Preferably, the surfactant is polysorbate 80. Preferably, the surfactant is poloxamer. Preferably, the surfactant is Poloxamer 188. Preferably, the surfactant is Captisol. Preferably, the surfactant is TWEEN. Preferably, the surfactant is TWEEN 20. Preferably, the surfactant is solutol. The surfactant may be selected from a wide variety of soluble non-ionic surface active agents including surfactants that are generally commercially available under the IGEPAL™ trade name from GAF Company. The IGEPAL™ liquid non-ionic surfactants are polyethylene glycol p-isooctylphenyl ether compounds and are available in various molecular weight designations, for example, IGEPAL™ CA720, IGEPAL™ CA630, and IGEPAL™ CA890. Other suitable non-ionic surfactants include those available under the trade name TETRONIC™ 909 from BASF Wyandotte Corporation. This material is a tetrafunctional block copolymer surfactant terminating in primary hydroxyl groups. Suitable non-ionic surfactants are also available under the VISTA ALPHONIC™ trade name from Vista Chemical Company and such materials are ethoxylates that are non-ionic biodegradables derived from linear primary alcohol blends of various molecular weights. The surfactant may also be selected from poloxamers, such as polyoxyethylene-polyoxypropylene block copolymers, such as those available under the trade names Synperonic PE series (ICI), Pluronic® series (BASF), Supronic, Monolan, Pluracare™, and Plurodac™; polysorbate surfactants, such as Tween® 20 (PEG-20 sorbitan monolaurate); nonionic detergents (e.g., nonyl phenoxypolyethoxylethanol (NP-40), 4-octylphenol polyethoxylate (Triton-X100™), Brij nonionic surfactants); and glycols such as ethylene glycol and propylene glycol. In particular embodiments, the surfactant is a non-ionic surfactant including a polyglycolized glyceride, a poloxamer, an alkyl saccharide, an ester saccharide, a polysorbate surfactant, or a mixture thereof.

[0455] Cyclodextrin Complexes

[0456] The pharmaceutical compositions of the invention include a cyclodextrin complexed to a compound of Formula I, or an amorphous form of a compound of Formula I.

[0457] Examples of a cyclodextrin for use in the inclusion complexes in the formulations of the invention include, but are not limited to, water soluble unsubstituted or substituted alpha-cyclodextrin, betacyclodextrin, and gamma-cyclodextrin. Examples of substituted beta-cyclodextrins that may be employed in the inclusion complexes herein include, but are not limited to, methyl beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, and sulfobutylether beta-cyclodextrin. Examples of substituted gamma-cyclodextrins that may be employed in the inclusion complexes herein include, but are not limited to, hydroxypropyl gamma-cyclodextrin. Mixtures of cyclodextrins may also be employed. For example, a formulation comprising cannabinoid and a mixture of two or three or four or more cyclodextrins can also be used. Where a more than one cyclodextrin is employed, it may be of the same cyclodextrin class (e.g., two alpha-cyclodextrins) or different chemical classes (e.g., one alpha-cyclodextrin and one beta- or gamma- cyclodextrin). In one preferred embodiment, the cyclodextrin is hydroxypropyl beta-cyclodextrin or methyl beta-cyclodextrin.

[0458] In some embodiments, a cyclodextrin is obtained from a commercial source, including, but not limited to cyclodextrins sold under the following tradenames CAVASOL® W6 HP (Wacker Chemie AG, Munich, Germany), CAVASOL® W6 HP TL (Wacker Chemie AG, Munich, Germany), CAVAMAX® W6 Pharma (Wacker Chemie AG, Munich, Germany), CAVASOL® W7 HP (Wacker Chemie AG, Munich, Germany), CAVASOL® W7 HP Pharma (Wacker Chemie AG, Munich, Germany), CAVASOL® W7 HP TL (Wacker Chemie AG, Munich, Germany), CAVASOL® W7 M (Wacker Chemie AG, Munich, Germany), CAVASOL® W7 M Pharma (Wacker Chemie AG, Munich, Germany), CAVASOL® W7 M TL (Wacker Chemie AG, Munich, Germany), CAVASOL® W8 HP (Wacker Chemie AG, Munich, Germany), CAVASOL® W8 HP Pharma (Wacker Chemie AG, Munich, Germany), KLEPTOSE® HPB (Roquette Pharma, Geneva, III.), and CAPTISOL® (Cydex Pharmaceuticals, Inc. Lenexa, Kans.). In some embodiments, the cyclodextrin is CAVASOL® W7 M Pharma. In some embodiments, the cyclodextrin is KLEPTOSE® HPB. Mechanical

[0459] Mechanical methods of preparing formulations include, but are not limited to, jet mills, disc mills, attritors and bead mills, ball mills, planetary mills, vibration and vibrocentrifugal mills, roller and centrifugal roller mills, extruders, hammer mills, knife mills, pin mills, and disintegrators.

[0460] In a jet mill, particles are accelerated to a desired speed in a gas flow, followed by a collision with an immobile body. In cyclone mills, particles collide with each other as they cross each other’s trajectories rather than colliding with an immobile target. In some embodiments, a formulation of the present disclosure is prepared using a jet mill.

[0461] In disc mills, particles pass between two rotating discs, causing friction of the particles against the discs as well as grinding. Mills with a variable gap between the discs and discs with notches are used to increase milling efficiency. In some embodiments, a formulation of the present disclosure is prepared using a disc mill.

[0462] Attritors comprise a reactor with an impeller submerged in grinding bodies. As the impeller is rotating, it grinds the particles between the grinding bodies. In some embodiments, a formulation of the present disclosure is prepared using an attritor.

[0463] In ball mills, a large number of grinding bodies and the material being ground are placed inside a cylinder rotating around its central axis. Forces of friction between the walls of the cylinder and the grinding bodies cause the grinding bodies to move and grind the material. Sometimes grinding bodies are not used, and particles of the material grind themselves in a process known as “auto-grinding”. Planetary activator mills are a specific type of ball mill in which reservoirs are secured to a frame and rotate around a common axis, while the reactors rotate around their axes in the opposite direction. Disintegration occurs due to interactions between the material and grinding bodies, which are put into motion by centrifugal force, Coriolis force, and gravity. In some embodiments, a formulation of the present disclosure is prepared using a ball mill. In some embodiments, a formulation of the present disclosure is prepared using a planetary activator.

[0464] Vibration mills are used for fine and ultrafine grinding and use a vertical vibration for grinding instead of a circular motion used in ball mills. In some embodiments, a formulation of the present disclosure is prepared using a vibration mill.

[0465] Roller mills are a type of grinder in which the material is simultaneously subjected to two types of impact: abrasion and crushing. Centrifugal roller mills comprise roller axes that are oriented vertically, and the particles are ground as they travel between the rollers and the stator. In some embodiments, a formulation of the present disclosure is prepared using a roller mill.

[0466] Mechanical treatment of a material by an extruder is not necessarily accompanied by grinding. In an extruder, a screw (usually one or two) is the main working part, and as the screw rotates, it presses the particles along the treatment zones. In some embodiments, a formulation of the present disclosure is prepared using an extruder.

[0467] Hammer mills, knife mills, pin mills, and disintegrators all share a common feature in that the milling body is one or more discs with grinding elements secured on a surface. Material typically passes from the disc center into the treatment zone and is dispersed to the chamber periphery by centrifugal force, where it is exposed to grinding elements. In some embodiments, a formulation of the present disclosure is prepared using a hammer mill. In some embodiments, a formulation of the present disclosure is prepared using a knife mill. In some embodiments, a formulation of the present disclosure is prepared using a pin mill. In some embodiments, a formulation of the present disclosure is prepared using a disintegrator.

[0468] In some embodiments, a formulation of the present disclosure is prepared using a jet mill, disc mill, attritor, bead mill, ball mill, planetary mill, vibration mill, roller mill, centrifugal roller mills, extruder, hammer mill, knife mill, pin mill, or disintegrator.

[0469] Excipients

[0470] Pharmaceutical formulations of the compounds described herein may additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes, but is not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surfactants (surface active agents), isotonic agents, thickening or emulsifying agents, stabilizers, preservatives, and the like, as suited to the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro, Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety). The use of a conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium may be incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition. Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, surfactants and / or emulsifiers, solvents, preservatives, buffering agents, lubricating agents, and / or oils. Such excipients may optionally be included in the pharmaceutical formulations of the compounds described herein.

[0471] In some embodiments, a pharmaceutically acceptable excipient may be at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure. In some embodiments, an excipient may be approved for use for humans and for veterinary use. In some embodiments, an excipient may be approved by United States Food and Drug Administration. In some embodiments, an excipient may be of pharmaceutical grade. In some embodiments, an excipient may meet the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and / or the International Pharmacopoeia.

[0472] Exemplary vehicles, solvents and / or diluents include, but are not limited to, water, saline (including normal saline, 0.9% sodium chloride solution), saline and polysorbate 20, dichloromethane, dimethyl sulfoxide (DMSO), dimethyl formamide, ethyl acetate, ethyl formate, ethyl ether, methyl ethyl ketone, tetrahydrofuran, ethyl benzoate, chlorobenzene, benzyl alcohol, methyl n-propyl ketone, n-butyl acetate, trichloroethylene, ethyl-L-lactate, 2-methyl tetrahydrofuran, 1 ,2-dichlorobenzene, toluene, methyl isobutyl ketone, butyl lactate, p-xylene, acetone, ethanol, isopropanol, butanol, propylene carbonate, methyl acetate, triacetin, benzyl alcohol, methylene chloride, chloroform, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and / or a combination thereof. Exemplary granulating and / or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, sodium carboxymethyl cellulose (CMC Na), crosslinked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (VEEGUM®), sodium lauryl sulfate, quaternary ammonium compounds, and / or a combination thereof.

[0473] Exemplary surfactants (surface active agents) and / or emulsifiers and / or stabilizers include, but are not limited to, natural emulsifiers {e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and VEEGUM [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate), carbomers (e.g. carboxy polymethylene, polyacrylic acid, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. sodium carboxymethyl cellulose (CMC Na), powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate or polysorbate 20 [TWEENO20], polyoxyethylene sorbitan or polysorbate 60 [TWEENO60], polyoxyethylene sorbitan monooleate or polysorbate 80 [TWEENO80], sorbitan monopalmitate [SPANO40], sorbitan monostearate [SPANO60], sorbitan tristearate [SPANO65], glyceryl monooleate, sorbitan monooleate [SPANO80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [MYRJO45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and SOLUTOL®), sucrose fatty acid esters, polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [BRIJ®30]), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, sodium dodecyl sulfate (SDS), PLUORINC®F 68, POLOXAMER®188, POLOXAMER®407, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, transcutol, glycofurol, ethanol, isopropanol, bile salts, dipotassium glycyrrhizinate, and / or a combination thereof.

[0474] Exemplary polymers include, but are not limited to, poly(urethane), poly(siloxane), poly(silicone), poly(methyl methacrylate), poly(vinyl alcohol), poly(ethylene), poly(vinyl pyrrolidone), poly(2-hydroxy ethyl methacrylate), poly(N-vinyl pyrrolidone), poly(methyl methacrylate), poly(vinyl alcohol), poly(acrylic acid), polyacrylamide, poly(ethylene-co-vinyl acetate), poly(ethylene glycol), poly(methacrylic acid), polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), polyanhydrides, polyorthoester, and / or a combination thereof.

[0475] Exemplary binding agents include, but are not limited to, starch (e.g. cornstarch and starch paste); gelatin; sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol,); natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (VEEGUM®), and larch arabogalactan); alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts; silicic acid; polymethacrylates; waxes; water; alcohol, and / or a combination thereof.

[0476] Exemplary preservatives include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and / or other preservatives. Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and / or sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and / or trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and / or thimerosal. Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxy benzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and / or sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and / or phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and / or phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, GLYDANT PLUS®, PHENONIP®, methylparaben, GERM ALL® 115, GERMABEN®II, NEOLONE™, KATHON™, and / or EUXYL®, and / or a combination thereof.

[0477] Exemplary cryoprotectants include, but are not limited to mannitol, glycerol, propylene glycol, dimethyl sulfoxide (DMSO), ethylene glycol, 2-methyl-2,4-pentadiol (MPD)or hexylene glycol, sucrose, trehalose, and / or a combination thereof.

[0478] Exemplary buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, d-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and / or a combination thereof.

[0479] Exemplary lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and / or a combination thereof.

[0480] Exemplary oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and / or a combination thereof.

[0481] Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and / or perfuming agents can be present in the composition.

[0482] In one aspect, the present disclosure provides a pharmaceutically acceptable composition comprising a solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I or pharmaceutically acceptable salt, that reduces the level and / or activity of a protein, or a pharmaceutically acceptable salt thereof.

[0483] In one aspect, the present disclosure provides a pharmaceutically acceptable composition comprising a solid dispersion of a pharmaceutically acceptable carrier, surfactant, and an amorphous form of a compound of Formula I or pharmaceutically acceptable salt.

[0484] In some embodiments, the formulation comprises a pharmaceutically acceptable excipient. In some embodiments, the excipient includes a solvent, a diluent, a granulating agent, a dispersing agent, a surfactant, an emulsifier, a stabilizer, a polymer, a binding agent, a preservative, a cryoprotectant, a buffering agent, a lubricating agent, an oil, or a combination thereof.

[0485] In some embodiments, the excipient is a solvent and / or diluent. In some embodiments, the solvent and / or diluent is water, saline (including normal saline, 0.9% sodium chloride solution), saline and polysorbate 20, dichloromethane, dimethyl sulfoxide, dimethyl formamide, ethyl acetate, methyl ethyl ketone, tetrahydrofuran, ethyl benzoate, chlorobenzene, benzyl alcohol, methyl n-propyl ketone, n-butyl acetate, trichloroethylene, ethyl-L-lactate, 2-methyl tetrahydrofuran, 1 ,2-dichlorobenzene, toluene, methyl isobutyl ketone, dichloromethane, methanol, butyl lactate, p-xylene, acetone, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, or a combination thereof.

[0486] In some embodiments, the excipient is a diluent. In some embodiments, the diluent is calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, or a combination thereof. In some embodiments, the excipient is a surfactant. In some embodiments, the surfactant is polyvinylpyrrolidone (PVP), sodium carboxymethyl cellulose (CMC Na), PEG 4000, TWEENO20 (polysorbate 20), TWEENO80 (polysorbate 80), POLOXAMERO188, POLOXAMERO407, monooleate [SPANO80], or a combination thereof. Preferably, the surfactant is 0.5% TWEENO20 (polysorbate 20). Preferably, the surfactant is 0.2% TWEENO20 (polysorbate 20). Preferably, the surfactant is 20% captisol. Preferably, the surfactant is 2% TWEENO20 (polysorbate 20).

[0487] In some embodiments, the excipient is a polymer. In some embodiments, the polymer is poly(urethane), poly(siloxane), poly(silicone), poly(methyl methacrylate), poly(vinyl alcohol), poly(ethylene), poly(vinyl pyrrolidone), poly(2-hydroxy ethyl methacrylate), poly(N-vinyl pyrrolidone), poly(methyl methacrylate), poly(vinyl alcohol), poly(acrylic acid), polyacrylamide, poly(ethylene-co-vinyl acetate), poly(ethylene glycol), poly(methacrylic acid), polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), polyanhydrides, polyorthoester, and / or a combination thereof.

[0488] In some embodiments, the excipient is a cryoprotectant. In some embodiments, the cryoprotectant is mannitol, glycerol, propylene glycol, dimethyl sulfoxide (DMSO), ethylene glycol, 2- methyl-2,4-pentadiol (MPD)or hexylene glycol, sucrose, trehalose, or a combination thereof.

[0489] In some embodiments, a pharmaceutical composition can comprise a percentage by weight of an excipient. In some embodiments, a pharmaceutical composition of the present disclosure comprises 5% excipient by weight of the total mass of the formulation. In some embodiments, a pharmaceutical composition of the present disclosure comprises 10% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 15% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 20% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 25% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 30% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 35% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 40% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 45% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 50% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 55% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 60% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 65% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 70% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 75% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 80% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 85% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 90% excipient by weight of the total mass of the pharmaceutical composition. In some embodiments, a pharmaceutical composition of the present disclosure comprises 95% excipient by weight of the total mass of the pharmaceutical composition.

[0490] Dosages

[0491] The dosage (e.g., effective amount) of the compounds described herein, and / or compositions including a compound described herein, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response.

[0492] A pharmaceutical composition in accordance with the present disclosure may be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a "unit dose" refers to a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient may generally be equa...

Claims

What is claimed:ClaimsA solid dispersion of a pharmaceutically acceptable carrier and an amorphous form of a compound of Formula I:A-L-BFormula I, or a pharmaceutical salt thereof, whereinA is a protein binding moiety;B is the degradation moiety;L is a linker;A1is a bond between the linker and A;A2is a bond between B and the linker;A has the structure of Formula II:pendently, absent, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alky ny I, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C6-C12 aryl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C1-C10 heteroalkyl, optionally wherein ifare C2-C10 heterocyclyl, C2-C6 heteroaryl, C6-C12 aryl, C3-C10 cycloalkyl, or C3-C10 carbocyclyl, thenmay be joined tothrough one or more atoms; optionally wherein ifare C2-C10 heterocyclyl, C2-C6 heteroaryl, C6-C12 aryl, C3-C10 cycloalkyl, or C3-C10 carbocyclyl, thenmay be joined tothrough one or more atoms; optionally wherein if -C10 heterocyclyl, C2-C6 heteroaryl, C6-C12 aryl, C3-C10 cycloalkyl, or C3-C10, may be joined tothrough one or more atoms;B has the structure of Formula III:whereinR1is, independently, H, A2, C(O)A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, or C(O)R1a, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;R2is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, or C(O)R1a, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen or C1-C4 alkyl;R3is, independently, A2, C(O)A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted Ce-C-io aryl;R4is, independently, H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted Ce-C-io aryl;R5is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;R6is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl, optionally substituted Ci-Ce alkyl Ce-C-io aryl, or optionally substituted Ci-Ce alkyl C3-C10 heteroaryl; each R1ais, independently, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted Ce-C-io aryl, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A2and / or halogen, CN, or C1-C4 alkyl; and wherein one and only one of R1, R3, or R6comprises A2or C(O)A2; and wherein one and only one of ®, ® , ®, or ® comprises A1.

2. The compound of claim 1 , wherein the amorphous form of a compound of Formula I is substantially amorphous.

3. The compound of claim 1 or 2, whereinR9is H, optionally substituted Ci-Ce alkyl, or A2;R10is H, optionally substituted Ci-Ce alkyl, or A2; each R11is, independently, halogen, A2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-C6heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, hydroxy, thiol; c is 0, 1 , 2, 3, or 4; and wherein if R6comprises A2or C(O)A2, then one and only one of R9, R10, or R11comprises A2.

4. The solid dispersion of any one of claims 1 to 3, wherein A iswherein each E1is, independently, CRE1, O, or NRE2; each F1is, independently, CRF1, O, or NRF2; each RE1is, independently, H, A1, halogen, CN, NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, amino, hydroxy, thiol, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A1and / or halogen or C1-C4 alkyl; each RE2is, independently, absent, H, A1, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A1and / or halogen or C1-C4 alkyl; each RF1is, independently, H, A1, halogen, CN, NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, amino, hydroxy, thiol, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A1and / or halogen or C1-C4 alkyl; each RF2is, independently, absent, H, A1, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A1 and / or halogen or C1-C4 alkyl; d is 0, 1 , 2, or 3; e is 0, 1 , 2, or 3; wherein one and only one of E1, F1, RE1, RE2, RF1, or RF2comprises A1.

5. The solid dispersion of any one of claims 1 to 3, wherein A iswherein each E2is, independently, CRE3, O, or NRE4; each F2is, independently, CRF3, O, or NRF4; each RE3is, independently, H, halogen, CN, NO2, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, amino, hydroxy, thiol, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with halogen or C1-C4 alkyl; each RE4is, independently, absent, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with halogen or C1-C4 alkyl; each RF3is, independently, H, halogen, CN, NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, amino, hydroxy, thiol, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with halogen or C1-C4 alkyl; each RF4is, independently, absent, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with A1 and / or halogen or C1-C4 alkyl;RF3bis optionally substituted Ci-Ce heteroalkyl;RF3cis H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, or optionally substituted C2-C9 heteroaryl;RF3dis optionally substituted Ci-Ce alkyl;RF3eis H or optionally substituted Ci-Ce alkyl; andRF3fis H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-Cio aryl, or optionally substituted C2-C9 heteroaryl; andK is C or N; and q is 0, 1 , 2, 3, 4, or 5; r is 0, 1 , or 2.

6. The solid dispersion of any one of claims 1 to 3, wherein A isC1is CRC3or N;C2is CRC3or N;D1is optionally substituted C2-C9 heteroaryl;E3is optionally substituted Ce-Cio aryl, or optionally substituted C2-C9 heteroaryl;RC1is hydrogen, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl;RC2is hydrogen, NH2, optionally substituted Ci-Ce alkyl;each RC3is, independently, H, optionally substituted Ci-Ce alkyl, or optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, or optionally substituted C2-C9 heteroaryl;RD1is hydrogen, acyl, oxo, thiol, CN, acyl, hydroxy, amino, thiol, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, or optionally substituted C2-C9 heteroaryl;RE5is hydrogen, acyl, oxo, thiol, CN, acyl, hydroxy, amino, thiol, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl; each s is, independently 0, 1 , 2, or 3.

7. The solid dispersion of any one of claims 1 to 3, wherein A iswherein each RD4is, independently, absent, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with halogen or C1-C4 alkyl; andRE6is, independently, H, halogen, CN, NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted Ce-C-io aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alky ny I, amino, hydroxy, thiol, wherein the alkyl, heteroalkyl, carbocyclyl, or aryl is optionally substituted with halogen or C1-C4 alkyl.

10. The solid dispersion of any one of claims 1 to 9, wherein L has the structure ofFormula IV:A1-(B1)f-(C1a)g-(B2)h-(D1a)-(B3)r(C2a)r(B4)k-A2,Formula IV or a pharmaceutically acceptable salt thereof, whereinA1is a bond between the linker and A;A2is a bond between Formula III and the linker; each of B1, B2, B3, and B4is, independently, optionally substituted C1-C4 alkyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-4 alkyl, optionally substituted C1-C4 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C10 heterocyclyl, optionally substituted C2-C6 heteroaryl, optionally substituted C6-12 aryl, O, S, S(O)2, or NRN; each RNis, independently, H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-C4 alky ny I, optionally substituted C2-C10 heterocyclyl, optionally substituted C2- Ce heteroaryl, or optionally substituted C1-C7 heteroalkyl;each of C1aand C2ais, independently, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; each of f, g, h, i, j, and k is, independently, 0 or 1 ; andD1ais optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alky ny I, optionally substituted C2-10 heterocyclyl, optionally substituted C2-6 heteroaryl, optionally substituted C6-12 aryl, optionally substituted C2-C10 polyethylene glycol, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 carbocyclyl, or optionally substituted C1-10 heteroalkyl; or D is absent, and the linker is A1-(B1)f-(C1a)g-(B2)h-(B3)i-(C2a)j-(B4)k-A2.11 . The solid dispersion of any one of claims 1 to 9, wherein L has the structure of Formula V:A1-G-(H)-(J)i-G-A2,Formula V whereinA1is a bond between the linker and A;A2is a bond between Formula III and the linker;I is 0 or 1 ; each G is, independently, absent, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl;J is absent, O, S, NRN, optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C2-C10 polyethylene glycol, optionally substituted C1-C10 heteroalkylene, optionally substituted C2-io carboocyclylene, or optionally substituted C2-C10 heterocyclylene; each RNis, independently, H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alky ny I, optionally substituted C2-6 heterocyclylene, optionally substituted C6-12 aryl, or optionally substituted C1-7 heteroalkyl; andH is optionally substituted C3-C10 carbocyclylene, optionally substituted C2-12 heterocyclylene, optionally substituted Ce-C-io arylene, or optionally substituted C2-C9 heteroarylene.

12. The solid dispersion of any one of claims 1 to 9, wherein L is absent.

13. The solid dispersion of any one of claims 1 to 12, wherein the compound is any one of compounds of Table 1 , or a pharmaceutically acceptable salt thereof.

14. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is a compound having the structure of Formula IA:Formula IAwhereinXi is absent, H, or OH (H and OH only when m is 0);X2 is absent or O;X3is O or CR4bR5b;R2bis H or R2band R3bcombine to form C=O;R3bis H, hydroxy, or optionally substituted heterocycle;R4bis H, methyl, or OH;R5band R6bis H or methyl, or R5band R6bare C=O; andR7bis absent, H, or OH; m is 0 or 1 ; n is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15;0 is O, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20; and p is 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, or 28.

15. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is a compound having the structure of Formula Ila:Formula Ila; whereineach of R8b, R9b, and R10bis, individually, H or16. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is a compound having the structure of Formula lib:each of R8b, R9b, and R10bis, individually,17. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is a compound having the structure of Formula lie:each of R8b, R9b, and R10bis, individually,18. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is polyethylene glycol, Polyvinylpyrrolidone, poly(lactic-co-glycolic) acid, polyvinyl alcohol, phospholipids, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, 1 ,2-Distearoyl-sn- glycero-3-phosphocholine, polymethacrylates, polyvinyl acetate, cellulose derivatives, poloxamer, glyceryl behenate, polyethyleneglycol derivatives of a mono-glyceride, vitamin E, polyethylene or polyoxyethylene esters of hydroxyl stearic acid, polyoxylglycerides, polyethoxylated castor oil or combinations thereof.

19. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is polyethylene glycol (PEG).

20. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is Polyvinylpyrrolidone.21 . The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is alpha cyclodextrin.

22. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is beta cyclodextrin.

23. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is gamma cyclodextrin.

24. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is sulfobutylether-p-cyclodextrin.

25. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is poly(lactic-co-glycolic) acid (PLGA).

26. The solid dispersion of claim 25, wherein the poly(lactic-co-glycolic) acid (PLGA) is PLGA 85:15.

27. The solid dispersion of claim 25, wherein the poly(lactic-co-glycolic) acid (PLGA) is PLGA 75:25.

28. The solid dispersion of claim 25, wherein the poly(lactic-co-glycolic) acid (PLGA) is PLGA 60:40.

29. The solid dispersion of claim 25, wherein the poly(lactic-co-glycolic) acid (PLGA) is PLGA 50:50.

30. The solid dispersion of claim 25, wherein the poly(lactic-co-glycolic) acid (PLGA) is PLGA 10:90.31 . The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is Polyvinylpyrrolidone PVP K12.

32. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is albumin.

33. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is polyvinyl alcohol (PVA).

34. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is a mixture of Polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG).

35. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is dipalmitoylphosphatidylcholine (DPPC).

36. The solid dispersion of any one of claims 1 to 13, wherein the pharmaceutically acceptable carrier is 1 ,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC).

37. The solid dispersion of any one of claims 1 to 36, wherein a) the amorphous form of a compound of Formula I , in an amount of about 15 percent to about 85 percent by weight of the solid dispersion; and b) the pharmaceutically acceptable carrier in an amount of about 15 percent to about 85 percent by weight of the solid dispersion.

38. The solid dispersion of claim 37, comprising the amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the pharmaceutical composition.

39. The solid dispersion of claim 37, comprising the amorphous form of a compound of Formula I, in an amount of about 49 percent by weight of the pharmaceutical composition.

40. The solid dispersion of any one of claims 37 to 39, comprising the pharmaceutically acceptable carrier in an amount of about 50 percent by weight of the pharmaceutical composition.41 . The solid dispersion of any one of claims 37 to 39, comprising the pharmaceutically acceptable carrier in an amount of about 49 percent by weight of the pharmaceutical composition.

42. A pharmaceutical composition comprising the solid dispersion of any one of claims 1 to 41.

43. The pharmaceutical composition of claim 42, comprising: a) the amorphous form of a compound of Formula I , in an amount of about 15 percent to about 85 percent by weight of the pharmaceutical composition; and b) the pharmaceutically acceptable carrier in an amount of about 15 percent to about 85 percent by weight of the pharmaceutical composition.

44. The pharmaceutical composition of claim 43, comprising the amorphous form of a compound of Formula I, in an amount of about 50 percent by weight of the pharmaceutical composition.

45. The pharmaceutical composition of claim 43, comprising the amorphous form of a compound of Formula I, in an amount of about 49 percent by weight of the pharmaceutical composition.

46. The pharmaceutical composition of any one of claims 43 to 45, comprising the pharmaceutically acceptable carrier in an amount of about 50 percent by weight of the pharmaceutical composition.M . The pharmaceutical composition of any one of claims 43 to 45, comprising the pharmaceutically acceptable carrier in an amount of about 49 percent by weight of the pharmaceutical composition.

48. The pharmaceutical composition of any one of claims 1 to 47, wherein the pharmaceutical composition further comprises a particle size of between 1 pm and 25 pm.

49. The pharmaceutical composition of claim 43, wherein the pharmaceutical composition further comprises a particle size of between 5 pm and 25 pm.

50. The pharmaceutical composition of claim 49, wherein the pharmaceutical composition further comprises a particle size of between 10 pm and 25 pm.51 . The pharmaceutical composition of claim 49, wherein the pharmaceutical composition further comprises a particle size of between 15 pm and 25 pm.

52. The pharmaceutical composition of any one of claims 42 to 51 , wherein pharmaceutical composition is suspended in a vehicle prior to administration.

53. The pharmaceutical composition of claim 52, wherein the vehicle further comprises a surfactant.

54. The pharmaceutical composition of claim 53, wherein the surfactant is a compound having the structure:wherein each of t, u, v, and w are, independently, a whole number from 1 to 17, wherein the sum of t, u, v, and w = 20;R11 b= (CH2)x(CH = CH)y(CH2)zCH3; x = 1 , 2, 3, 4, or 5; y = 0 or 1 ; and z = 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 'I'’55. The pharmaceutical composition of claim 53, wherein the surfactant is a compound having the structure:wherein a = 2-130; and b = 15-67.

56. The pharmaceutical composition of claim 53, wherein the surfactant is a compound having the structure:

57. The pharmaceutical composition of claim 53, wherein the surfactant is sodium dodecyl sulfate, phospholipids (e.g., lecithin), quaternary ammonium salts (e.g., cetrimonium bromide), pyridinium salts (e.g., cetylpyridinium chloride), fatty acid salts, poloxamers, poloxamines, polysorbates, fatty acid esters of sorbitan, polyethylene glycol alkyl ethers, fatty acid esters of polyethylene glycol, alkyl polyglycosides (e.g., alkyl polyglucosides), cyclodextrins, and fatty acid monoglycerides (e.g., monolaurin).

58. The pharmaceutical composition of claim 53, wherein the surfactant is polysorbate.

59. The pharmaceutical composition of claim 53, wherein the surfactant is polysorbate 20.

60. The pharmaceutical composition of claim 53, wherein the surfactant is polysorbate 80.61 . The pharmaceutical composition of claim 53, wherein the surfactant is poloxamer.

62. The pharmaceutical composition of claim 61 , wherein the poloxamer is Poloxamer 188.

63. The pharmaceutical composition of claim 53, wherein the surfactant is TWEEN 20.

64. The pharmaceutical composition of claim 53, wherein the surfactant is solutol.

65. The pharmaceutical composition of any one of claims 53 to 64, comprising the surfactant in an amount of about 0.1 to about 25 percent by weight of the pharmaceutical composition.

66. The pharmaceutical composition of claim 65, comprising the surfactant in an amount of about 0.2 percent by weight of the pharmaceutical composition.

67. The pharmaceutical composition of claim 66, comprising the surfactant in an amount of about 0.5 percent by weight of the pharmaceutical composition.

68. The pharmaceutical composition of claim 67, comprising the surfactant in an amount of about 20 percent by weight of the pharmaceutical composition.

69. The pharmaceutical composition of any one of claims 53 to 64, comprising the pharmaceutically acceptable carrier in an amount of about 49 percent by weight of the pharmaceutical composition, the amorphous form of a compound of Formula I, in an amount of about 49 percent by weight of the pharmaceutical composition, and the surfactant in an amount of about 2 percent by weight of the pharmaceutical composition.

70. The pharmaceutical composition of any one of claims 53 to 65, wherein the vehicle is saline.71 . The pharmaceutical composition of any one of claims 42 to 51 , further comprising a surfactant.

72. The pharmaceutical composition of claim 71 , wherein the surfactant is a compound having the structure:wherein each of t, u, v, and w are, independently, a whole number from 1 to 17, wherein the sum of t, u, v, and w = 20;R11 b= (CH2)x(CH = CH)y(CH2)zCH3; x = 1 , 2, 3, 4, or 5; y = 0 or 1 ; and z = 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 173. The pharmaceutical composition of claim 71 , wherein the surfactant is a compound having the structure:wherein a = 2-130; and b = 15-67.

74. The pharmaceutical composition of claim 71 , wherein the surfactant is a compound having the structure:

75. The pharmaceutical composition of claim 71 , wherein the surfactant is sodium dodecyl sulfate, phospholipids (e.g., lecithin), quaternary ammonium salts (e.g., cetrimonium bromide), pyridinium salts (e.g., cetylpyridinium chloride), fatty acid salts, poloxamers, poloxamines, polysorbates, fatty acid esters of sorbitan, polyethylene glycol alkyl ethers, fatty acid esters of polyethylene glycol, alkyl polyglycosides (e.g., alkyl polyglucosides), cyclodextrins, and fatty acid monoglycerides (e.g., monolaurin).

76. The pharmaceutical composition of claim 71 , wherein the surfactant is polysorbate.

77. The pharmaceutical composition of claim 71 , wherein the surfactant is polysorbate 20.

78. The pharmaceutical composition of claim 71 , wherein the surfactant is polysorbate 80.

79. The pharmaceutical composition of claim 71 , wherein the surfactant is poloxamer.

80. The pharmaceutical composition of claim 79, wherein the poloxamer is Poloxamer 188.81 . The pharmaceutical composition of claim 79, wherein the poloxamer is Poloxamer407 / Pluronic 127.

82. The pharmaceutical composition of claim 71 , wherein the surfactant is TWEEN.

83. The pharmaceutical composition of claim 82, wherein the TWEEN is TWEEN 20.

84. The pharmaceutical composition of claim 71 , wherein the surfactant is solutol.

85. The pharmaceutical composition of any one of claims 71 to 84, comprising the surfactant in an amount of about 1 to about 15 percent by weight of the pharmaceutical composition.

86. The pharmaceutical composition of claim 85, comprising the surfactant in an amount of about 1 to about 2 percent by weight of the pharmaceutical composition.

87. The pharmaceutical composition of claim 86, comprising the surfactant in an amount of about 2 percent by weight of the pharmaceutical composition.

88. The pharmaceutical composition of claim 87, comprising the pharmaceutically acceptable carrier in an amount of about 49 percent by weight of the pharmaceutical composition, the amorphous form of a compound of Formula I, in an amount of about 49 percent by weight of the pharmaceutical composition, and the surfactant in an amount of about 2 percent by weight of the pharmaceutical composition.

89. The pharmaceutical composition of any one of claims 71 to 88, wherein pharmaceutical composition is suspended in a vehicle prior to administration.

90. The pharmaceutical composition of claim 89, wherein the vehicle is saline.91 . The pharmaceutical composition of claim 89, wherein the vehicle is saline and TWEEN 20.

92. The pharmaceutical composition of claim 89, wherein the vehicle is saline and 0.5% TWEEN 20.

93. The pharmaceutical composition of claim 89, wherein the vehicle is saline and 0.2% TWEEN 20.

94. The pharmaceutical composition of any one of claims 42 to 88, wherein the pharmaceutical composition reduces the level and / or activity of a protein.

95. The pharmaceutical composition of any one of claims 42 to 94, wherein the pharmaceutical composition is administered intramuscularly.

96. The pharmaceutical composition of any one of claims 42 to 94, wherein the pharmaceutical composition is administered subcutaneously.

97. A surfactant-inclusive pharmaceutical composition of the solid dispersion of any one of claims 1 to 41 , wherein the amorphous form of a compound of Formula I and a surfactant are combined prior to spray-drying.

98. The surfactant-inclusive pharmaceutical composition of claim 97, wherein the surfactant- inclusive pharmaceutical composition reduces the level and / or activity of a protein.

99. The surfactant-inclusive pharmaceutical composition of claim 97 or 98, wherein the surfactant is a compound having the structure:wherein each of t, u, v, and w are, independently, a whole number from 1 to 17, wherein the sum of t, u, v, and w = 20;R11 b= (CH2)x(CH = CH)y(CH2)zCH3; x = 1 , 2, 3, 4, or 5; y = 0 or 1 ; and z = 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12.

100. The surfactant-inclusive pharmaceutical composition of claim 97 or 98, wherein the surfactant is a compound having the structure:wherein a = 2-130; and b = 15-67.101 . The surfactant-inclusive pharmaceutical composition of claim 97 or 98, wherein the surfactant is a compound having the structure:

102. The surfactant-inclusive pharmaceutical composition of claim 97 or 98, wherein the surfactant is sodium dodecyl sulfate, phospholipids (e.g., lecithin), quaternary ammonium salts (e.g., cetrimonium bromide), pyridinium salts (e.g., cetylpyridinium chloride), fatty acid salts, poloxamers, poloxamines, polysorbates, fatty acid esters of sorbitan, polyethylene glycol alkyl ethers, fatty acid esters of polyethylene glycol, alkyl polyglycosides (e.g., alkyl polyglucosides), cyclodextrins, and fatty acid monoglycerides (e.g., monolaurin).

103. The surfactant-inclusive pharmaceutical composition of claim 97 or 98, wherein the surfactant is polysorbate.

104. The surfactant-inclusive pharmaceutical composition of claim 97 or 98, wherein the surfactant is polysorbate 20.

105. The surfactant-inclusive pharmaceutical composition of claim 97 or 98, wherein the surfactant is polysorbate 80.

106. The surfactant-inclusive pharmaceutical composition of claim 97 or 98, wherein the surfactant is poloxamer.

107. The surfactant-inclusive pharmaceutical composition of claim 106, wherein the poloxamer is Poloxamer 188.

108. The surfactant-inclusive pharmaceutical composition of claim 97 or 98, wherein the poloxamer is Poloxamer 407 / Pluronic 127.

109. The surfactant-inclusive pharmaceutical composition of claim 97 or 98, wherein the surfactant is TWEEN.

110. The surfactant-inclusive pharmaceutical composition of claim 109, wherein the TWEEN is TWEEN 20.

111. The surfactant-inclusive pharmaceutical composition of any one of claims 97 to 110, further comprising the surfactant in an amount of about 1 to about 15 percent by weight of the pharmaceutical composition.

112. The surfactant-inclusive pharmaceutical composition of claim 111 , comprising the surfactant in an amount of about 1 to about 2 percent by weight of the pharmaceutical composition.

113. The surfactant-inclusive pharmaceutical composition of claim 112, comprising the surfactant in an amount of about 1 percent by weight of the pharmaceutical composition.

114. The surfactant-inclusive pharmaceutical composition of claim 112, comprising the surfactant in an amount of about 2 percent by weight of the pharmaceutical composition.

115. The surfactant-inclusive pharmaceutical composition of any one of claims 97 to 113, comprising the pharmaceutically acceptable carrier in an amount of about 49 percent by weight of the pharmaceutical composition, the amorphous form of a compound of Formula I, in an amount of about 49 percent by weight of the pharmaceutical composition, and the surfactant in an amount of about 2 percent by weight of the pharmaceutical composition.

116. The surfactant-inclusive pharmaceutical composition of any one of claims 97 to 115, wherein the pharmaceutical composition further comprises a particle size of between 1 pm and 25 pm.

117. The surfactant-inclusive pharmaceutical composition of claim 116, wherein the pharmaceutical composition further comprises a particle size of between 5 pm and 25 pm.

118. The surfactant-inclusive pharmaceutical composition of claim 117, wherein the pharmaceutical composition further comprises a particle size of between 10 pm and 25 pm.

119. The surfactant-inclusive pharmaceutical composition of claim 118, wherein the pharmaceutical composition further comprises a particle size of between 15 pm and 25 pm.

120. The surfactant-inclusive pharmaceutical composition of any one of claims 97 to 119, wherein the surfactant-inclusive pharmaceutical composition further comprises PVP K12.

121. The surfactant-inclusive pharmaceutical composition of any one of claims 97 to 120, wherein the amorphous form of a compound of Formula I is suspended in a vehicle prior to administration.

122. The surfactant-inclusive pharmaceutical composition of claim 121 , wherein the vehicle is saline.

123. The surfactant-inclusive pharmaceutical composition of claim 121 , wherein the vehicle is saline and TWEEN 20.

124. The surfactant-inclusive pharmaceutical composition of claim 121 , wherein the vehicle is saline and 0.2% TWEEN 20 by weight of the pharmaceutical composition.

125. The surfactant-inclusive pharmaceutical composition of claim 121 , wherein the vehicle is saline and 0.5% TWEEN 20 by weight of the pharmaceutical composition.

126. The surfactant-inclusive pharmaceutical composition of claim 121 , wherein the vehicle is saline and 1% TWEEN 20 by weight of the pharmaceutical composition.

127. The surfactant-inclusive pharmaceutical composition of any one of claims 97 to 126, wherein the surfactant-inclusive pharmaceutical composition is administered intramuscularly.

128. The surfactant-inclusive pharmaceutical composition of any one of claims 97 to 126, wherein the surfactant-inclusive pharmaceutical composition is administered subcutaneously.

129. A kit comprising: a) The surfactant-inclusive pharmaceutical composition of any one of claims 97 to 128 in one vial, and b) a vehicle in a separate vial.

130. The kit of claim 129, wherein the vehicle is saline and TWEEN 20.

131. The kit of claim 129 or 130, wherein the surfactant-inclusive pharmaceutical composition and the vehicle are mixed to form a solution, and administering the resulting solution.

132. The kit of any one of claims 129 to 131 wherein the resulting solution is administered intramuscularly.

133. The kit of claim any one of claims 129 to 131 , wherein the resulting solution is administered subcutaneously.

134. A method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of the pharmaceutical composition of any one of claims 42 to 96, the surfactant-inclusive pharmaceutical composition of any one of claims 97 to 128, or the kit of any one of claims 129 to 133.

135. The method of claim 134, wherein the cancer is osteosarcoma, colorectal cancer, bladder cancer, gastric cancer, breast cancer, head and neck cancer, prostate cancer, acute leukemias, ovarian cancer, neuroblastoma, myelofibrosis, lymphoma, leukemia, esophageal, stomach, or lung cancer.

136. The method of claim 135, wherein the cancer is gastric cancer.

137. A method of treating gastric cancer in a subject in need thereof, the method including administering to the subject an effective amount of the pharmaceutical composition of any one of claims 42 to 96, the surfactant-inclusive pharmaceutical composition of any one of claims 97 to 128, or the kit of any one of claims 129 to 133.

138. The method of any one of claims 134 to 137, wherein the cancer is metastatic.

139. The method of any one of claims 134 to 138, wherein the method further comprises administering to the subject an anticancer therapy.

140. The method of claim 139, wherein the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, or a combination thereof.141 . A method of treating inflammatory and / or autoimmune disorders in a subject in need thereof, the method including administering to the subject an effective amount of the pharmaceutical composition of any one of claims 42 to 96, the surfactant-inclusive pharmaceutical composition of any one of claims 97 to 128, or the kit of any one of claims 129 to 133.

142. The method of claim 141 , wherein the inflammatory and / or autoimmune disorder is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, or plaque psoriasis.

143. The method of claim 141 or 142, wherein the method further comprises administering to the subject a JAK inhibitor.

144. The method of claim 143, wherein the JAK inhibitor is abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, peficitinib, pacritinib, ruxolitinib, tofacitinib, or upadacitinib.

145. A method of treating a disease, disorder, or medical condition mediated by member of the JAK-STAT pathway, the method including administering to the subject an effective amount of the pharmaceutical composition of any one of claims 42 to 96, the surfactant-inclusive pharmaceutical composition of any one of claims 97 to 128, or the kit of any one of claims 129 to 133.

146. The method of claim 145, wherein the member of the JAK-STAT pathway is a janus kinase (JAK).

147. The method of claim 146, wherein the member of the JAK-STAT pathway is a signal transducer and activator of transcription (STAT).

148. The method of claim 147, wherein the disease, disorder, or medical condition mediated by mediated by member of the JAK-STAT pathway is rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata, cicatricial alopecia, Crohn’s disease, graft-versus-host disease, systemic lupus erythematosus, Aicardi Goutieres syndrome, Sjogren’s syndrome, chronic hand eczema, non-anterior uveitis, dermatomyositis, vitiligo, plaque psoriasis, or myelofibrosis.

149. A method of inducing immune tolerance in a subject in need thereof, including administering to the subject an effective amount of the pharmaceutical composition of any one of claims 42 to 96, the surfactant-inclusive pharmaceutical composition of any one of claims 97 to 128, or the kit of any one of claims 129 to 133.

150. A method for inhibiting an inflammatory or autoimmune response in a subject in need thereof, including administering to the subject an effective amount of the pharmaceutical composition of any one of claims 42 to 96, the surfactant-inclusive pharmaceutical composition of any one of claims 97 to 128, or the kit of any one of claims 129 to 133.

151. A method of suppressing a memory CD8+T cell response in a subject in a subject having or at risk of developing an inflammatory response, including administering to the subject an effective amount of the pharmaceutical composition of any one of claims 42 to 96, the surfactant-inclusive pharmaceutical composition of any one of claims 97 to 128, or the kit of any one of claims 129 to 133.

152. A method of treating an infection in a subject in need thereof, the method including administering to the subject an effective amount of the pharmaceutical composition of any one of claims 42 to 96, the surfactant-inclusive pharmaceutical composition of any one of claims 97 to 128, or the kit of any one of claims 129 to 133.

153. The method of claim 152, wherein the infection is Herpesvirus K*.

154. A method of treating Rubinstein Tayib syndrome in a subject in need thereof, the method including administering to the subject an effective amount of the pharmaceutical composition of any one of claims 42 to 96, the surfactant-inclusive pharmaceutical composition of any one of claims 97 to 128, or the kit of any one of claims 129 to 133.

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