Pyrrolo[2,1-f][1,2,4]triazine compounds acting against cancers, inflammatory diseases, and fibrotic disease via interaction with ras superfamily proteins

Abstract

Provided herein are compounds of Formula (I), or a pharmaceutically acceptable form thereof, and pharmaceutical compositions comprising the same. Also provided herein methods of modulating the activity of cellular targets by administering to a subject a compound of Formula (I), or a pharmaceutically acceptable form thereof. Further provided herein are methods of treating cancer, fibrotic diseases, and inflammatory diseases by administering to a subject a compound of or a pharmaceutically acceptable form thereof.

Description

Attorney Docket No.014202-0024-228 COMPOUNDS THAT INTERACT WITH RAS SUPERFAMILY PROTEINS FOR TREATMENT OF CANCERS, INFLAMMATORY DISEASES, RASOPATHIES, AND FIBROTIC DISEASE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 589,174 filed October 10, 2023, the content of which is incorporated herein by reference in its entirety. 1. FIELD

[0002] Provided herein are compounds of Formula I, or a pharmaceutically acceptable form thereof, and pharmaceutical compositions comprising the same. Also provided herein methods of modulating the activity of cellular targets by administering to a subject a compound of Formula I, or a pharmaceutically acceptable form thereof. Further provided herein are methods of treating cancer, fibrotic diseases, and inflammatory diseases by administering to a subject a compound of Formula I, or a pharmaceutically acceptable form thereof. 2. SUMMARY

[0003] Provided herein is a compound of Formula I: R1R2or a pharmaceutically acceptable form thereof, wherein: Y is an imidazolyl; wherein the imidazolyl is optionally substituted with 1 R5substituent and optionally substituted with 1-2 R6substituents; H3CO H3CO R1,, NAI-1541502036v1OCH3OCH3OCH3OCH3N H3CO , , , R22 NAI-1541502036v1NN NNorR5and R6are each independently C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, C1-6heteroalkyl, halo, –NR9R10, C1-6alkoxy, C1-6haloalkoxy, –C(O)NR9R10, –(CO)R8, –(CO)OH, –(CO)OR8, or CN, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, and C1-6heteroalkyl are each independently optionally substituted with 1-3 R7substituents; R7is independently selected from the group consisting of halo, CN, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, 3-6 membered heterocycloalkyl, –NR9R10, –(CO)R8, –(CO)OH, –(CO)OR8, –C(O)NR9R10, oxo, –OH, C1-6alkoxy, C3-6cycloalkoxy, C1-6haloalkoxy, or 5-6 membered heteroaryl; R8is C1-6alkyl, C3-6cycloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R7substituents; and R9and R10are each independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, -OH, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, or 5-10 membered heteroaryl, wherein the C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 R7substituents, or R9and R10are combined to form a 3-7 membered heterocycloalkyl including the nitrogen atom to which they are both attached.

[0004] Also provided herein is a compound of Formula IA: 3 NAI-1541502036v1R1R2N or a pharmaceutically acceptable R1, R2, R3, R4, R5wherein , R6, m, are as

[0005] Also provided herein is a compound of Formula IA(1): R1R2wherein R1, R2, R3, R4, and R5, are as defined herein; or a pharmaceutically acceptable form thereof.

[0006] Also provided herein is a compound of Formula IB: R1R2or a pharmaceutically acceptable form thereof, wherein: OCH3H3CO H3CO O ;R4is hydrogen or C1-6alkyl; R5and R6are each independently C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, C1-6heteroalkyl, halo, –NR9R10, C1-6alkoxy, 4 NAI-1541502036v1C1-6haloalkoxy, –C(O)NR9R10, –(CO)R8, –(CO)OH, –(CO)OR8, or CN, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, and C1-6heteroalkyl are each independently optionally substituted with 1-3 R7substituents; R7is independently selected from the group consisting of halo, CN, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, 3-6 membered heterocycloalkyl, –NR9R10, –(CO)R8, –(CO)OH, –(CO)OR8, –C(O)NR9R10, oxo, –OH, C1-6alkoxy, C3-6cycloalkoxy, C1-6haloalkoxy, or 5-6 membered heteroaryl; R8is C1-6alkyl, C3-6cycloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R7substituents; R9and R10are each independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, -OH, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, or 5-10 membered heteroaryl, wherein the C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 R7substituents, or R9and R10are combined to form a 3-7 membered heterocycloalkyl including the nitrogen atom to which they are both attached; and m is 0, 1 or 2.

[0007] Also provided herein is a compound of Formula IB(1): R1R2wherein R1, R2, R3, R4, and R5, are as defined herein; or a pharmaceutically acceptable form thereof. 5 NAI-1541502036v1

[0008] Also provided herein is a compound of Formula IB(2): R1R2N wherein R1, R2, R3, R4, R5, andor a pharmaceutically

[0009] Also provided herein is a compound of Formula II: R11R12or a pharmaceutically acceptable form thereof, wherein: Y is an imidazolyl; wherein the imidazolyl is optionally substituted with 1 R15substituent and optionally substituted with 1-2 R16substituents; OCH3OCH3OCH3R11,,N R12,6 NAI-1541502036v1OCH3OCH3O ;and are each independently C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, aryl, C5-10 heteroaryl, C3-7heterocycloalkyl, C1-6heteroalkyl, halo, –NR19R20, C1-6alkoxy, C1-6haloalkoxy, –C(O)NR19R20, –(CO)R18, –(CO)OH, –(CO)OR18, or CN, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, and C1-6heteroalkyl are each independently optionally substituted with 1-3 R17substituents; R17is independently selected from the group consisting of halo, CN, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, 3-6 membered heterocycloalkyl, –NR19R20, –(CO)R18, –(CO)OH, –(CO)OR18, -C(O)NR19R20, oxo, –OH, C1-6alkoxy, C3-6cycloalkoxy, C1-6haloalkoxy, or 5-6 membered heteroaryl; R18is C1-6alkyl, C3-6cycloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R17substituents; and R19and R20are each independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, -OH, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, or 5-10 membered heteroaryl, wherein the C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-67 NAI-1541502036v1hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 R17substituents, or R19and R20are combined to form a 3-7 membered heterocycloalkyl including the nitrogen atom to which they are both attached.

[0010] Also provided herein is a compound of Formula IIA: R11R12Nwherein R11, R12, R13, R14, R15, and are as defined herein; and wherein m is 0, 1 or 2; or a pharmaceutically acceptable form thereof.

[0011] Also provided herein is a compound of Formula IIA(1): R11R12wherein R11, R12, R13, R14, and R15, are as defined herein; and or a pharmaceutically acceptable form thereof.

[0012] Also provided herein is a compound of Formula IIB: R11R12wherein R11, R12, R13, R14, R15, and R16, are as defined herein; and wherein m is 0, 1 or 2; 8 NAI-1541502036v1or a pharmaceutically acceptable form thereof.

[0013] Also provided herein is a compound of Formula IIB(1): R11R12Nwherein R11, R12, R13, R14, and R15, are as defined herein; and or a pharmaceutically acceptable form thereof.

[0014] Also provided herein is a compound of Formula IIB(2): R11R12wherein R11, R12, R13, R14, R15, and R16, are as defined herein; and or a pharmaceutically acceptable form thereof.

[0015] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0016] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound is a modulator of Ras superfamily activity according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, 9 NAI-1541502036v1the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 20 µM according to a Ras Superfamily Activity Assay.

[0017] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound inhibits phosphorylation of Erk1 / 2 according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to Erk1 / 2 Phosphorylation Assay.

[0018] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound activates phosphorylation of Erk1 / 2 according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay.

[0019] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound inhibits phosphorylation of Akt according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM 10 NAI-1541502036v1according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to Akt Phosphorylation Assay.

[0020] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound activates phosphorylation of Akt according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 µM according to Akt Phosphorylation Assay.

[0021] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound inhibits phosphorylation of Smad2 / 3 according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay.

[0022] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater 11 NAI-1541502036v1than 100% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 µM according to Phospho- Smad2 / 3 Inhibition Assay.

[0023] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound inhibits JNK according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to JNK Activation Assay.

[0024] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound activates JNK according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 µM according to JNK Activation Assay.

[0025] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound inhibits MAPK p38 according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof 12 NAI-1541502036v1inhibits MAPK p38 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to MAPK p38 Activation Assay.

[0026] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound activates MAPK p38 according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 µM according to MAPK p38 Activation Assay.

[0027] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound inhibits proliferation in MiaPaca2 according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1 µM or less, 0.9 µM or less, 0.8 µM or less, 0.75 µM or less, 0.7 µM or less, 0.6 µM or less, 0.5 µM or less, 0.4 µM or less, 0.3 µM or less, 0.25 µM or less, 0.2 µM or less, 0.15 µM or less, 0.1 µM or less, 0.09 µM or less, 0.05 µM or less, or 0.03 µM or less, according to Proliferation Assay.

[0028] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound inhibits IL-6 according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to IL-6 Quantification Assay.

[0029] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, 13 NAI-1541502036v1IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits TNF-alpha according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to TNF-alpha Quantification Assay.

[0030] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof that has a half-life of 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, or 50 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay.

[0031] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof that has a kinetic solubility of 10 µM or more, 20 µM or more, 30 µM or more, 40 µM or more, 50 µM or more, 60 µM or more, 70 µM or more, 80 µM or more, 90 µM or more, 100 µM or more, 150 µM or more, or 200 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay.

[0032] Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof that inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI- H727, MiaPaca-2, or Panc1, according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in Kasumi-1, BT- 549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC50 value of 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MM.R1 with an IC50 value of 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay.

[0033] Also provided herein are methods of modulating a Ras superfamily protein, 14 NAI-1541502036v1comprising contacting the Ras superfamily protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0034] Also provided herein are methods of modulating a Ras superfamily protein, comprising contacting the Ras superfamily protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0035] Also provided herein are methods of modulating caspase activity, comprising contacting the caspase with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0036] Also provided herein are methods of modulating caspase activity, comprising contacting the caspase with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0037] Also provided herein are methods of modulating Erk1 / 2 activity, comprising contacting an Erk1 / 2 protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0038] Also provided herein are methods of modulating Erk1 / 2 activity, comprising contacting an Erk1 / 2 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0039] Also provided herein are methods of modulating Akt activity, comprising contacting an Akt protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0040] Also provided herein are methods of modulating Akt activity, comprising contacting an AKT protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0041] Also provided herein are methods of modulating Smad2 / 3 activity, comprising contacting a Smad2 / 3 protein with an effective amount of a compound of Formula I, IA, IA(1), 15 NAI-1541502036v1IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating Smad2 / 3 activity, comprising contacting a Smad2 / 3 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0043] Also provided herein are methods of modulating JNK activity, comprising contacting a JNK protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0044] Also provided herein are methods of modulating JNK activity, comprising contacting a JNK protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0045] Also provided herein are methods of modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0046] Also provided herein are methods of modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0047] Also provided herein are methods of modulating IL-6 activity, comprising contacting a IL-6 protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0048] Also provided herein are methods of modulating IL-6 activity, comprising contacting a IL-6 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0049] Also provided herein are methods of modulating TNF-alpha activity, comprising contacting a TNF-alpha protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form 16 NAI-1541502036v1thereof.

[0050] Also provided herein are methods of modulating TNF-alpha activity, comprising contacting a TNF-alpha protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.

[0051] Also provided herein are methods of treating cancer in a subject, comprising administering a therapeutically effective amount of the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject having cancer. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0052] Also provided herein are methods of treating cancer in a subject, comprising administering a therapeutically effective amount of a pharmaceutical comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject having cancer.

[0053] Also provided herein are methods of treating a fibrotic disease in a subject, comprising administering a therapeutically effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject.

[0054] Also provided herein are methods treating a fibrotic disease in a subject, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject.

[0055] Also provided herein are methods treating an inflammatory disease in a subject, comprising administering a therapeutically effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject.

[0056] Also provided herein are methods of treating an inflammatory disease in a subject, 17 NAI-1541502036v1comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject.

[0057] Also provided herein are pharmaceutical compositions provided herein comprising therapeutically effective amounts of one or more of compounds provided herein (e.g. compounds of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2)) and a pharmaceutically acceptable carrier, diluent or excipient. 3. DETAILED DESCRIPTION 3.1. DEFINITIONS

[0058] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0059] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0060] The singular forms “a,” “an,” and “the” include plural references, unless the context clearly dictates otherwise.

[0061] As used herein “subject” is an animal, such as a mammal, including human, such as a patient.

[0062] As used herein, biological activity refers to the in vivo activities of a compound or physiological responses that result upon in vivo administration of a compound, composition or other mixture. Biological activity, thus, encompasses therapeutic effects and pharmacokinetic behavior of such compounds, compositions and mixtures. Biological activities can be observed in in vitro systems designed to test for such activities.

[0063] As used herein, pharmaceutically acceptable derivatives of a compound include, but are not limited to, salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, clathrates, solvates or hydrates thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization. The compounds produced may be administered to animals or humans without substantial toxic effects 18 NAI-1541502036v1and either are pharmaceutically active or are prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'- dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and inorganic salts, such as but not limited to, sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, mesylates, and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of formula C=C(OR) where R is alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of formula C=C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.

[0064] As used herein, treatment means any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as use for treating a fibrotic disease, for example DMD.

[0065] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.

[0066] As used herein, and unless otherwise indicated, the terms “manage,” “managing” and 19 NAI-1541502036v1“management” encompass preventing the recurrence of the specified disease or disorder in a subject who has already suffered from the disease or disorder, and / or lengthening the time that a subject who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and / or duration of the disease or disorder, or changing the way that a subject responds to the disease or disorder.

[0067] As used herein, the terms “fibrosis” or “fibrotic disease” may be used interchangeably and refer to any pathological wound healing process in which connective tissue replaces normal parenchymal tissue, leading to considerable tissue re-modeling and the formation of permanent scar tissue. For example, in some embodiments, the fibrotic disease may be fibrosis of the kidney, such as progressive kidney disease. In some embodiments, the fibrotic disease may be fibrosis of the cardiovascular system, such as atherosclerosis or restenosis. In some embodiments, the fibrotic disease may be pulmonary fibrosis. In some embodiments, the fibrotic disease may be cystic fibrosis. In some embodiments, the fibrotic disease may be idiopathic fibrosis, such as idiopathic pulmonary fibrosis. In some embodiments, the fibrotic disease may be fibrosis of the lung, such as progressive massive fibrosis or radiation-induced lung injury. In some embodiments, the fibrotic disease may be bridging fibrosis. In some embodiments, the fibrotic disease may be fibrosis of the liver, such as cirrhosis. In some embodiments, the fibrotic disease may be fibrosis of the intestine, such as Crohn’s disease. In some embodiments, the fibrotic disease may be fibrosis of the muscular system, such as Duchenne muscular dystrophy (DMD). In some embodiments, the fibrotic disease may be fibrosis of the brain, such as glial scar. In some embodiments, the fibrotic disease may be fibrosis of the joints, such as arterial stiffness, fibrosis of the knee or fibrosis of the shoulder. In some embodiments, the fibrotic disease may be fibrosis of the skin, such as Keloid. In some embodiments, the fibrotic disease may be fibrosis of the bone marrow, such as myelofibrosis. In some embodiments, the fibrotic disease may be fibrosis of the heart, such as myocardial fibrosis. In some embodiments, the fibrotic disease may be fibrosis of the soft tissue. In some embodiments, the fibrotic disease may be fibrosis of the tendons. In some embodiments, the fibrotic disease may be fibrosis of the lymph nodes. In some embodiments, the fibrotic disease may be fibrosis of the eyes. In some embodiments, the fibrotic disease may be retroperitoneum. In some embodiments, the fibrotic disease may be scleroderma. In some embodiments, the fibrotic disease may be surgical scarring.

[0068] As used herein, “Duchenne muscular dystrophy” (“DMD”) refers to muscular 20 NAI-1541502036v1dystrophy and all forms of Duchenne muscular dystrophy (DMD). For example, in some embodiments, the DMD may be Becker Muscular Dystrophy (BMD), an intermediate clinical presentation between DMD and BMD, or DMD-associated dilated cardiomyopathy (heart- disease) with little or no clinical skeletal, or voluntary, muscle disease.

[0069] As used herein, the IC50refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.

[0070] As used herein, the Kdrefers to the measured equilibrium dissociation constant between a compound (or ligand) and a protein (or binding domain of a protein).

[0071] As used herein, “Smad 2 / 3” means the members of the receptor-regulated Smad (R- Smads) family of transcription factors, Smad2 and Smad3, collectively.

[0072] As used herein, “MAPK” means mitogen-activated protein kinase, which includes the stress-activated MAPK protein, MAPK p38, or simply p38.

[0073] As used herein, “JNK” means the stress-activated MAPK protein c-Jun NH2-terminal kinase.

[0074] As used herein, “Ras superfamily” means the protein superfamily of small guanosine triphosphatases (GTPases) which consists of the five main families Ras, Rho, Rab, Ran and Arf, or mutants thereof. Subfamilies of the five main families are also included, e.g., the Rac subfamily of the Rho main family.

[0075] Without being bound by theory, the Ras superfamily of proteins are small GTPases with substantial amino acid sequence homology that act as signal transducers between cell surface receptors and several intracellular signaling cascades. These proteins are involved in the regulation of essential cellular functions such as cell survival, proliferation, motility and cytoskeletal organization (see Karnoub et al., Nat. Rev. Mol. Cell Biol., 9: 517-531 (2008)). These proteins play essential roles in regulating many biological processes including, without limitation, cell growth, cell differentiation, cell migration, lipid vesicle trafficking, fibrosis, inflammation and apoptosis.

[0076] Research has defined a number of subfamilies of the Ras superfamily, based largely on amino acid sequence homologies. These subfamilies are often referred to in an abbreviated manner based on the most commonly studied member of the class.

[0077] The GTP binding domains of one subfamily of the Ras superfamily having substantial 21 NAI-1541502036v1sequence homology is commonly referred to as the Ras family or Ras.

[0078] There are four isoforms of Ras proteins, expressed from three different genes: H-Ras (Harvey sarcoma viral oncogene), N-Ras (neuroblastoma oncogene), and the splice variants K- Ras4A and K-Ras4B (Kirsten sarcoma viral oncogene) (see Karnoub et al., supra).

[0079] The GTP binding domains of another subfamily of the Ras superfamily having substantial sequence homology is commonly referred to as the Rho family and includes proteins and groups of proteins referred to as Rho, Rac and Cdc42.

[0080] Without being bound by theory, all Ras isoforms share sequence identity in all of the regions that are responsible for GDP / GTP binding, GTPase activity, and effector interactions, suggesting a functional redundancy. However, studies clearly demonstrate that each Ras isoform can function in a unique, different way from the other Ras proteins in normal physiological processes as well as in pathogenesis (Quinlan et al., Future Oncol., 5: 105-116 (2009)).

[0081] Without being bound by theory, several cell surface receptors activate Ras, such as Receptor Tyrosine Kinases (RTKs), growth factor receptors, cytokine receptors and integrins.

[0082] Without being bound by theory, Ras proteins cycle between 'on' and 'off' conformations that are conferred by the binding of GTP and GDP, respectively. Under physiological conditions, the transition between these two states is regulated by guanine nucleotide exchange factors (GEFs), such as Son of sevenless (Sos) (Bar-Sagi D, Trends Endocrin. Metab.5, 165-169 (1994)), which promote the activation of Ras proteins by stimulating the exchange of GDP for GTP exchange, and by GTPase-activating proteins (GAPs), which accelerate Ras-mediated GTP hydrolysis to GDP.

[0083] Without being bound by theory, the region of Sos functional for nucleotide exchange on Ras spans about 500 residues, and contains blocks of sequence that are conserved in Sos and other Ras-specific GEF’s such as Cdc25, Sdc25 and Ras guanine-nucleotide-release factor (GRF) (Boguske et al, Nature 366, 643-654 (1993)).

[0084] Without being bound by theory, once activated, Ras initiates signaling of the “MAPK pathway” (also referred to as the Ras-RAF-MEK-MAPK / ERK1 / 2 pathway) that affects cell growth, differentiation, proliferation, apoptosis and migration. The MAPK pathway operates through a sequence of interactions among kinases. Activated by Ras in the “on”, GTP bound, state, a MAPK kinase kinase (MAPK3), such as Raf, MLK, or TAK, phosphorylates and activates a MAPK kinase, such as MEK, which then phosphorylates and increases the activity of 22 NAI-1541502036v1one or more MAPKs, such as ERK1 / 2.

[0085] Without being bound by theory, Ras activation also initiates signaling of the “Akt pathway” that affects cellular survival, proliferation, migration, anti-apoptotic and cell cycle regulation. Ras in the “on”, GTP bound, state, activates phosphoinositide 3-kinase (PI3K) which, in turn, induces the production of phosphatidylinositol (3,4,5) trisphosphates (PIP3). These lipids serve as plasma membrane docking sites for proteins that harbor pleckstrin-homology (PH) domains, including Akt (also known as protein kinase B or PKB) and its upstream activator PDK1.There are three highly related isoforms of Akt (Akt1, Akt2 and Akt3) that phosphorylate shared substrates, but isoform-specific Akt substrates have also been identified. At the membrane, Akt is phosphorylated and activated by PDK1, PDK2 and mTORC2. The Akt pathway can also be activated by receptor tyrosine kinases, integrins, B and T cell receptors, cytokine receptors and G-protein-coupled receptors that directly interact and activate PI3K.

[0086] Without being bound by theory, Ras activation is also associated with signaling through other molecular pathways other than phosphoinositide 3-kinases (PI3Ks), such as Rac1 GEF and the Ral-guanine nucleotide dissociation stimulator (GDS). Regarding PI3K, that is part of the PI3K / AKT / mTOR pathway regulating intracellular signaling important for several cellular functions such as survival, anti-apoptotic and cell cycle regulation.

[0087] Without being bound by theory, Ras and its downstream pathways, including ERK1 / 2 and Akt, have been studied extensively. They are causally associated with a range of diseases, including certain cancers, inflammatory disorders, Ras-associated autoimmune leukoproliferative disorder, type II diabetes, and certain Rasopathies.

[0088] Without being bound by theory, activation of MAPKs, in particular ERK1 / 2, is a component of the inflammatory response. Thus, the compounds provided herein, which are ERK1 / 2 inhibitors via inhibition of Ras and / or a Ras superfamily member, are useful in the treatment of inflammatory diseases.

[0089] Without being bound by theory, activation of Akt is a component of the inflammatory response. Thus, the compounds provided herein, which are Akt inhibitors via inhibition of Ras and / or a Ras superfamily member, are useful in the treatment of inflammatory diseases.

[0090] Without being bound by theory, there is more than one distinct route to aberrant Ras activation including mutational activation of Ras itself, excessive activation of the wild-type protein through upstream signaling, and loss of a GAP function that is required to terminate 23 NAI-1541502036v1activity of the protein.

[0091] One million deaths per year are attributed in the literature to mutations in K-Ras alone. (Frank McCormick. “K-Ras protein as a drug target.” Journal of Molecular Medicine (Berlin) 2016: 94: 253-258)

[0092] Without being bound by theory, Ras is causally associated with inflammatory diseases including the following: rheumatoid arthritis (Abreu JR, de Launay D, Sanders ME, Grabiec AM, Sande van de MG, Tak PP, Reedquist KA: The Ras guanine nucleotide exchange factor RasGRF1 promotes matrix metalloproteinase-3 production in rheumatoid arthritis synovial tissue (Arthritis Res Ther.2009, 11: R121-10.1186 / ar2785), which is the most common cause of disability (Hootman JM, Brault MW, Helmick CG, Theis KA, Armour BS. Prevalence and most common causes of disability among adults—United States 2005, MMWR, 2009, 58(16):421-6); atherosclerosis (Fonarow G (2003), Cleve. Clin. J. Med.70: 431–434); inflammatory bowel disease (IBD), such as Crohn’s disease (Ignacio CS, Sandvik AK, Bruland T, Andreu-Ballester JC, J. Crohns Colitis, 2017 Mar 16. doi: 10); ulcerative colitis; spondyloarthropathies; idiopathic pulmonary fibrosis; juvenile arthritis; psoriasis; psoriatic arthritis; and others.

[0093] Without being bound by theory, Ras has been causally associated with Ras-associated autoimmune leukoproliferative disorder, a nonmalignant clinical syndrome initially identified in a subset of putative autoimmune lymphoproliferative syndrome (ALPS) patients. (Katherin Calvo, et al. “JMML and RALD (Ras-associated autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities” Blood, 2015 Apr 30; 125(18): 2753– 2758)

[0094] Without being bound by theory, Ras signaling is causally implicated in rasopathies. Thus, the compounds provided herein, which inhibit the function of one or more members of the Ras superfamily, are useful in the treatment of rasopathies including neurofibromatosis type 1, Noonan’s syndrome, and Costello syndrome.

[0095] As used herein, “Ras” or “Ras family” or “Ras subfamily” or “Ras group” means DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; RRAS2, or mutants thereof.

[0096] As used herein, “Rho” or “Rho family” or “Rho subfamily” or “Rho group” means 24 NAI-1541502036v1RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; RAC1; RAC2; RAC3; CDC42, or mutants thereof.

[0097] As used herein, “Rac” or “Rac family” or “Rac subfamily” or “Rac group” means RAC1; RAC2; RAC3; RHOG, or mutants thereof.

[0098] Without being bound by theory, the Rho subfamily of the Ras superfamily currently includes approximately 22 proteins most of which scientists commonly divide into subgroups including those referred to as Cdc42, Rac, and Rho. (Boureux A, Vignal E, Faure S, Fort P (2007)."Evolution of the Rho family of ras-like GTPases in eukaryotes". Mol Biol Evol 24 (1): 203–16).

[0099] Without being bound by theory, the three most commonly studied members of the Rho subfamily have been Cdc42, Rac1, and RhoA.

[0100] Without being bound by theory, the Cdc42 group includes Cdc42, TC10, TCL, Chip, and Wrch-1.

[0101] Without being bound by theory, the Rac group includes Rac1, Rac2, Rac3, and RhoG.

[0102] Without being bound by theory, the RhoA group includes RhoA, RhoB, and RhoC.

[0103] Without being bound by theory, other Rho subfamily GTPases not included in the Cdc42, Rac, or Rho groups include RhoE / Rnd3, RhoH / TTF, Rif, RhoBTB1, RhoBTB2, Miro-1, Miro-2, RhoD, Rnd1, and Rnd2.

[0104] Without being bound by theory, like other Ras superfamily proteins, the Rho subfamily GTPases cycle between 'on' and 'off' conformations that are conferred by the binding of GTP and GDP, respectively. Under physiological conditions, the transition between these two states is regulated by guanine nucleotide exchange factors (GEFs), which promote the activation of Rho subfamily proteins by stimulating the release of GDP and the binding of GTP, and by GTPase-activating proteins (GAPs), which accelerate Rho subfamily member-mediated GTP hydrolysis to GDP. Guanine nucleotide dissociation inhibitors (GDIs) proteins form a large complex with the Rho protein, helping to prevent diffusion within the membrane and into the cytosol and thus acting as an anchor and allowing tight spatial control of Rho activation.

[0105] Without being bound by theory, the Rho subfamily members are intracellular proteins that affect a large number of downstream pathways broadly involving cytoskeleton organization, cell polarity, migration, transcription and proliferation, and, more particularly, membrane and 25 NAI-1541502036v1vesicular trafficking, cell cycling, microtubule stability, actin membrane linkages, actin polymerization, myosin phosphorylation, API dependent gene expression, cell adhesion, cell contractility, cell adhesion, and MTOC orientation. (Martin Schwartz. “Rho Signalling at a Glance.” Journal of Cell Science.2004: (117:pp.5457-5458).and (Bustelo XR, Sauzeau V, Berenjeno IM (2007). "GTP-binding proteins of the Rho / Rac family: regulation, effectors and functions in vivo" BioEssays.29 (4): 356–370).

[0106] Without being bound by theory, Rho subfamily associated kinases (ROCK1 and ROCK2) are implicated as mediators of multiple profibrotic processes including those associated with idiopathic pulmonary fibrosis. (Knipe RS, Tager EM, and Liao JK. “The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis.” Pharmacol Rev.201567(1):103-17.)

[0107] Without being bound by theory, given their roles in disease processes, Rho subfamily members have been identified as potential Therapeutic Molecular Targets.

[0108] Without being bound by theory, Rho subfamily members have been identified as potential Therapeutic Molecular Targets in cancer.

[0109] Without being bound by theory, Rho subfamily members have been identified as potential Therapeutic Molecular Targets in fibrotic disease.

[0110] As used herein, “GTP binding site” or “GTP binding domain” both mean the region of a protein which binds GTP, and the surrounding region of said protein in which another compound may bind, wherein such binding blocks the ability of GTP to bind to said protein.

[0111] As used herein, “GDP binding site” or “GDP binding domain” both mean the region of a protein which binds GDP, and the surrounding region of said protein in which another compound may bind, wherein such binding blocks the ability of GDP to bind to said protein.

[0112] As used herein, “guanosine binding region” means a region of a protein which is part of the GDP binding domain or GTP binding domain, that mediates interaction with the guanosine portion of GDP or GTP.

[0113] As used herein, “metal region” means a region of a protein which is part of the GDP binding domain or GTP binding domain, that is proximal to a magnesium (Mg202) binding site.

[0114] As used herein, “alternative Tyr32 conformation” means the conformation of the GTP or GDP binding domain in the region of Tyr 32 in KRas crystal structure PDB code:3gft in comparsion to the KRas crystal structure PDB code:4epr. 26 NAI-1541502036v1

[0115] Without being bound by theory, as used herein “apoptosis” refers to a process of programmed cell death which plays important roles in physiology and pathology. It is activated during embryonic development and beyond to eliminate unwanted or damaged cells. Apoptosis also plays important roles in preventing cancer. Loss of apoptotic control allows tumor cells to survive longer and provides them time to accumulate mutations which can increase invasiveness during cancer progression, stimulate angiogenesis, deregulate cell proliferation, and interfere with differentiation.

[0116] Without being bound by theory, in regard to apoptosis, it has been demonstrated that several members of the Ras superfamily of small GTPases have pro- and anti-apoptosis functions. Members of the Rho family of GTPases such as Rho, Rac and cdc42 can activate apoptosis via the JNK or p38 pathways. On the other hand, members of the Ras and Rab families of GTPases have anti-apoptotic activity mediated by activating the PI3K / Akt / mTOR survival pathway which prevent apoptosis and leads to increased cellular proliferation. In addition, it has been demonstrated that GTPase Activating Proteins (GAPs) can promote apoptosis in tumor cells by regulating apoptosis-related proteins and pathways. It should be noted that some GAPs also exert apoptosis-inhibiting effects and thus promote tumor progression

[0117] Without being bound by theory, the c-Jun N-terminal kinase (JNK) pathway is one of the major signaling cascades of the mitogen-activated protein kinase (MAPK) signaling pathway. It functions in the control of a number of cellular processes, including proliferation, embryonic development and apoptosis. The JNK pathway is activated by environmental stresses (ionizing radiation, heat, oxidative stress such as reactive oxygen species (ROS) and DNA damage), inflammatory cytokines, as well as growth factors. JNK activation often involves the Rho family of GTPases such as Rho, Cdc42 and Rac.

[0118] Without being bound by theory, JNK activates apoptotic signaling by the upregulation of pro-apoptotic genes through transactivation of c-Jun / AP1-dependent or p53 / 73 protein-dependent mechanisms. In these pathways directed at mitochondrial apoptotic proteins, activated JNK directly modulates the activities of mitochondrial pro-apoptotic proteins through distinct phosphorylation events.

[0119] Without being bound by theory, another member of the MAPK signaling pathway is p38 MAPK (also referred to herein as MAPK p38) which allows cells to interpret a wide range of external signals and respond by activating downstream pathways mediating several biological 27 NAI-1541502036v1effects. This pathway also functions in the control of apoptosis and the release of cytokines by macrophages and neutrophils.

[0120] Without being bound by theory, apoptosis can be activated by both extrinsic (death ligand) and intrinsic (mitochondrial) pathways. Members of the Bcl-2 family of proteins, like Bax and Bak, regulate and mediate the intrinsic apoptosis process by which mitochondria contributes to cell death. Upon apoptotic stimuli, these proteins are activated and oligomerize at the mitochondrial outer membrane to mediate its permeabilization. Permeabilization enables the release of cytochrome c from mitochondria which, in turn, induces a series of biochemical reactions resulting in caspase activation and subsequent cell death.

[0121] Without being bound by theory, induction of apoptosis, such as in mammalian cells, can be mediated by several mechanisms, including inhibition of the ubiquitin proteasome system (UPS). The UPS system is a major proteolytic pathway for the removal of cytosolic, nuclear, and membrane associated proteins and has essential functions in homeostasis, which include preventing the accumulation of misfolded or deleterious proteins. The proteins targeted for degradation are selected by tagging them covalently with ubiquitin, typically with lysine48- linked tetraubiquitin chains, followed by proteolysis within the 26S proteasome. The 26S proteasome holoenzyme consists of a 19S regulatory particle (RP) which is responsible for recognizing the ubiquitin signal and unfolding the target protein, and a 20S core particle (CP), which hydrolyzes the unfolded polypeptide into short peptides of varying lengths. Accordingly, impairment of the UPS has been associated with several pathological conditions including cancers. Tumor cells can be characterized by the loss of cell cycle checkpoint control and can often be subjected to elevated levels of stress because of hyperactivation of oncogenic signaling and / or adverse microenvironmental conditions. Therefore, transformed cells can rely to a great extent on the correct function of UPS for survival and proliferation. Inhibition of the UPS, such as with proteasome inhibitors, can induce cell death and apoptosis. To date, three proteasome inhibitors have gained FDA approval to treat multiple myeloma cancer patients. The three proteasome inhibitors, Velcade (bortezomib), Kyprolis (carfilzomib), and Ninlaro (ixazomib), are reported as targeting the proteolytic sites within the 20S CP.

[0122] Without being bound by theory, as used herein “caspase(s)” refers to one or more of a family of cysteine proteases that cleave proteins following aspartic acid residues. All caspases are synthesized in cells as catalytically inactive zymogens and must undergo a cleavage 28 NAI-1541502036v1activation process to yield large and small subunits which dimerize to create active enzymes. Caspases exist in a hierarchy including so-called upstream caspases 2, 8, 9, and 10 and downstream caspases 3, 6, and 7. Active caspase-9 initiates caspase cleavage which activate downstream executioner caspases 3, 6 and 7 which cleave other cellular targets and initiate apoptosis. In some embodiments, the anti-proliferative inhibitory activity of the compounds disclosed herein is mediated by the induction of apoptosis, as determined by an Anexin V apoptosis assay kit.

[0123] It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.

[0124] As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter enzymatic and biological activities of the substance. Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound. The instant disclosure is meant to include all such possible isomers, as well as, their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chiral reverse phase HPLC. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. For example, Formula A includes, but is not limited to, the three tautomeric structures below. 29 NAI-1541502036v1NRNRH NRN NH

[0125] As used acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, the IUPAC-IUB Commission on Biochemical Nomenclature (see, (1972) Biochem.11:942-944), or the IUPAC Nomenclature of Organic Chemistry (see, Favre HA and Powell WH, Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013, Cambridge, UK: The Royal Society of Chemistry, 2013: Print ISBN 978-0-85404- 182-4, PDF eISBN 978-1-84973-306-9, DOI 10.1039 / 9781849733069; Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979. Copyright 1979 IUPAC; and A Guide to IUPAC Nomenclature of Organic Compounds (Recommendations 1993), 1993, Blackwell Scientific publications, Copyright 1993 IUPAC).

[0126] As used herein, alkyl, alkenyl and alkynyl carbon chains, if not specified, contain from 1 to 20 carbons, or 1 to 16 carbons, and are straight or branched. Alkenyl carbon chains of from 2 to 20 carbons, in certain embodiments, contain 1 to 8 double bonds, and the alkenyl carbon chains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 double bonds. Alkynyl carbon chains of from 2 to 20 carbons, in certain embodiments, contain 1 to 8 triple bonds, and the alkynyl carbon chains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 triple bonds. Exemplary alkyl, alkenyl and alkynyl groups herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, ethenyl, propenyl, butenyl, pentenyl, acetylenyl and hexynyl. As used herein, lower alkyl, lower alkenyl, and lower alkynyl refer to carbon chains having from about 1 or about 2 carbons up to about 6 carbons. As used herein, "alk(en)(yn)yl" refers to an alkyl group containing at least one double bond and at least one triple bond.

[0127] As used herein, "heteroalkyl" refers to a straight or branched aliphatic hydrocarbon group having, inserted in the hydrocarbon chain one or more oxygen, sulfur, including S(=O) and S(=O)2groups, or substituted or unsubstituted nitrogen atoms, including -NR- and -N+RR- groups, where the nitrogen substituent(s) is(are) alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, S(=O)2R' or COR', where R' is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OY or –NYY’, 30 NAI-1541502036v1where Y and Y’ are each independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, in some embodiments having from 1 to about 20 atoms, in another embodiment having from 1 to 12 atoms in the chain.

[0128] As used herein, "cycloalkyl" refers to a saturated mono- or multicyclic ring system, in certain embodiments of 3 to 10 carbon atoms, in other embodiments of 3 to 6 carbon atoms; cycloalkenyl and cycloalkynyl refer to mono- or multicyclic ring systems that respectively include at least one double bond and at least one triple bond. Cycloalkenyl and cycloalkynyl groups may, in certain embodiments, contain 3 to 10 carbon atoms, with cycloalkenyl groups, in further embodiments, containing 4 to 7 carbon atoms and cycloalkynyl groups, in further embodiments, containing 8 to 10 carbon atoms. The ring systems of the cycloalkyl, cycloalkenyl and cycloalkynyl groups may be composed of one ring or two or more rings which may be joined together in a fused, bridged or spiro-connected fashion. "Cycloalk(en)(yn)yl" refers to a cycloalkyl group containing at least one double bond and at least one triple bond. In some embodiments, the cycloalkyl ring is unsaturated or partially saturated.

[0129] As used herein, "carbocyclic" refers to a mono- or multicyclic ring system, in which all of the atoms composing the ring are carbon atoms, such as benzene or cyclopropane. In some embodiments, the carbocyclic ring is unsaturated or partially saturated.

[0130] As used herein, "substituted alkyl," "substituted alkenyl," "substituted alkynyl," "substituted cycloalkyl," "substituted cycloalkenyl," and "substituted cycloalkynyl" refer to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl groups, respectively, that are substituted with one or more substituents, in certain embodiments one to three or four substituents, where the substituents are as defined herein.

[0131] As used herein, “aryl” refers to aromatic monocyclic or multicyclic groups containing from 6 to 19 carbon atoms. Aryl groups include, but are not limited to groups such as fluorenyl, substituted fluorenyl, phenyl, substituted phenyl, naphthyl and substituted naphthyl.

[0132] As used herein, "heteroaryl" refers to a monocyclic or multicyclic aromatic ring system, in certain embodiments, of about 5 to about 15 members where one or more, in some embodiments 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur. The heteroaryl group may be optionally fused to a benzene ring. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl and 31 NAI-1541502036v1isoquinolinyl. In certain embodiments, the heteroaryl may be optionally fused to a heterocycloalkyl ring. In certain embodiments, the heteroaryl may be a partially saturated heteroaryl, such as a phenyl ring fused to a heterocycloalkyl ring, for example a phenyl ring fused to a tetrahydrofuryl ring.

[0133] As used herein, “heterocycloalkyl,” “heterocyclyl” or “heterocyclic” refers to a monocyclic or multicyclic non-aromatic ring system, in some embodiments of 3 to 10 members, in another embodiment of 4 to 7 members, in a further embodiment of 5 to 6 members, where one or more, in certain embodiments, 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur. In embodiments where the heteroatom(s) is(are) nitrogen, the nitrogen is optionally substituted with hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acyl, guanidino, amidino, sulfonyl or the nitrogen may be quaternized to form an ammonium group where the substituents are selected as above. In some embodiments, the heterocyclyl ring is saturated. In some embodiments, the heterocyclyl ring is unsaturated or partially saturated.

[0134] As used herein, “substituted aryl,” “substituted heteroaryl” and “substituted heterocyclyl” refer to aryl, heteroaryl and heterocyclyl groups, respectively, that are substituted with one or more substituents, in certain embodiments one to three or four substituents, where the substituents are as defined herein.

[0135] As used herein, "aralkyl" or “arylalkyl” refers to an alkyl group in which one of the hydrogen atoms of the alkyl is replaced by an aryl group.

[0136] As used herein, "heteroaralkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl is replaced by a heteroaryl group.

[0137] As used herein, "halo", "halogen" or "halide" refers to F, Cl, Br or I.

[0138] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl and 1-chloro-2-fluoroethyl.

[0139] As used herein, "haloalkoxy" refers to RO in which R is a haloalkyl group.

[0140] As used herein, “hydroxalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxyl group (-OH).

[0141] As used herein, “cycloalkoxy” refers to an -OR group, in which R is a cycloalkyl 32 NAI-1541502036v1group.

[0142] As used herein, "carboxy" refers to a divalent radical, -C(O)O-.

[0143] As used herein, "aminocarbonyl" refers to -C(O)NH2.

[0144] As used herein, "alkylaminocarbonyl" refers to -C(O)NHR in which R is alkyl, including lower alkyl. As used herein, "dialkylaminocarbonyl" refers to -C(O)NR'R in which R' and R are independently alkyl, including lower alkyl; "carboxamide" refers to groups of formula -NR'COR in which R' and R are independently alkyl, including lower alkyl.

[0145] As used herein, "arylalkylaminocarbonyl" refers to -C(O)NRR' in which one of R and R' is aryl, including lower aryl, such as phenyl, and the other of R and R' is alkyl, including lower alkyl.

[0146] As used herein, "arylaminocarbonyl" refers to -C(O)NHR in which R is aryl, including lower aryl, such as phenyl.

[0147] As used herein, "hydroxycarbonyl" refers to -COOH.

[0148] As used herein, "alkoxycarbonyl" refers to -C(O)OR in which R is alkyl, including lower alkyl.

[0149] As used herein, "aryloxycarbonyl" refers to -C(O)OR in which R is aryl, including lower aryl, such as phenyl.

[0150] As used herein, "alkoxy" and "alkylthio" refer to RO- and RS- , in which R is alkyl, including lower alkyl.

[0151] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, in which R is aryl, including lower aryl, such as phenyl.

[0152] Where the number of any given substituent is not specified (e.g., "haloalkyl"), there may be one or more substituents present. For example, "haloalkyl" may include one or more of the same or different halogens.

[0153] As used herein, "cyclic structure" may be a cycloalkyl, carbocyclic, heterocyclic, aryl or heteroaryl group.

[0154] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, the IUPAC-IUB Commission on Biochemical Nomenclature (see, (1972) Biochem.11:942-944), or the IUPAC Nomenclature of Organic Chemistry (see, Favre HA and Powell WH, Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred 33 NAI-1541502036v1Names 2013, Cambridge, UK: The Royal Society of Chemistry, 2013: Print ISBN 978-0-85404- 182-4, PDF eISBN 978-1-84973-306-9, DOI 10.1039 / 9781849733069; Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979. Copyright 1979 IUPAC; and A Guide to IUPAC Nomenclature of Organic Compounds (Recommendations 1993), 1993, Blackwell Scientific publications, Copyright 1993 IUPAC).

[0155] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in some embodiments, a human.

[0156] The terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0157] The terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and / or precluding the onset of a disorder, disease, or condition, and / or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.

[0158] The term “therapeutically effective amount” are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective amount” also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician. A therapeutically effective amount of a compound provided herein can be administered in one dose (i.e., a single dose administration) or divided and administered over time (i.e., continuous administration or multiple sub-dose administration). Single dose administration, continuous administration, or multiple sub-dose administration can be repeated, for example, to maintain the level of the compound in a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human.

[0159] The term “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers 34 NAI-1541502036v1to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In some embodiments, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, Remington: The Science and Practice of Pharmacy, 22nd ed.; Loyd et al., Eds.; The Pharmaceutical Press, 2012; Handbook of Pharmaceutical Excipients, 7th ed.; Rowe et al., Eds.; The Pharmaceutical Press, 2012; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse Information Resources, Inc., 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC, 2009.

[0160] As used herein, a “pharmaceutically acceptable form” of compounds disclosed herein includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of compounds disclosed herein. In some embodiments, a “pharmaceutically acceptable form” includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), as disclosed herein.

[0161] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0162] The term “percent by weight” or “% by weight” refers to the weight of a specified component (e.g., an active compound or excipient) in a composition (e.g., a pharmaceutical composition) as a percentage of the total weight of the composition. Thus, the sum of the weight percentages of all the components in a composition is 100%.

[0163] The terms “active ingredient” and “active substance” refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, 35 NAI-1541502036v1disorder, or disease. As used herein, “active ingredient” and “active substance” may be an optically active isomer or an isotopic variant of a compound described herein.

[0164] The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent” refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.

[0165] In certain embodiments, “optically active” and “enantiomerically active” and “diastereomerically active” refer to a collection of molecules which has an enantiomeric excess or a diasteromeric excess. For example, in some embodiments the collection of enantiomerically active molecules may have an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the racemate in question. For example, in some embodiments the collection of diastereomerically active molecules may have a diastereomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, the compound comprises about 95% or more of one diastereomer and about 5% or less of the other diastereomers based on the total weight of the diastereomeric mixture in question.

[0166] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the molecule, R and S.

[0167] The term “racemate” is understood to refer to an equimolar mixture of a pair of 36 NAI-1541502036v1enantiomers. It does not exhibit optical activity. The chemical name or formula of a racemate is distinguished from those of the enantiomers by the prefix (±)-, or rac- (or rac. or racem-) or by the symbols RS and SR. See IUPAC Recommendations 1996, Basic Terminology of Stereochemistry, Pure & Appl. Chem.,Vol.68, No.12, pp.2193-2222, 1996.

[0168] Racemic compounds disclosed herein that contain two asymmetric centers with known relative configuration are named using the configurational descriptors R,S or R,R, preceded by the prefix rac-. For example, Racemic Compound A below is named rac-(1R,3S)-1- bromo-3-chlorocyclohexane and is a 1:1 mixture of enantiomers (1R,3S)-1-bromo-3- chlorocyclohexane and (1S,3R)-1-bromo-3-chlorocyclohexane.

[0169] centers, according to Cahn-Ingold-Prelog Rules (see R.S. Cahn, C.K. Ingold and V. Prelog, Angew. Chem. Internat. Ed. Eng.5, 385-415, 511 (1966); and V. Prelog and G. Helmchen, Angew. Chem Internat. Ed. Eng.21, 567-583 (1982)). For example, Compound B below is named (1s,4s)-1-bromo-4-chlorocyclohexane.

[0170] Compound names included herein were generated from the corresponding chemical structures using ChemDraw® version 22.2.0.3348. If there is a discrepancy between the chemical structure and the name disclosed herein, the structure shall control.

[0171] The term “isotopic variant” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such compounds. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon- 37 NAI-1541502036v111 (11C), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35Cl), chlorine-36 (36Cl), and chlorine-37 (37Cl). In certain embodiments, an “isotopic variant” of a compound is in a stable form, that is, non-radioactive. It will be understood that, in a compound as provided herein, any hydrogen can be2H, for example, or any carbon can be13C, as example, or any nitrogen can be15N, as example, and any oxygen can be18O, where feasible according to the judgment of one of skill. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of deuterium. In some embodiments, a pharmaceutically acceptable deriviative of a compound is an isotopic variant.

[0172] The term “solvate” refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which present in stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In some embodiments, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0173] The phrase “an isotopic variant thereof; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof” has the same meaning as the phrase “an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable salt of the compound referenced therein; or a pharmaceutically acceptable salt of an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable solvate of the compound referenced therein; or a pharmaceutically acceptable solvate of an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of the compound referenced therein; or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of an isotopic variant of the compound referenced therein or its variant or its variant.” 3.2. COMPOUNDS 38 NAI-1541502036v1

[0174] Provided herein is a compound of Formula I: R1R2Nor a pharmaceutically acceptable Y is an imidazolyl; wherein the imidazolyl is optionally substituted with 1 R5substituent and optionally substituted with 1-2 R6substituents; H3CO H3CO , , ,O O O , R2R3or; R4C1-6alkyl; R5and R6are each independently C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, C1-6heteroalkyl, halo, –NR9R10, C1-6alkoxy, C1-6haloalkoxy, –C(O)NR9R10, –(CO)R8, –(CO)OH, –(CO)OR8, or CN, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, and C1-6heteroalkyl are each independently optionally substituted with 1-3 R7substituents; R7is independently selected from the group consisting of halo, CN, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, 3-6 membered heterocycloalkyl, –NR9R10, –(CO)R8, –(CO)OH, –(CO)OR8, 40 NAI-1541502036v1–C(O)NR9R10, oxo, –OH, C1-6alkoxy, C3-6cycloalkoxy, C1-6haloalkoxy, or 5-6 membered heteroaryl; R8is C1-6alkyl, C3-6cycloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R7substituents; and R9and R10are each independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, -OH, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, or 5-10 membered heteroaryl, wherein the C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 R7substituents, or R9and R10are combined to form a 3-7 membered heterocycloalkyl including the nitrogen atom to which they are both attached.

[0175] In some embodiments, the compound of Formula I is such that Y is an imidazolyl optionally substituted with 1 R5substituent and optionally substituted with 1-2 R6substituents. In some embodiments, the compound of Formula I is such that Y is a C-linked imidazolyl that is substituted with 1 R5substituent at a nitrogen of the imidazolyl ring and optionally substituted with 1-2 R6substituents at carbons of the imidazolyl ring. In some embodiments, the compound of Formula I is a compound of Formula IA: R1R2or a pharmaceutically acceptable form thereof; wherein m is 0, 1 or 2. In some embodiments, the compound is a compound of Formula I, wherein m is 0, and the compound is a compound of Formula IA(1): 41 NAI-1541502036v1R1R2Nor a pharmaceutically acceptable some the compound is a compound of Formula I, wherein m is 1. In some embodiments, the compound is a compound of Formula I, wherein m is 2.

[0176] In some embodiments, the compound of Formula I, Formula IA, or Formula IA(1), is H3CO H3CO ., is F OCH3OCH3OCH3OCH3O , ,O OCH3O N . of Formula I, Formula IA, or FormulaO O O ,(1), is O N or, is 43 NAI-1541502036v13 NN such that R is .

[0181] the compound of Formula I, Formula IA, or Formula IA(1), is3NN such that R is .

[0182] the compound of Formula I, Formula IA, or Formula IA(1), isNNthe compound of Formula I, Formula IA, or Formula IA(1), isNNsuch .

[0184] the compound of Formula I, Formula IA, or Formula IA(1), isN N such .

[0185] the compound of Formula I, Formula IA, or Formula IA(1), is such

[0186] a compound of Formula IB: R1R2or a pharmaceutically acceptable form thereof, wherein: OCH3H3COH CO O3;R4is hydrogen or C1-6alkyl; R5and R6are each independently C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, C1-6heteroalkyl, halo, –NR9R10, C1-6alkoxy, C1-6haloalkoxy, –C(O)NR9R10, –(CO)R8, –(CO)OH, –(CO)OR8, or CN, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, and C1-6heteroalkyl are each independently optionally substituted with 1-3 R7substituents; R7is independently selected from the group consisting of halo, CN, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, 3-6 membered heterocycloalkyl, –NR9R10, –(CO)R8, –(CO)OH, –(CO)OR8, –C(O)NR9R10, oxo, –OH, C1-6alkoxy, C3-6cycloalkoxy, C1-6haloalkoxy, or 5-6 membered heteroaryl; R8is C1-6alkyl, C3-6cycloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R7substituents; R9and R10are each independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, -OH, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, or 5-10 membered heteroaryl, wherein the C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 R7substituents, or R9and R10are combined to form a 3-7 membered heterocycloalkyl including the nitrogen atom to which they are both attached; and m is 0, 1 or 2.

[0187] In some embodiments, the compound is a compound of Formula IB, wherein m is 0, and the compound is a compound of Formula IB(1): 45 NAI-1541502036v1R1R2Nor a pharmaceutically acceptable

[0188] In some embodiments, the compound is a compound of Formula IB, wherein m is 1, and, for example, the compound is a compound of Formula IB(2): R1R2or a pharmaceutically

[0189] In some embodiments, the compound is a compound of Formula IB, wherein m is 2, or a pharmaceutically acceptable form thereof.

[0190] In some embodiments, the compound of Formula IB, Formula IB(1), or Formula OCH3IB(2), is such .

[0191] Inthe compound of Formula IB, Formula IB(1), or Formula O IB(2), is such .

[0192] Incompound of Formula IB, Formula IB(1), or Formula H3CO IB(2), is such .46 NAI-1541502036v1

[0193] In some embodiments, the compound of Formula IB, Formula IB(1), or Formula H3CO IB(2), is such .

[0194] In of Formula I, Formula IA, Formula IA(1),Formula IB, , or IB(2), is such that R2is methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CH3, or -CF2CF3. In some embodiments, R2is methyl.

[0195] In some embodiments, the compound of Formula I, Formula IA, Formula IA(1), Formula IB, Formula IB(1), or Formula IB(2), is such that R4is hydrogen or C1-6alkyl. In some embodiments, R4is hydrogen, methyl, ethyl, or isopropyl. In some embodiments, R4is hydrogen.

[0196] In some embodiments, the compound of Formula I, Formula IA, Formula IA(1), Formula IB, Formula IB(1), or Formula IB(2), is such that R5is C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6haloalkoxy, –C(O)NR9R10, –(CO)R8, or –C(O)OR8, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, and C1-6heteroalkyl are each independently optionally substituted with 1-3 R7substituents. In some embodiments, R5is C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R7substituents. In some embodiments, R5is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R7, wherein R7is -OH, C1-3alkoxy, or C1-3haloalkoxy. In some embodiments, R5is methyl, ethyl, or isopropyl. In some embodiments, R5is methyl.

[0197] In some embodiments, the compound of Formula I, Formula IA, Formula IA(1), Formula IB, Formula IB(1), or Formula IB(2), is such that R6is C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R7substituents. In some embodiments, R6is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R7, wherein R7is -OH, C1-3alkoxy, or C1-3haloalkoxy. In some embodiments, R6is methyl, ethyl, or isopropyl. In some embodiments, R6is methyl. 47 NAI-1541502036v1

[0198] In some embodiments, the compound of Formula I, Formula IA, Formula IA(1), Formula IB, Formula IB(1), or Formula IB(2), is such that R7is independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, 3-6 membered heterocycloalkyl, –NR9R10, –(CO)R8, oxo, C1-6alkoxy, or C3-6cycloalkoxy. In some embodiments, R7is independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, C3-5cycloalkyl, C1-4hydroxyalkyl, C1-4heteroalkyl, 3-5 membered heterocycloalkyl, –NR9R10, –(CO)R8, oxo, C1-4alkoxy, or C3-5cycloalkoxy. In some embodiments, R7is independently selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, C2-3hydroxyalkyl, C2-4heteroalkyl, –NR9R10, –(CO)R8, oxo, methoxy, ethoxy, isopropoxy, cyclopropoxy, or cyclobutoxy.

[0199] In some embodiments, the compound of Formula I, Formula IA, Formula IA(1), Formula IB, Formula IB(1), or Formula IB(2), is such that R8is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or C2-4heteroalkyl.

[0200] In some embodiments, the compound of Formula I, Formula IA, Formula IA(1), Formula IB, Formula IB(1), or Formula IB(2), is such that R9and R10are each independently selected from the group consisting of hydrogen, C1-4alkyl, C3-5cycloalkyl, C1-4hydroxyalkyl, C1-4heteroalkyl, –OH, or C1-4alkoxy. In some embodiments, R9and R10are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, or ethoxy. In some embodiments, R9and R10are each independently selected from the group consisting of hydrogen or methyl. In some embodiments, R9and R10are each hydrogen.

[0201] Provided herein is a compound of Formula II: R11R12or a pharmaceutically acceptable form thereof, wherein: Y is an imidazolyl; wherein the imidazolyl is optionally substituted with 1 R15substituent and optionally substituted with 1-2 R16substituents; 48 NAI-1541502036v1OCH3OCH3OCH3N N NH3CO;R15and R16are each independently C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7 heterocycloalkyl, C1-6 heteroalkyl, halo, –NR19R20, C1-6 alkoxy, C1-6haloalkoxy, –C(O)NR19R20, –(CO)R18, –(CO)OH, –(CO)OR18, or CN, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-1049 NAI-1541502036v1heteroaryl, C3-7heterocycloalkyl, and C1-6heteroalkyl are each independently optionally substituted with 1-3 R17substituents; R17is independently selected from the group consisting of halo, CN, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, 3-6 membered heterocycloalkyl, –NR19R20, –(CO)R18, –(CO)OH, –(CO)OR18, -C(O)NR19R20, oxo, –OH, C1-6alkoxy, C3-6cycloalkoxy, C1-6haloalkoxy, or 5-6 membered heteroaryl; R18is C1-6alkyl, C3-6cycloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R17substituents; and R19and R20are each independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, -OH, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, or 5-10 membered heteroaryl, wherein the C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 R17substituents, or R19and R20are combined to form a 3-7 membered heterocycloalkyl including the nitrogen atom to which they are both attached.

[0202] In some embodiments, the compound of Formula II is such that Y is an imidazolyl optionally substituted with 1 R15substituent and optionally substituted with 1-2 R16substituents. In some embodiments, the compound of Formula I is such that Y is a C-linked imidazolyl that is substituted with 1 R15substituent at a nitrogen of the imidazolyl ring and optionally substituted with 1-2 R16substituents at carbons of the imidazolyl ring.

[0203] In some embodiments, the compound of Formula II is a compound of Formula IIA: R11R12or a pharmaceutically acceptable0, 1 or 2. In some embodiments, the 50 NAI-1541502036v1compound is a compound of Formula II, wherein m is 0, and the compound is a compound of Formula IIA(1): R11R12Nor a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound of Formula I, wherein m is 1. In some embodiments, the compound is a compound of Formula I, wherein m is 2.

[0204] In some embodiments, the compound of Formula II is a compound of Formula IIB: R11R12or a pharmaceutically acceptable form thereof; wherein m is 0, 1 or 2. In some embodiments, the compound is a compound of Formula IIB, wherein m is 0, and the compound is a compound of Formula IIB(1): R11R12or a pharmaceutically acceptable form thereof.

[0205] In some embodiments, the compound is a compound of Formula IIB, wherein m is 1, and, for example, the compound is a compound of Formula IIB(2): 51 NAI-1541502036v1R11R12Nor a pharmaceutically acceptable

[0206] In some embodiments, the compound is a compound of Formula IIB, wherein m is 2, or a pharmaceutically acceptable form thereof.

[0207] In some embodiments, the compound of Formula II, Formula IIA, Formula IIA(1), OCH3OCH3Formula IIB, Formula IIB(1), or Formula IIB(2), is such or OCH3is , ,.IIA, Formula IIA(1), Formula IIB, Formula IIB(1), or Formula IIB(2), is such that R1252 NAI-1541502036v1N or ,, N Formula IIB, Formula IIB(1), or Formula IIB(2), is such that R13orN . In some embodiments, R13is . In some embodiments, R13isFormula IIA(1), Formula IIB, Formula IIB(1), or Formula IIB(2), is such that R14is hydrogen or C1-6alkyl. In some embodiments, R14is hydrogen, methyl, ethyl, or isopropyl. In some embodiments, R14is hydrogen. 53 NAI-1541502036v1

[0211] In some embodiments, the compound of Formula II, Formula IIA, Formula IIA(1), Formula IIB, Formula IIB(1), or Formula IIB(2), is such that R15is C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6haloalkoxy, –C(O)NR19R20, –(CO)R18, or –C(O)OR18, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, and C1-6heteroalkyl are each independently optionally substituted with 1-3 R17substituents. In some embodiments, R15is C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R17substituents. In some embodiments, R15is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R17, wherein R17is -OH, C1-3alkoxy, or C1-3haloalkoxy. In some embodiments, R15is methyl, ethyl, or isopropyl. In some embodiments, R15is methyl.

[0212] In some embodiments, the compound of Formula II, Formula IIA, Formula IIA(1), Formula IIB, Formula IIB(1), or Formula IIB(2), is such that R16is C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R17substituents. In some embodiments, R16is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R17, wherein R17is -OH, C1-3alkoxy, or C1-3haloalkoxy. In some embodiments, R16is methyl, ethyl, or isopropyl. In some embodiments, R16is methyl.

[0213] In some embodiments, the compound of Formula II, Formula IIA, Formula IIA(1), Formula IIB, Formula IIB(1), or Formula IIB(2), is such that R17is independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, 3-6 membered heterocycloalkyl, –NR19R20, –(CO)R18, oxo, C1-6alkoxy, or C3-6cycloalkoxy. In some embodiments, R17is independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, C3-5cycloalkyl, C1-4hydroxyalkyl, C1-4heteroalkyl, 3-5 membered heterocycloalkyl, –NR19R20, –(CO)R18, oxo, C1-4alkoxy, or C3-5cycloalkoxy. In some embodiments, R17is independently selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, C2-3hydroxyalkyl, C2-4heteroalkyl, –NR19R20, –(CO)R18, oxo, methoxy, ethoxy, isopropoxy, cyclopropoxy, or cyclobutoxy.

[0214] In some embodiments, the compound of Formula II, Formula IIA, Formula IIA(1), 54 NAI-1541502036v1Formula IIB, Formula IIB(1), or Formula IIB(2), is such that R18is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or C2-4heteroalkyl.

[0215] In some embodiments, the compound of Formula II, Formula IIA, Formula IIA(1), Formula IIB, Formula IIB(1), or Formula IIB(2), is such that R19and R20are each independently selected from the group consisting of hydrogen, C1-4alkyl, C3-5cycloalkyl, C1-4hydroxyalkyl, C1-4heteroalkyl, –OH, or C1-4alkoxy. In some embodiments, R19and R20are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, or ethoxy. In some embodiments, R19and R20are each independently selected from the group consisting of hydrogen or methyl. In some embodiments, R19and R20are each hydrogen.

[0216] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), has a molecular weight (MW) of no more than 1000 g / mol. In some embodiments, the compound has a MW of no more than 900 g / mol, no more than 800 g / mol, no more than 700 g / mol, no more than 600 g / mol, or no more than 500 g / mol. In some embodiments, the compound has a MW of no more than 900 g / mol. In some embodiments, the compound has a MW of no more than 800 g / mol. In some embodiments, the compound has a MW of no more than 700 g / mol. In some embodiments, the compound has a MW of no more than 600 g / mol. In some embodiments, the compound has a MW of no more than 500 g / mol. In some embodiments, the compound has a MW of no more than 450 g / mol.

[0217] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 9, 10, 11, 13, 14, 15, 16, 18, 19, 22, and 23, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 9, 11, 19, 22, and 23, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 9 and 11, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of 55 NAI-1541502036v1Compounds 36, 37, 38, 39, 40, and 62, or a pharmaceutically acceptable form thereof.

[0218] In some embodiments, the compound of Formula I is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 69, 70, 71, 72, 73, 74, 75, 76, 84, 85, 86, 87, 88, 89, 90, and 91, or a pharmaceutically acceptable form thereof.

[0219] In some embodiments, the compound of Formula IA or IA(1) is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 25, 26, 27, 28, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 70, 71, 72, 73, 74, 75, 76, 84, 85, 86, 87, 88, 89, 90, and 91, or a pharmaceutically acceptable form thereof.

[0220] In some embodiments, the compound of Formula IB(1) is selected from the group consisting of Compounds 22, 23, 24, and 30, or a pharmaceutically acceptable form thereof.

[0221] In some embodiments, the compound of Formula IB(2) is selected from the group consisting of Compounds 31, 32, 33, and 69, or a pharmaceutically acceptable form thereof.

[0222] In some embodiments, the compound of Formula II is selected from the group consisting of Compounds 16, 17, 18, 19, 20, 21, 29, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 77, 78, 79, 80, 81, 82, 83, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0223] In some embodiments, the compound of Formula IIA or IIA(1) is selected from the group consisting of Compounds 16, 17, 18, 19, 20, 21, 29, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 77, 78, 79, 80, 81, 82, 83, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0224] In some embodiments, the compound of Formula IIB(1) is selected from the group consisting of Compounds 63, 64, and 65, or a pharmaceutically acceptable form thereof.

[0225] In some embodiments, the compound of Formula IIB(2) is selected from the group consisting of Compounds 66, 67, and 68, or a pharmaceutically acceptable form thereof.

[0226] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof is a modulator of Ras superfamily activity according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 µM 56 NAI-1541502036v1according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 75% or more at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 90% or more at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 95% or more at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 50% to about 60% at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 60% to about 70% at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 70% to about 80% at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 80% to about 90% at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 90% to about 100% at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 9, 10, 11, 12, 13, 16, 18, 22, 23, 24, 27, 28, 32, 33, 36, 37, 38, 39, 40, 57, 62, 75, 84, 86, and 92, or a pharmaceutically acceptable form thereof.

[0227] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits 57 NAI-1541502036v1phosphorylation of Erk1 / 2 according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 50% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 75% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 80% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 85% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 90% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 95% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by about 50% to about 60% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by about 60% to about 70% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by about 70% to about 80% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by about 80% to about 90% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by about 90% to about 100% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound is 58 NAI-1541502036v1selected from the group consisting of Compounds 19, 20, 21, 49, 51, 53, 56, 67, 68, 79, 80, 81, 82, 89, and 94, or a pharmaceutically acceptable form thereof.

[0228] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 50% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 75% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 85% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 90% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 95% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by equal or greater than 100% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by about 50% to about 60% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by about 60% to about 70% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by about 70% to about 80% at 10 µM according to Erk1 / 2 59 NAI-1541502036v1Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by about 80% to about 90% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by about 90% to about 100% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by about 100% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 16, 18, 23, 27, 28, 36, 37, 38, 40, 54, 55, 57, 60, 61, 62, 75, and 83, or a pharmaceutically acceptable form thereof.

[0229] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 75% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 85% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 90% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 95% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 50% to about 60% at 10 µM according to 60 NAI-1541502036v1Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 60% to about 70% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 70% to about 80% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 80% to about 90% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 90% to about 100% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 49, 51, 53, 56, 79, 80, 81, and 94, or a pharmaceutically acceptable form thereof. In some embodiments, the compound

[0230] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof activates phosphorylation of Akt according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 75% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 85% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 90% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 95% or more at 10 µM according to Akt Phosphorylation Assay. In 61 NAI-1541502036v1some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by equal or greater than 100% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 50% to about 60% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 60% to about 70% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 70% to about 80% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 80% to about 90% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 90% to about 100% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 100% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, 22, 27, 28, 32, 36, 37, 38, 39, 40, 47, 54, 55, 57, 59, 60, 61, 62, 66, 67, 74, 75, 76, 83, 84, 86, 87, 88, and 91, or a pharmaceutically acceptable form thereof.

[0231] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 50% or more at 10 µM according to Phospho-Smad2 / 3 62 NAI-1541502036v1Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 75% or more at 10 µM according to Phospho- Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 80% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 85% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 90% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 95% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by about 50% to about 60% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by about 60% to about 70% at 10 µM according to Phospho- Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by about 70% to about 80% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by about 80% to about 90% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by about 90% to about 100% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 21, 29, 49, 51, 56, 58, 61, 63, 64, 65, 68, 77, 79, 80, 81, 87, 88, 89, and 94, or a pharmaceutically acceptable form thereof.

[0232] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater 63 NAI-1541502036v1than 100% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 50% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 75% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 85% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 90% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 95% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by equal or greater than 100% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 50% to about 60% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 60% to about 70% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 70% to about 80% at 10 µM according to Phospho- Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 80% to about 90% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 90% to about 100% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 100% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In 64 NAI-1541502036v1some embodiments, the compound is Compound 12, 14, 25, 26, 31, 32, 33, 37, 78, 90 or a pharmaceutically acceptable form thereof.

[0233] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits JNK according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 50% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 75% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 85% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 90% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 95% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by about 50% to about 60% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by about 60% to about 70% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by about 70% to about 80% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by about 80% to about 90% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by about 90% to about 100% at 10 µM according to JNK Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 29, 30, 32, 33, and 34, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is Compound 8, or a pharmaceutically acceptable form thereof. In some 65 NAI-1541502036v1embodiments, the compound is selected from the group consisting of Compounds 29, 32, and 34, or a pharmaceutically acceptable form thereof.

[0234] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof activates JNK according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 50% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 75% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 85% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 90% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 95% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by equal or greater than 100% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by about 50% to about 60% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by about 60% to about 70% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by about 70% to about 80% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by about 80% to about 90% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by about 90% to about 100% at 10 µM according to JNK Activation Assay. In some embodiments, 66 NAI-1541502036v1the compound or pharmaceutically acceptable form thereof activates JNK by about 100% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.

[0235] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits MAPK p38 according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 50% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 75% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 85% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 90% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by about 50% to about 60% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by about 60% to about 70% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by about 70% to about 80% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by about 80% to about 90% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by about 90% to about 100% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or 67 NAI-1541502036v1pharmaceutically acceptable form thereof inhibits MAPK p38 by 95% or more at 10 µM according to MAPK p38 Activation Assay.

[0236] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof activates MAPK p38 according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 75% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 85% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 90% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 95% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by equal or greater than 100% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 50% to about 60% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 60% to about 70% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 70% to about 80% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 80% to about 90% at 10 68 NAI-1541502036v1µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 90% to about 1000% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 100% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.

[0237] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.25 µM or less, 1.1 µM or less, 1 µM or less, 0.9 µM or less, 0.8 µM or less, 0.75 µM or less, 0.7 µM or less, 0.6 µM or less, 0.5 µM or less, 0.4 µM or less, 0.3 µM or less, 0.25 µM or less, 0.2 µM or less, 0.15 µM or less, 0.1 µM or less, 0.09 µM or less, 0.05 µM or less, or 0.03 µM or less, according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 1.25 µM to about 1.1 µM, about 1.1 µM to about 1 µM, about 1.0 µM to about 0.9 µM, about 0.9 µM to about 0.8 µM, about 0.8 µM to about 0.75 µM, about 0.75 µM to about 0.7 µM, about 0.7 µM to about 0.6 µM, about 0.6 µM to about 0.5 µM, about 0.5 µM to about 0.4 µM, about 0.4 µM to about 0.3 µM, about 0.3 µM to about 0.25 µM, about 0.25 µM to about 0.2 µM, about 0.2 µM to about 0.15 µM, about 0.15 µM to about 0.1 µM, about 0.1 µM to about 0.01 µM, about 0.01 µM to about 0.001 µM, about 0.001 µM to about 0.0001 µM, or less than about 0.0001 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.25 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.6 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.5 µM or less according to Proliferation Assay. In some embodiments, the compound or 69 NAI-1541502036v1pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.4 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.3 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.25 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.20 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.15 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.10 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.09 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.05 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.03 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 1.25 µM to about 1.1 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 1.1 µM to about 1 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 1.0 µM to about 0.9 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.9 µM to about 0.8 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.8 µM to about 0.75 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.75 µM to about 0.7 µM according to Proliferation Assay. In some embodiments, the 70 NAI-1541502036v1compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.7 µM to about 0.6 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.6 µM to about 0.5 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.5 µM to about 0.4 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.4 µM to about 0.3 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.3 µM to about 0.25 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.25 µM to about 0.2 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.2 µM to about 0.15 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.15 µM to about 0.1 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value about 0.1 µM to about 0.01 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.01 µM to about 0.001 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.001 µM to about 0.0001 µM according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of less than about 0.0001 µM according to Proliferation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 3, 4, 9, 10, 11, 12, 13, 16, 18, 19, 22, 23, 28, 31, 32, 36, 37, 38, 39, 40, 47, 48, 49, 52, 57, 62, 65, 68, 75, 80, 81, 82, 83, 85, 87, and 94, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 9, 10, 11, 16, 18, 19, 28, 36, 37, 38, 39, 40, 48, 57, 62, and 65, or a pharmaceutically 71 NAI-1541502036v1acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 9, 10, 11, 36, 37, 38, 39, 40, 62, and 65, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 9 and 11, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 36, 37, 38, 39, 40, and 62, or a pharmaceutically acceptable form thereof.

[0238] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits IL-6 according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 50% or more at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 75% or more at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 85% or more at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 90% or more at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 95% or more at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 50% to about 60% at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 60% to about 70% at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 70% to about 80% at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 80% to about 90% at 10 µM 72 NAI-1541502036v1according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 90% to about 100% at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound is selected from the group consisting of Compounds 4, 9, 10, 11, 16, 17, 19, 20, 92, and 94, or a pharmaceutically acceptable form thereof.

[0239] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits TNF- alpha according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF- alpha by 50% or more at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 75% or more at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 85% or more at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 90% or more at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 95% or more at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 50% to about 60% at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 60% to about 70% at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 70% to about 80% at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 80% to about 90% at 10 73 NAI-1541502036v1µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 90% to about 100% at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound is Compound 20 and 94, or a pharmaceutically acceptable form thereof.

[0240] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof has a kinetic solubility of 10 µM or more, 20 µM or more, 30 µM or more, 40 µM or more, 50 µM or more, 60 µM or more, 70 µM or more, 80 µM or more, 90 µM or more, 100 µM or more, 150 µM or more, or 200 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 10 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 20 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 30 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 40 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 50 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 60 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 70 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 80 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 90 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 100 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 150 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 200 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound is selected from the group consisting of 74 NAI-1541502036v1Compounds 9 and 11, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is Compound 9, or a pharmaceutically acceptable form thereof.

[0241] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof has a half-life of 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, or 50 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In some embodiments, the compound has a half-life of 10 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In some embodiments, the compound has a half-life of 20 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In some embodiments, the compound has a half-life of 30 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In some embodiments, the compound has a half- life of 40 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In some embodiments, the compound has a half-life of 50 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In some embodiments, the compound is Compound 11, or a pharmaceutically acceptable form thereof.

[0242] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI- H727, MiaPaca-2, or Panc1, according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Kasumi-1 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in BT-549 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in GP2d according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in A375 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in MM.1R according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in IM.9 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in RPMI8226 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in NCI-H358 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in NCI-H727 according to Proliferation 75 NAI-1541502036v1Assay. In some embodiments, the compound inhibits proliferation in MiaPaca-2 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Panc1 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC50value of 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC50value of 50 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI- H727, MiaPaca-2, or Panc1, with an IC50value of 40 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC50value of 30 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC50value of 20 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC50value of 10 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC50value of 1 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC50value of 0.1 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC50value of 0.01 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in MM.R1 with an IC50value of 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in MM.R1 with an IC50value of 1 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in MM.R1 with an IC50value of 0.1 nM or less according to Proliferation Assay. In 76 NAI-1541502036v1some embodiments, the compound inhibits proliferation in MM.R1 with an IC50value of 0.01 nM or less according to Proliferation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 9 and 11, or a pharmaceutically acceptable form thereof.

[0243] In some embodiments, the pharmaceutically acceptable form of the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is an isomer, isotopic variant, pharmaceutically acceptable salt, polymorph, or solvate of said compound. In some embodiments, the pharmaceutically acceptable form of the compound is exclusive of a salt form. In some embodiments, the isomer of the compound is a diastereomer or enantiomer of the compound.

[0244] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is a tautomer of the compound.

[0245] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is a racemate or a mixture of diasteromers.

[0246] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is a single enantiomer or a single diasteromer.

[0247] In one embodirment, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is a single enantiomer, such as an (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of greater than 10% of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of 15% or more of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of 25% or more of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of 50% or more of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of 75% or more of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of 90% or more of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of 95% or more of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of 98% or more of the (R) enantiomer. 77 NAI-1541502036v1In some embodiments, the compound has an enantiomeric excess of 99% or more of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (R) enantiomer.

[0248] In one embodirment, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is a single enantiomer, such as an (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of greater than 10% of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 15% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 25% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 50% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 75% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 90% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 95% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 98% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 99% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (S) enantiomer.

[0249] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is a single diastereomer, such as a (R) / (R)-, (R) / (S)-, (S) / (R)-, or (S) / (S)-single diastereomer. In some embodiments, the compound is an (R) / (R)-single diastereomer. In some embodiments, the compound is an (R) / (S)-single diastereomer. In some embodiments, the compound is an (S) / (R)-single diastereomer. In some embodiments, the compound is an (S) / (S)-single diastereomer.

[0250] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) has a diastereomeric excess of greater than 10% of the 78 NAI-1541502036v1(R) / (R)-, (R) / (S)-, (S) / (R)-, or (S) / (S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (R) / (R)-, (R) / (S)-, (S) / (R)-, or (S) / (S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of 15% or more of the (R) enantiomer. In some embodiments, the compound has a diastereomeric excess of 25% or more of the (R) / (R)-, (R) / (S)-, (S) / (R)-, or (S) / (S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of 50% or more of the (R) / (R)-, (R) / (S)-, (S) / (R)-, or (S) / (S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of 75% or more of the (R) / (R)-, (R) / (S)-, (S) / (R)-, or (S) / (S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of 90% or more of the (R) / (R)-, (R) / (S)-, (S) / (R)-, or (S) / (S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of 95% or more of the (R) / (R)-, (R) / (S)-, (S) / (R)-, or (S) / (S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of 98% or more of the (R) / (R)-, (R) / (S)-, (S) / (R)-, or (S) / (S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of 99% or more of the (R) / (R)-, (R) / (S)-, (S) / (R)-, or (S) / (S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (R) / (R)-, (R) / (S)-, (S) / (R)-, or (S) / (S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (R) / (R)-, (R) / (S)-, (S) / (R)-, or (S) / (S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of the (R) / (R)-diastereomer. In some embodiments, the compound has a diastereomeric excess of the (R) / (S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of the (S) / (R)-diastereomer. In some embodiments, the compound has a diastereomeric excess of the (S) / (S)-diastereomer.

[0251] In certain embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, is suitable for conjugation to an antibody or a fragment of an antibody. In certain embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, is suitable for delivery to a subject in the form of an 79 NAI-1541502036v1antibody-drug conjugate. 3.3. METHODS OF MODULATING ACTIVITY OF CELLULAR TARGETS

[0252] Provided herein are methods of modulating a Ras superfamily protein, comprising contacting the Ras superfamily protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating a Ras superfamily protein, comprising contacting the Ras superfamily protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0253] In some embodiments of the methods provided herein, the Ras superfamily protein is present in a cell.

[0254] In some embodiments, the method comprises contacting the Ras superfamily protein with a compound or pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily proteins by 50% or more at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 9, 10, 11, 12, 13, 16, 18, 22, 23, 24, 27, 32, 33, 36, 37, 38, 39, 40, 57, 62, 75, 84, 86, and 92, or a pharmaceutically acceptable form thereof.

[0255] In some embodiments, the methods provided herein inhibit the Ras superfamily protein.

[0256] In some embodiments of the methods provided herein, the Ras superfamily protein is a Ras protein, or a mutant thereof. In some embodiments, the Ras protein is DIRAS I; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRASI; NKIRAS2; NRAS; RALA; RALB; RAPIA; RAPIB; RAP2A; RAP2B; RAP2C; RASDI; RASD2; RASLIOA; RASLIOB; RASLI IA; RASLIIB; RASL12; REMI; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2. In some embodiments, the Ras protein is HRAS; KRAS; or NRAS, or a mutant thereof. In some embodiments, the Ras protein is a KRAS mutant. In some embodiments, the KRAS mutant is a 80 NAI-1541502036v1KRas G12D mutant, KRas G12C mutant, or KRas Q61H mutant. In some embodiments, the Ras protein is HRAS or a mutant thereof. In some embodiments, the Ras protein is NRAS or a mutant thereof.

[0257] In some embodiments of the methods provided herein, the Ras superfamily protein is a Rac protein, or a mutant thereof. In some embodiments, the Rac protein is RAC1; RAC2; RAC3; RHOG, or a mutant thereof. In some embodiments, the Rac protein is wild-type RAC1.

[0258] In some embodiments of the methods provided herein, the Ras superfamily protein is a Rho protein, or a mutant thereof. In some embodiments, the Rho protein is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; CDC42, or a mutant thereof. In some embodiments, the Rho protein is wild-type RHOA.

[0259] In some embodiments of the methods provided herein, the Ras superfamily protein is a Cdc42 protein, or a mutant thereof.

[0260] In some embodiments of the methods provided herein, the Ras superfamily protein is a Rheb protein, or a mutant thereof.

[0261] In some embodiments of the methods provided herein, the contacting of the Ras superfamily protein takes place in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the subject suffers from a cancer. In some embodiments, the subject is a human.

[0262] In some embodiments of the methods provided herein, the modulation takes place in a subject suffering from a cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a blood borne tumor (or a hematological cancer). In some embodiments, the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, esophageal carcinoma, mesothelioma, or multiple myeloma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is triple negative breast cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non- small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer 81 NAI-1541502036v1(SCLC). In some embodiments, the lung cancer is mesothelioma. In some embodiments, the cancer is hepatocellular carcinoma, pancreatic cancer, glioblastoma, esophageal carcinoma, mesothelioma, or small cell lung cancer (SCLC). In some embodiments, the cancer is a cancer dependent on a Ras superfamily protein.

[0263] Provided herein are methods of modulating caspase activity, comprising contacting the caspase with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating caspase activity, comprising contacting the caspase with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0264] In some embodiments, the methods provided herein activate the caspase. In some embodiments, the caspase is caspase 3, caspase 6, or caspase 9.

[0265] In some embodiments of the methods provided herein, the contacting of the caspase takes place in a cell. In some embodiments, the modulation of caspase activity induces apoptosis of the cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the subject suffers from a cancer. In some embodiments, the modulation takes place in a subject suffering from a cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a blood borne tumor (or a hematological cancer). In some embodiments, the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, esophageal carcinoma, mesothelioma, or multiple myeloma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is triple negative breast cancer. In some embodiments, the cancer is multiple myeloma. 82 NAI-1541502036v1In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non- small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is mesothelioma. In some embodiments, the cancer is hepatocellular carcinoma, pancreatic cancer, glioblastoma, esophageal carcinoma, mesothelioma, or small cell lung cancer (SCLC). In some embodiments, the subject is a human.

[0266] Provided herein are methods of inhibiting a proteasome ATPase, comprising contacting a proteasome ATPase with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. Also provided herein are methods of inhibiting an AAA-ATPase of a 19S regulatory particle, comprising contacting an AAA-ATPase with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. Also provided herein are methods of inhibiting one or more proteasome ATPases, comprising contacting a proteasome ATPase with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. Also provided herein are methods of inhibiting one or more AAA-ATPases of a 19S regulatory particle, comprising contacting an AAA-ATPase with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0267] In certain embodiments of the methods of inhibiting a proteasome ATPase and / or an AAA-ATPase of a 19S regulatory particle described herein, the method inhibits ATPase activity. In some embodiments, the method comprises contacting the proteasome ATPase and / or the AAA-ATPase of a 19S regulatory particle with a compound or pharmaceutically acceptable form thereof that inhibits ATPase activity by 33% or more at 100 µM according to ATPase Activity Inhibition Assay. In some embodiments, the compound is selected from the group consisting of Compounds A, B, 9, and 38, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is a compound specifically disclosed in International Patent 83 NAI-1541502036v1Application PCT / US2023 / 065530, filed April 7, 2023, now published as WO 2023 / 196975.

[0268] Provided herein are methods of modulating Erk1 / 2 activity, comprising contacting an Erk1 / 2 protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating Erk1 / 2 activity, comprising contacting an Erk1 / 2 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0269] In certain embodiments of the methods of of modulating Erk1 / 2 activity described herein, the method inhibits phosphorylation of the Erk1 / 2 protein. In some embodiments, the method comprises contacting the Erk1 / 2 protein with a compound or pharmaceutically acceptable form thereof that inhibits phosphorylation of the Erk1 / 2 protein by 50% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 21, 49, 51, 53, 56, 67, 68, 79, 80, 81, 82, 89, and 94, or a pharmaceutically acceptable form thereof.

[0270] In certain embodiments of the methods of of modulating Erk1 / 2 activity described herein, the method activates phosphorylation of the Erk1 / 2 protein. In some embodiments, the method comprises contacting the Erk1 / 2 protein with a compound or pharmaceutically acceptable form thereof that activates phosphorylation of the Erk1 / 2 protein by 50% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 16, 18, 23, 27, 28, 36, 37, 38, 40, 54, 55, 57, 60, 61, 62, 75, and 83, or a pharmaceutically acceptable form thereof.

[0271] In some embodiments of the methods provided herein, the contacting of the Erk1 / 2 protein takes place in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell.

[0272] Provided herein are methods of modulating Akt activity, comprising contacting an 84 NAI-1541502036v1Akt protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating Akt activity, comprising contacting an AKT protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0273] In certain embodiments of the methods of of modulating Akt activity described herein, the method inhibits phosphorylation of the Akt protein. In some embodiments, the method comprises contacting the Akt protein with a compound or pharmaceutically acceptable form thereof that inhibits phosphorylation of the Akt protein by 50% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 49, 51, 53, 56, 79, 80, 81, and 94, or a pharmaceutically acceptable form thereof.

[0274] In certain embodiments of the methods of of modulating Akt activity described herein, the method activates phosphorylation of the Akt protein. In some embodiments, the method comprises contacting the Akt protein with a compound or pharmaceutically acceptable form thereof that activates phosphorylation of the Akt protein by 50% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, 22, 27, 28, 32, 36, 37, 38, 39, 40, 47, 54, 55, 57, 59, 60, 61, 62, 66, 67, 74, 75, 76, 83, 84, 86, 87, 88, and 91, or a pharmaceutically acceptable form thereof.

[0275] In some embodiments of the methods provided herein, the contacting of the Akt protein takes place in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell.

[0276] Provided herein are methods of modulating Smad2 / 3 activity, comprising contacting a Smad2 / 3 protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), 85 NAI-1541502036v1IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating Smad2 / 3 activity, comprising contacting a Smad2 / 3 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0277] In certain embodiments of the methods of of modulating Smad2 / 3 activity described herein, the method inhibits phosphorylation of the Smad2 / 3 protein. In some embodiments, the method comprises contacting the Smad2 / 3 protein with a compound or pharmaceutically acceptable form thereof that inhibits phosphorylation of the Smad2 / 3 protein by 50% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the method comprises contacting the Smad2 / 3 protein with a compound or pharmaceutically acceptable form thereof that inhibits phosphorylation of the Smad2 / 3 protein by 85% or more. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 21, 29, 49, 51, 56, 58, 61, 63, 64, 65, 68, 77, 79, 80, 81, 87, 88, 89, and 94, or a pharmaceutically acceptable form thereof.

[0278] In certain embodiments of the methods of of modulating Smad2 / 3 activity described herein, the method activates phosphorylation of the Smad2 / 3 protein. In some embodiments, the method comprises contacting the Smad2 / 3 protein with a compound or pharmaceutically acceptable form thereof that activates phosphorylation of the Smad2 / 3 protein by 50% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound is Compound 12, 14, 25, 26, 31, 32, 33, 37, 78, and 90, or a pharmaceutically acceptable form thereof.

[0279] In some embodiments of the methods provided herein, the contacting of the Smad2 / 3 protein takes place in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell.

[0280] Provided herein are methods of modulating JNK activity, comprising contacting a 86 NAI-1541502036v1JNK protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating JNK activity, comprising contacting a JNK protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0281] In certain embodiments of the methods of of modulating JNK activity described herein, the method inhibits phosphorylation of the JNK protein. In some embodiments, the method comprises contacting the JNK protein with a compound or pharmaceutically acceptable form thereof that inhibits phosphorylation of the JNK protein by 50% or more according to JNK Activation Assay. In some embodiments, the compound is Compound 8, or a pharmaceutically acceptable form thereof.

[0282] In certain embodiments of the methods of of modulating JNK activity described herein, the method activates phosphorylation of the JNK protein. In some embodiments, the method comprises contacting the JNK protein with a compound or pharmaceutically acceptable form thereof that activates phosphorylation of the JNK protein by 50% or more according to JNK Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.

[0283] In some embodiments of the methods provided herein, the contacting of the JNK protein takes place in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell.

[0284] Provided herein are methods of modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of a pharmaceutical composition 87 NAI-1541502036v1comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0285] In certain embodiments of the methods of of modulating MAPK p38 described herein, the method inhibits phosphorylation of the MAPK p38 protein. In some embodiments, the method comprises contacting the MAPK p38 with a compound or pharmaceutically acceptable form thereof that inhibits phosphorylation of the MAPK p38 by 50% or more at 10 µM according to MAPK p38 Activation Assay.

[0286] In certain embodiments of the methods of of modulating MAPK p38 described herein, the method activates phosphorylation of the MAPK p38 protein. In some embodiments, the method comprises contacting the MAPK p38 with a compound or pharmaceutically acceptable form thereof that activates phosphorylation of the MAPK p38 by 50% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.

[0287] In some embodiments of the methods provided herein, the contacting of the MAPK p38 protein takes place in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell.

[0288] Provided herein are methods of modulating IL-6 activity, comprising contacting a IL- 6 protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating IL-6 activity, comprising contacting a IL-6 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 88 NAI-1541502036v146, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0289] In certain embodiments of the methods of of modulating IL-6 activity described herein, the method inhibits IL-6 activity. In some embodiments, the method comprises contacting the IL-6 protein with a compound or pharmaceutically acceptable form thereof that inhibits IL-6 activity by 50% or more at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound is selected from the group consisting of Compounds 4, 9, 10, 11, 16, 17, 19, 20, 92, and 94, or a pharmaceutically acceptable form thereof.

[0290] In some embodiments of the methods provided herein, the contacting of the IL-6 protein takes place in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell.

[0291] Provided herein are methods of modulating TNF-alpha activity, comprising contacting a TNF-alpha protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating TNF-alpha activity, comprising contacting a TNF-alpha protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0292] In certain embodiments of the methods of of modulating IL-6 activity described herein, the method inhibits TNF-alpha activity. In some embodiments, the method comprises contacting the TNF-alpha protein with a compound or pharmaceutically acceptable form thereof that inhibits TNF-alpha activity by 50% or more at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound is Compound 20 and 94, or a pharmaceutically acceptable form thereof.

[0293] In some embodiments of the methods provided herein, the contacting of the TNF- 89 NAI-1541502036v1alpha protein takes place in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell.

[0294] International Patent Application No. PCT / US2023 / 65530, filed April 7, 2023, now published as WO 2023 / 196975, is incorporated herein by reference in its entirety. 3.4. METHODS OF TREATING CANCER

[0295] Without being bound by theory, cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites. Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia. The neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host’s immune surveillance. (Roitt, I., Brostoff, J. and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993))

[0296] Without being bound by theory, various stages of tumor development can be described generally as follows:

[0297] a) Tumor evolution commences when a cell within a normal population sustains a genetic mutation that expands its tendency to proliferate.

[0298] b) Such genetically altered cells and their offspring continue to appear normal, but they reproduce excessively and lead to a condition termed hyperplasia. The altered cells may also secrete signaling factors or other molecules that cause changes in their local cellular and extracellular environment, including without limitation, the response of the immune system to them. Such environmental effects may in turn affect the viability, proliferation, and further mutations of the altered cells. After some time (months or years) a very small fraction of these altered cells may sustain additional mutation with subsequent loss of control of cell growth and further potential effects on their environment.

[0299] c) The offspring of these cells not only proliferate excessively but also appear abnormal in shape and in orientation. The tissue is now said to exhibit a condition termed dysplasia. After some time, one or more additional mutations may further alter cell behavior and the effect of the cells on their environment.

[0300] d) The influenced and genetically altered cells turn still more abnormal in growth and 90 NAI-1541502036v1appearance. If the tumor mass does not invade through any boundaries between tissues, it is termed an in situ tumor. This tumor may stay contained indefinitely, however, some cells may acquire still more mutations.

[0301] e) A malignant or invasive tumor results if the genetic changes allow the tumor mass to initiate invading underlying tissue and to cast off cells into the blood or lymph. The defector cells may install new tumors loci (metastases) throughout the body.

[0302] Without being bound by theory, metastases represent the end products of a multistep cell-biological process termed the invasion-metastasis cascade, which involves dissemination of cancer cells to anatomically distant organ sites and their subsequent adaptation to foreign tissue microenvironments. Each of these events is driven by the acquisition of genetic and / or epigenetic alterations within tumor cells and the co-option of non-neoplastic stromal cells, which together endow incipient metastatic cells with traits needed to generate macroscopic metastases. (Volastyan, S., et al., Cell, 2011, vol.147, 275-292)

[0303] Without being bound by theory, an enormous variety of cancers affect different tissues throughout the body, which are described in detail in the medical literature. Over 85% of human cancers are solid tumors, including carcinomas, sarcomas and lymphomas. Different types of solid tumors are named for the type of cells that form them. Examples include cancer of the lung, colon, rectum, pancreatic, prostate, breast, brain, and intestine. Other human tumors derive from cells involved in the formation of immune cells and other blood cells, including leukemias and myelomas.

[0304] The incidence of cancer continues to climb as the general population ages, as new cancers develop, and as susceptible populations grow. A tremendous demand therefore exists for new methods and compositions that can be used to treat subjects with cancer.

[0305] Without being bound by theory, current cancer therapy may involve surgery, chemotherapy, hormonal therapy, biological therapy, targeted therapy, immunotherapy and / or radiation treatment to eradicate neoplastic cells in a patient (see, e.g., Stockdale, 1998, Medicine, vol.3, Rubenstein and Federman, eds., Chapter 12, Section IV; and Baudino TA “Targeted Cancer Therapy: The Next Generation of Cancer Treatment”, Curr Drug Discov Technol.2015; 12(1):3-20).

[0306] Without being bound by theory, such therapies may be used independently or in combinations. Choices of therapy will depend on the history and nature of the cancer, the 91 NAI-1541502036v1condition of the patient, and, under the circumstances, the anticipated efficacy and adverse effects of the therapeutic agents and methods considered.

[0307] Without being bound by theory, with respect to chemotherapy, there are a variety of chemotherapeutic agents and methods of delivery of such agents available for the treatment of different cancers. Most first generation chemotherapeutic agents were not tumor specific, have broad systemic effects, are toxic, and may cause significant and often dangerous side effects, including severe nausea, bone marrow depression, and immunosuppression.

[0308] Without being bound by theory, even with administration of combinations of chemotherapeutic agents, many tumor cells are or become resistant to chemotherapeutic agents. In fact, cells resistant to the particular chemotherapeutic agents used in a treatment protocol often prove to be resistant to other drugs, even if those agents act by different mechanism from those of the drugs used in the specific treatment. This phenomenon is referred to as multidrug resistance. Because of drug resistance, many cancers prove refractory to standard chemotherapeutic treatment protocols.

[0309] Thus, there exists a significant need for alternative compounds, compositions and methods for treating, preventing and managing cancer.

[0310] Without being bound by theory, whereas surgical resection and adjuvant therapy can cure well-confined primary tumors, metastatic disease is largely incurable because of its systemic nature and the resistance of disseminated tumor cells to existing therapeutic agents. This explains why greater than 90% of mortality from cancer is attributable to metastases, not the primary tumors from which these malignant lesions arise.

[0311] Provided herein are methods of treating cancer in a subject, comprising administering a therapeutically effective amount of the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject having cancer. Also provided herein are methods of treating cancer in a subject, comprising administering a therapeutically effective amount of a pharmaceutical comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below, to the subject having cancer. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 92 NAI-1541502036v160, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0312] In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily protein. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits the activity one or more Ras superfamily protein. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 45% or more at 20 µM according to a Ras Superfamily Activity. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 50% or more at 20 µM according to a Ras Superfamily Activity. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 9, 10, 11, 12, 13, 16, 18, 22, 23, 24, 27, 28, 32, 33, 36, 37, 38, 39, 40, 57, 62, 75, 84, 86, and 92, or a pharmaceutically acceptable form thereof.

[0313] In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Erk1 / 2 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1 / 2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1 / 2 protein by 80% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1 / 2 protein by 85% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 21, 49, 51, 53, 56, 67, 68, 79, 80, 81, 82, 89, and 94, or a 93 NAI-1541502036v1pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1 / 2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1 / 2 protein by 45% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1 / 2 protein by 50% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 16, 18, 23, 27, 28, 36, 37, 38, 40, 54, 55, 57, 60, 61, 62, 75, and 83, or a pharmaceutically acceptable form thereof.

[0314] In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Akt activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein by 85% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 49, 51, 53, 56, 79, 80, 81, and 94, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein by 50% or more at 10 µM according to 94 NAI-1541502036v1Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, 22, 27, 28, 32, 36, 37, 38, 39, 40, 47, 54, 55, 57, 59, 60, 61, 62, 66, 67, 74, 75, 76, 83, 84, 86, 87, 88, and 91, or a pharmaceutically acceptable form thereof.

[0315] In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Smad2 / 3 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2 / 3 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2 / 3 protein by 80% or more at 10 µM according to Phospho- Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2 / 3 protein by 85% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 21, 29, 49, 51, 56, 58, 61, 63, 64, 65, 68, 77, 79, 80, 81, 87, 88, 89, and 94, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2 / 3 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2 / 3 protein by 50% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound is Compound 12, 14, 25, 26, 31, 32, 33, 37, 78, and 90, or a pharmaceutically acceptable form thereof.

[0316] In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form that modulates JNK activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 95 NAI-1541502036v150% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by 50% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound is Compound 8, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by about 50% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.

[0317] In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates MAPK p38 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 by about 50% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof 96 NAI-1541502036v1activates phosphorylation of the MAPK p38 by 50% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.

[0318] In some embodiments, the compounds disclosed herein inhibit cell proliferation, such as inhibit cell proliferation in a cell viability assay. In some embodiments, the anti-proliferative activity of the compounds disclosed herein are administered according to the methods of treating disclosed herein to treat cancer, including solid, soft and blood-born tumors. In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form thereof that inhibits proliferation in MiaPaca2. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.25 µM or less, 1.1 µM or less, 1 µM or less, 0.9 µM or less, 0.8 µM or less, 0.75 µM or less, 0.7 µM or less, 0.6 µM or less, 0.5 µM or less, 0.4 µM or less, 0.3 µM or less, 0.25 µM or less, 0.2 µM or less, 0.15 µM or less, 0.1 µM or less, 0.09 µM or less, 0.05 µM or less, or 0.03 µM or less, according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.1 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.0 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.60 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.15 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.1 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.09 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.05 µM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.03 µM or less according to Proliferation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 3, 4, 9, 10, 97 NAI-1541502036v111, 12, 13, 16, 18, 19, 22, 23, 28, 31, 32, 36, 37, 38, 39, 40, 47, 48, 49, 52, 57, 62, 65, 68, 75, 80, 81, 82, 83, 85, 87, and 94, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 9, 10, 11, 16, 18, 19, 36, 37, 38, 39, 40, 62, and 65, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 9, 10, and 11, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 36, 37, 38, 39, 40, and 62, or a pharmaceutically acceptable form thereof.

[0319] In some embodiments of the methods provided herein, the cancer is a solid tumor. In some embodiments, the cancer is a blood borne tumor (or a hematological cancer). In some embodiments, the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, esophageal carcinoma, mesothelioma, or multiple myeloma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is triple negative breast cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non- small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is mesothelioma. In some embodiments, the cancer is hepatocellular carcinoma, pancreatic cancer, glioblastoma, esophageal carcinoma, mesothelioma, or small cell lung cancer (SCLC).

[0320] In some embodiments of the methods provided herein, the cancer is a cancer dependent on a Ras superfamily protein. In some embodiments, the Ras superfamily protein is a Ras protein, or a mutant thereof. In some embodiments, the Ras protein is DIRAS I; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRASI; NKIRAS2; NRAS; RALA; RALB; RAPIA; RAPIB; RAP2A; RAP2B; RAP2C; RASDI; RASD2; RASLIOA; RASLIOB; RASLI IA; RASLIIB; RASL12; REMI; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2. In some embodiments, the Ras protein is HRAS; KRAS; or NRAS, or a mutant thereof. In some embodiments, the Ras protein is a KRAS mutant. In some embodiments, the KRAS mutant is a KRas G12D mutant, KRas G12C mutant, or KRas Q61H mutant. In some embodiments, the Ras protein is HRAS or a mutant thereof. In some embodiments, the Ras protein is NRAS or a 98 NAI-1541502036v1mutant thereof. In some embodiments, the Ras superfamily protein is a Rac protein, or a mutant thereof. In some embodiments, the Rac protein is RAC1; RAC2; RAC3; RHOG, or a mutant thereof. In some embodiments, the the Rac protein is wild-type RAC1. In some embodiments, the Ras superfamily protein is a Rho protein, or a mutant thereof. In some embodiments, the Rho protein is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; CDC42, or a mutant thereof. In some embodiments, the Rho protein is wild-type RHOA. In some embodiments, the Ras superfamily protein is a Cdc42 protein, or a mutant thereof. In some embodiments, the Ras superfamily protein is a Rheb protein, or a mutant thereof.

[0321] In some embodiments of the methods provided herein, the administration activates caspase activity in a cancerous cell of the subject. In some embodiments, the activation induces apoptosis of the cancerous cell. In some embodiments, the subject is a human.

[0322] Also provided herein are methods of treating subjects who have been previously treated for cancer but are non-responsive to standard therapies, as well as those who have not previously been treated. Also provided are methods of treating subjects regardless of subject’s age, although some diseases or disorders are more common in certain age groups. Also provided are methods of treating subjects who have undergone surgery in an attempt to treat the disease or condition at issue, as well as those who have not. Because subjects with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a subject may vary, depending on his / her prognosis. The skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual subject with cancer.

[0323] As used herein, the term “cancer” includes, but is not limited to, solid tumors and blood borne tumors. The term “cancer” refers to disease of skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone, blood, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, and uterus. Specific cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant 99 NAI-1541502036v1giolma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi’s sarcoma, karotype acute myeloblastic leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, Waldenstrom’s macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma.

[0324] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the solid tumor is metastatic. In certain embodiments, the solid tumor is drug-resistant. In certain embodiments, the solid tumor is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, esophageal carcinoma, mesothelioma, or multiple myeloma. In some embodiments, the solid tumor is lung cancer. In some embodiments, the lung cancer is non- small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is mesothelioma. In some embodiments, the cancer is hepatocellular carcinoma, pancreatic cancer, glioblastoma, esophageal carcinoma, mesothelioma, or small cell lung cancer (SCLC).

[0325] In certain embodiments, the cancer is a blood borne tumor (or a hematological cancer). In certain embodiments, the blood borne tumor is metastatic. In certain embodiments, the blood borne tumor is drug resistant. In certain embodiments, the cancer is leukemia. In certain embodiments, the cancer is multiple myeloma.

[0326] In some embodiments, methods provided herein encompass treating, preventing or managing various types of leukemias such as chronic lymphocytic leukemia (CLL), chronic 100 NAI-1541502036v1myelocytic leukemia (CML), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acute myeloblastic leukemia (AML) by administering a therapeutically effective amount of a compound provided herein or a derivative thereof.

[0327] In some embodiments, the methods provided herein encompass treating, preventing or managing acute leukemia in a subject. In some embodiments, the acute leukemia is acute myeloid leukemia (AML), which includes, but is not limited to, undifferentiated AML (M0), myeloblastic leukemia (M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant (M3V)), myelomonocytic leukemia (M4 or M4 variant with eosinophilia (M4E)), monocytic leukemia (M5), erythroleukemia (M6), and megakaryoblastic leukemia (M7). In some embodiments, the acute myeloid leukemia is undifferentiated AML (M0). In some embodiments, the acute myeloid leukemia is myeloblastic leukemia (M1). In some embodiments, the acute myeloid leukemia is myeloblastic leukemia (M2). In some embodiments, the acute myeloid leukemia is promyelocytic leukemia (M3 or M3 variant (M3V)). In some embodiments, the acute myeloid leukemia is myelomonocytic leukemia (M4 or M4 variant with eosinophilia (M4E)). In some embodiments, the acute myeloid leukemia is monocytic leukemia (M5). In some embodiments, the acute myeloid leukemia is erythroleukemia (M6). In some embodiments, the acute myeloid leukemia is megakaryoblastic leukemia (M7). Thus, the methods of treating, preventing or managing acute myeloid leukemia in a subject comprise the step of administering to the subject an amount of a compound provided herein or a derivative thereof effective to treat, prevent or manage acute myeloid leukemia alone or in combination. In some embodiments, the methods comprise the step of administering to the subject a compound provided herein or a derivative thereof in combination with a second active agent in amounts effective to treat, prevent or manage acute myeloid leukemia.

[0328] In some embodiments, the methods provided herein encompass treating, preventing or managing acute lymphocytic leukemia (ALL) in a subject. In some embodiments, acute lymphocytic leukemia includes leukemia that originates in the blast cells of the bone marrow (B- cells), thymus (T-cells), and lymph nodes. The acute lymphocytic leukemia can be categorized according to the French-American-British (FAB) Morphological Classification Scheme as L1 - Mature-appearing lymphoblasts (T cells or pre-B-cells), L2 - Immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells), and L3 - Lymphoblasts (B-cells; Burkitt's cells). In some embodiments, the acute lymphocytic leukemia originates in the blast 101 NAI-1541502036v1cells of the bone marrow (B-cells). In some embodiments, the acute lymphocytic leukemia originates in the thymus (T-cells). In some embodiments, the acute lymphocytic leukemia originates in the lymph nodes. In some embodiments, the acute lymphocytic leukemia is L1 type characterized by mature-appearing lymphoblasts (T-cells or pre-B-cells). In some embodiments, the acute lymphocytic leukemia is L2 type characterized by immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells). In some embodiments, the acute lymphocytic leukemia is L3 type characterized by lymphoblasts (B-cells; Burkitt's cells). In certain embodiments, the acute lymphocytic leukemia is T cell leukemia. In some embodiments, the T-cell leukemia is peripheral T-cell leukemia. In another embodiment, the T-cell leukemia is T-cell lymphoblastic leukemia. In another embodiment, the T-cell leukemia is cutaneous T-cell leukemia. In another embodiment, the T-cell leukemia is adult T-cell leukemia. Thus, the methods of treating, preventing or managing acute lymphocytic leukemia in a subject comprise the step of administering to the subject an amount of a compound provided herein or a derivative thereof effective to treat, prevent or manage acute lymphocytic leukemia alone or in combination with a second active agent. In some embodiments, the methods comprise the step of administering to the subject a compound provided herein or a derivative thereof in combination with a second active agent in amounts effective to treat, prevent or manage acute lymphocytic leukemia.

[0329] In some embodiments, the methods provided herein encompass treating, preventing or managing chronic myelogenous leukemia (CML) in a subject. The methods comprise the step of administering to the subject an amount of a compound provided herein or a derivative thereof effective to treat, prevent or manage chronic myelogenous leukemia. In some embodiments, the methods comprise the step of administering to the subject a compound provided herein or a derivative thereof in combination with a second active agent in amounts effective to treat, prevent or manage chronic myelogenous leukemia.

[0330] In some embodiments, the methods provided herein encompass treating, preventing or managing chronic lymphocytic leukemia (CLL) in a subject. The methods comprise the step of administering to the subject an amount of a compound provided herein or a derivative thereof effective to treat, prevent or manage chronic lymphocytic leukemia. In some embodiments, the methods comprise the step of administering to the subject a compound provided herein or a derivative thereof in combination with a second active agent in amounts effective to treat, 102 NAI-1541502036v1prevent or manage chronic lymphocytic leukemia.

[0331] In certain embodiments, provided herein are methods of treating, preventing, and / or managing disease in subjects with impaired renal function. In certain embodiments, provided herein are method of treating, preventing, and / or managing cancer in subjects with impaired renal function. In certain embodiments, provided herein are methods of providing appropriate dose adjustments for subjects with impaired renal function due to, but not limited to, disease, aging, or other subject factors.

[0332] In certain embodiments, provided herein are methods of treating, preventing, and / or managing lymphoma, including non-Hodgkin’s lymphoma. In some embodiments, provided herein are methods for the treatment or management of non-Hodgkin's lymphoma (NHL), including but not limited to, diffuse large B-cell lymphoma (DLBCL), using prognostic factors.

[0333] In certain embodiments, provided herein are methods of treating, preventing, and / or managing multiple myeloma, including relapsed / refractory multiple myeloma in subjects with impaired renal function or a symptom thereof, comprising administering a therapeutically effective amount of a compound provided herein, or a derivative thereof to a subject having relapsed / refractory multiple myeloma with impaired renal function.

[0334] In certain embodiments, the subject to be treated with one of the methods provided herein has not been treated with anticancer therapy prior to the administration of the compound provided herein, or a derivative thereof. In certain embodiments, the subject to be treated with one of the methods provided herein has been treated with anticancer therapy prior to the administration of the compound provided herein, or a derivative thereof. In certain embodiments, the subject to be treated with one of the methods provided herein has developed drug resistance to the anticancer therapy.

[0335] The methods provided herein encompass treating a patient regardless of subject’s age, although some diseases or disorders are more common in certain age groups.

[0336] As discussed herein, Ras signaling is causally implicated in rasopathies. Thus, the compounds provided herein, which inhibit the function of one or more members of the Ras superfamily, are useful in the treatment of rasopathies including neurofibromatosis type 1, Noonan’s syndrome, and Costello syndrome. 3.5. METHODS OF TREATING FIBROSIS

[0337] Fibrosis, or the accumulation of extracellular matrix molecules that constitute scar 103 NAI-1541502036v1tissue, is a common result of tissue injury. Fibrosis can occur in many tissues within the body, typically as a result of inflammation or damage. Pulmonary fibrosis, renal fibrosis, and hepatic cirrhosis are among the common fibrotic diseases which altogether represent a large unmet medical need. (Friedman SL, Sheppard D, Duffield JS, Violette S. Sci Transl Med 2013 Jan9; 5(167): 167sr1).

[0338] Without being bound by theory, fibrosis, also known as fibrotic scarring, is a pathological wound healing process in which connective tissue replaces normal parenchymal tissue, leading to considerable tissue re-modeling and the formation of permanent scar tissue. Repeated injuries, chronic inflammation and repair are susceptible to fibrosis where excessive extracellular matrix (ECM) components, such as collagen and glycosaminoglycans, accumulate and lead to the formation of a permanent fibrotic scar which can interfere with normal organ and tissue functions. Mechanisms of fibrogenesis include inflammation as well as other pathways and generally involve reorganization of the actin cytoskeleton of affected cells, including epithelial cells, fibroblasts, endothelial cells, and macrophages.

[0339] Without being bound by theory, actin filament assembly and actomyosin contraction are directed by the Rho-associated coiled-coil forming protein kinase (ROCK) family of serine / threonine kinases (ROCK1 and ROCK2) and thus Rho is associated with fibrogenesis.

[0340] Tissue fibrosis is a leading cause of morbidity and mortality.45% of deaths in the United States are attributable to fibrotic disorders. (Wynn TA. “Fibrotic Disease and the TH1 / TH2 Paradigm.” Nat Rev Immunol 2004 Aug: 4(8): 583-594.) Treatments are generally palliative.

[0341] Without being bound by theory, idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung scarring, short median survival, and limited therapeutic options, creating great need for new pharmacologic therapies. It is thought to result from repetitive environmental injury to the lung epithelium.

[0342] As noted above, fibrosis can occur in many tissues within the body, typically as a result of inflammation or damage. Examples include: fibrosis of kidney, fibrosis of cardiovascular system, pulmonary fibrosis, cystic fibrosis, idiopathic fibrosis, fibrosis of the lung, bridging fibrosis, fibrosis of the liver, fibrosis of the intestine, fibrosis of the muscular system, fibrosis of the brain, fibrosis of the joints, fibrosis of the skin, fibrosis of the bone marrow, fibrosis of the heart, fibrosis of the soft tissue, fibrosis of the tendons, fibrosis of the 104 NAI-1541502036v1lymph nodes, fibrosis of the eyes, retroperitoneum, scleroderma and surgical scarring.

[0343] Without being bound by theory, the process of tissue repair is a complex one, with tight regulation of ECM synthesis and degradation ensuring maintenance of normal tissue architecture. However, the process can lead to a progressive irreversible fibrotic response if tissue injury is severe or repetitive, or if the wound healing response itself becomes deregulated. Fibrosis is initiated when immune cells such as macrophages and damaged tissue between surfaces called interstitium release soluble factors that stimulate fibroblasts. The best characterized pro-fibrotic mediators are the transforming growth factor-β (TGF-β ligands such as TGF-β1, -β2 and -β3, bone morphogenetic proteins (BMPs), and Activin.

[0344] Without being bound by theory, the pro-fibrotic TGF-β and its related ligands bind a heteromeric complex of type I and type II trans-membrane TGF-β receptors, each equipped with an intracellular kinase domain. Upon ligand binding the type II receptor kinases phosphorylate and thereby activate the type I receptors, which are also known as activin receptor–like kinases (ALKs). Downstream of this activated complex, a canonical signaling pathway is composed of the Smad family of transcription factors, among which Smad2 and Smad3 are phosphorylated and activated by type I TGF-β receptors. Activated Smad2 / 3 (RSmads) form a trimeric complex with Smad4 that translocates to the nucleus to regulate target gene expression.

[0345] Without being bound by theory, other soluble mediators of fibrosis include connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), and interleukin 10 (IL-10).

[0346] Without being bound by theory, inhibition of the TGF-β1 signaling pathway and Smad2 and 3 phosphorylation and activation represent potential therapeutic approaches for treating fibrosis.

[0347] Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness due to the alterations of a protein called dystrophin that helps keep muscle cells intact. DMD is one of four conditions known as dystrophinopathies. Three diseases that belong to this group are Becker Muscular Dystrophy (BMD, a mild form of DMD); an intermediate clinical presentation between DMD and BMD; and DMD-associated dilated cardiomyopathy (heart-disease) with little or no clinical skeletal, or voluntary, muscle disease.

[0348] DMD primarily affects boys, but in rare cases it can affect girls. In Europe and North 105 NAI-1541502036v1America, the prevalence of DMD is approximately 6 per 100,000 individuals.

[0349] Muscle weakness is the principal symptom of DMD. Symptom onset is in early childhood, usually between ages 2 and 3. The disease first affects the proximal muscles, and later the distal limb muscles. Usually, the lower external muscles are affected before the upper external muscles. Later on, the heart and respiratory muscles are affected. Progressive weakness and scoliosis result in impaired pulmonary function, which can eventually cause acute respiratory failure. Becker muscular dystrophy (BMD) is a similar to DMD, but with onset usually in the teens or early adulthood. The disease course for BMD is slower and less predictable compared to DMD.

[0350] DMD was first described by the French neurologist Guillaume Benjamin Amand Duchenne in the 1860s, but until the 1980s little was known about the cause of any kind of muscular dystrophy. In 1986, researchers identified a particular gene on the X chromosome that, when mutated, leads to DMD. In 1987, the protein associated with this gene was identified and named dystrophin. Lack of wild type dystrophin protein in muscle cells causes them to be fragile and easily damaged. DMD has an X-linked recessive inheritance pattern and is passed on by the mother, who is referred to as a carrier.

[0351] Until relatively recently, boys with DMD usually did not survive much beyond their teen years. Thanks to advances in cardiac and respiratory care, and targeted therapeutic products, life expectancy is increasing and survival into the early 30s is becoming more common but there is still an unmet need for therapeutics to reduce morbidity and lengthen lifespans.

[0352] Without being bound by theory, when skeletal muscle is unable to regenerate due to DMD, damaged muscle is eventually replaced with fibrotic tissue. Development of this fibrosis is partially mediated by the TGF-β1 signaling pathway, which, therefore may be a therapeutic target for DMD.

[0353] Without being bound by theory, a growing number of published studies also suggest that pharmacological activation of the stress-activated MAPK proteins p-38 MAPK and c-Jun NH2-terminal kinase (JNK) may also represent a therapeutic approach for the treatment of DMD related fibrosis.

[0354] Without being bound by theory, targeted therapies are a cornerstone of what is also referred to as precision medicine, a form of medicine that uses information about a person’s genes and proteins to prevent, diagnose, and treat disease. Such therapeutics are sometimes 106 NAI-1541502036v1called "molecularly targeted drugs," "molecularly targeted therapies," or similar names. The process of discovering them is often referred to as “rational drug design.” This concept can also be referred to as “personalized medicine.”

[0355] Without being bound by theory, a series of actions among molecules in a cell that leads to a certain end point or cell function is referred to as a molecular pathway.

[0356] Without being bound by theory, molecularly targeted drugs interact with a particular target molecule, or structurally related set of target molecules, in a pathway; thus modulating the endpoint effect of that pathway, such as a disease-related process; and, thus, yielding a therapeutic benefit.

[0357] Without being bound by theory, molecularly targeted drugs may be small molecules or biologics, usually antibodies. They may be useful alone or in combinations with other therapeutic agents and methods.

[0358] Without being bound by theory, because they target a particular molecule, or related set of molecules, and are usually designed to minimize their interactions with other molecules, targeted therapeutics may have fewer adverse side effects.

[0359] Without being bound by theory, some treatments for fibrotic disorders, such as idiopathic pulmonary fibrosis, hepatic fibrosis, and systemic sclerosis, target inflammatory pathways.

[0360] Provided herein are methods of treating a fibrotic disease in a subject, comprising administering a therapeutically effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject. Also provided herein are methods treating a fibrotic disease in a subject, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0361] In some embodiments of the methods of treating a fibrotic disease provided herein, 107 NAI-1541502036v1the method administering a compound or pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily protein. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 50% or more at 20 µM according to a Ras Superfamily Activity. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 9, 10, 11, 12, 13, 16, 18, 22, 23, 24, 27, 28, 32, 33, 36, 37, 38, 39, 40, 57, 62, 75, 84, 86, and 92, or a pharmaceutically acceptable form thereof.

[0362] In some embodiments of the methods of treating a fibrotic disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Erk1 / 2 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1 / 2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1 / 2 protein by 80% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1 / 2 protein by 85% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 21, 49, 51, 53, 56, 67, 68, 79, 80, 81, 82, 89, and 94, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1 / 2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1 / 2 108 NAI-1541502036v1protein by 45% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1 / 2 protein by 50% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 16, 18, 23, 27, 28, 36, 37, 38, 40, 54, 55, 57, 60, 61, 62, 75, and 83, or a pharmaceutically acceptable form thereof.

[0363] In some embodiments of the methods of treating a fibrotic disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Akt activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein by 85% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 49, 51, 53, 56, 79, 80, 81, and 94, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein by 50% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, 22, 27, 28, 32, 36, 37, 38, 39, 40, 47, 54, 55, 57, 59, 60, 61, 62, 66, 67, 74, 75, 76, 83, 84, 86, 87, 88, and 91, or a pharmaceutically acceptable form thereof.

[0364] In some embodiments of the methods of treating a fibrotic disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Smad2 / 3 activity. In some embodiments, the compound or pharmaceutically 109 NAI-1541502036v1acceptable form thereof inhibits phosphorylation of the Smad2 / 3 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2 / 3 protein by 80% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2 / 3 protein by 85% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 21, 29, 49, 51, 56, 58, 61, 63, 64, 65, 68, 77, 79, 80, 81, 87, 88, 89, and 94, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2 / 3 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2 / 3 protein by 50% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound is Compound 12, 14, 25, 26, 31, 32, 33, 37, 78, and 90, or a pharmaceutically acceptable form thereof.

[0365] In some embodiments of the methods of treating a fibrotic disease provided herein, the method administering a compound or pharmaceutically acceptable form that modulates JNK activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by 50% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound is Compound 8, or a pharmaceutically acceptable form thereof. In some embodiments, the 110 NAI-1541502036v1compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by about 50% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.

[0366] In some embodiments of the methods of treating a fibrotic disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates MAPK p38 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 by 50% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 by 50% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.

[0367] In some embodiments of the methods of treating a fibrotic disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates IL-6 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6. In some embodiments, the compound or pharmaceutically acceptable 111 NAI-1541502036v1form thereof inhibits IL-6 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 75% or more at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound is selected from the group consisting of Compounds 4, 9, 10, 11, 16, 17, 19, 20, 92, and 94, or a pharmaceutically acceptable form thereof.

[0368] In some embodiments of the methods of treating a fibrotic disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates TNF-alpha activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 75% or more at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound is Compound 20 and 94, or a pharmaceutically acceptable form thereof.

[0369] In some embodiments, the compound of Formula I administered according to any of the methods disclosed herein treats, prevents, or inhibits fibrosis in the subject. In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, administered according to any of the methods disclosed herein inhibits fibrosis in the liver, lung, skin, soft tissue, tendons, lymph nodes, lung, kidney, heart, eye, or retroperitoneum of said subject. In some embodiments, the compound administered according to any of the methods disclosed herein treats, prevents, or ameliorates one or more symptoms of a fibrotic disease in the subject. In some embodiments, the compound administered according to any of the methods disclosed herein treats, prevents, or ameliorates the fibrotic disease in the subject. In some embodiments, the fibrotic disease is selected from the group consisting of fibrosis of kidney, fibrosis of cardiovascular system, pulmonary fibrosis, cystic fibrosis, idiopathic fibrosis, fibrosis of the lung, bridging fibrosis, fibrosis of the liver, fibrosis of the intestine, fibrosis of the muscular system, fibrosis of the brain, fibrosis of the joints, fibrosis of the skin, fibrosis of the bone marrow, fibrosis of the heart, 112 NAI-1541502036v1fibrosis of the soft tissue, fibrosis of the tendons, fibrosis of the lymph nodes, fibrosis of the eyes, retroperitoneum, scleroderma and surgical scarring. In some embodiments, the fibrotic disease is fibrosis of the kidney. In some embodiments, the fibrosis of the kidney is progressive kidney disease. In some embodiments, the fibrotic disease is fibrosis of the cardiovascular system. In some embodiments, the fibrosis of the cardiovascular system is atherosclerosis or restenosis. In some embodiments, the fibrotic disease is pulmonary fibrosis. In some embodiments, the fibrotic disease is cystic fibrosis. In some embodiments, the fibrotic disease is idiopathic fibrosis. In some embodiments, the idiopathic fibrosis is idiopathic pulmonary fibrosis. In some embodiments, the fibrotic disease is fibrosis of the lung. In some embodiments, the fibrosis of the lung is progressive massive fibrosis and radiation-induced lung injury. In some embodiments, the fibrotic disease is bridging fibrosis. In some embodiments, the fibrotic disease is fibrosis of the liver. In some embodiments, the fibrosis of the liver is cirrhosis. In some embodiments, the fibrotic disease is fibrosis of the intestine. In some embodiments, the fibrosis of the intestine is Crohn’s disease. In some embodiments, the fibrotic disease is fibrosis of the muscular system. In some embodiments, the fibrosis of the muscular system is Duchenne muscular dystrophy (DMD). In some embodiments, the Duchenne muscular dystrophy is Becker Muscular Dystrophy (BMD), an intermediate clinical presentation between DMD and BMD, or DMD-associated dilated cardiomyopathy. In some embodiments, the fibrotic disease is fibrosis of the brain. In some embodiments, the fibrosis of the brain is glial scar. In some embodiments, the fibrotic disease is fibrosis of the joints. In some embodiments, the fibrosis of the joints is arterial stiffness. In some embodiments, the fibrosis of the joints is fibrosis of the knee. In some embodiments, the fibrosis of the joints is fibrosis of the shoulder. In some embodiments, the fibrotic disease is fibrosis of the skin. In some embodiments, the fibrosis of the skin is Keloid. In some embodiments, the fibrotic disease is fibrosis of the bone marrow. In some embodiments, the fibrosis of the bone marrow is Myelofibrosis. In some embodiments, the fibrotic disease is fibrosis of the heart. In some embodiments, the fibrosis of the heart is Myocardial fibrosis. In some embodiments, the fibrotic disease is fibrosis of the soft tissue. In some embodiments, the fibrotic disease is fibrosis of the tendons. In some embodiments, the fibrotic disease is fibrosis of the lymph nodes. In some embodiments, the fibrotic disease is fibrosis of the eyes. In some embodiments, the fibrotic disease is retroperitoneum. In some embodiments, the fibrotic disease is scleroderma. In some embodiments, the fibrotic disease is surgical scarring. 113 NAI-1541502036v13.6. METHODS OF TREATING INFLAMMATION

[0370] Inflammation is a complex protective biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and to initiate tissue repair. (Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE; Nielsen; Andersen; Girardin (February 2007) Clin. Exp. Immunol.147)

[0371] Inflammation is classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (especially granulocytes) from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue.

[0372] Prolonged inflammation, known as chronic inflammation, is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. It leads to a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, and increases in systemic concentrations of cytokines such as TNF-α, IL-6, and CRP. (Petersen, A. M.; Pedersen, B. K. (2005). J Appl Physiol.98 (4): 1154–1162)

[0373] Many proteins are involved in inflammation. Any of them are susceptible to genetic mutation which may impair or otherwise dysregulate their normal function and expression.

[0374] Both small molecules and biologics are used to treat inflammatory diseases. Most treatments, however, are largely palliative.

[0375] A clear unmet medical need remains to find treatments that can mechanistically reduce chronic inflammatory diseases.

[0376] Provided herein are methods treating an inflammatory disease in a subject, comprising administering a therapeutically effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject. Also provided herein are methods of treating an inflammatory disease in a subject, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 114 NAI-1541502036v13, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.

[0377] In some embodiments of the methods of treating an inflammatory disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily protein. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 µM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits the activity one or more Ras superfamily protein. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 45% or more at 20 µM according to a Ras Superfamily Activity. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 50% or more at 20 µM according to a Ras Superfamily Activity. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 9, 10, 11, 12, 13, 16, 18, 22, 23, 24, 27, 28, 32, 33, 36, 37, 38, 39, 40, 57, 62, 75, 84, 86, and 92, or a pharmaceutically acceptable form thereof.

[0378] In some embodiments of the methods of treating an inflammatory disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Erk1 / 2 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1 / 2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1 / 2 protein by 80% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1 / 2 protein by 85% or more at 10 µM 115 NAI-1541502036v1according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 21, 49, 51, 53, 56, 67, 68, 79, 80, 81, 82, 89, and 94, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1 / 2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1 / 2 protein by 45% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1 / 2 protein by 50% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 16, 18, 23, 27, 28, 36, 37, 38, 40, 54, 55, 57, 60, 61, 62, 75, and 83, or a pharmaceutically acceptable form thereof.

[0379] In some embodiments of the methods of treating an inflammatory disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Akt activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein by 85% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 49, 51, 53, 56, 79, 80, 81, and 94, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Akt 116 NAI-1541502036v1Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein by 50% or more at 10 µM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, 22, 27, 28, 32, 36, 37, 38, 39, 40, 47, 54, 55, 57, 59, 60, 61, 62, 66, 67, 74, 75, 76, 83, 84, 86, 87, 88, and 91, or a pharmaceutically acceptable form thereof.

[0380] In some embodiments of the methods of treating an inflammatory disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Smad2 / 3 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2 / 3 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2 / 3 protein by 80% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2 / 3 protein by 85% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 21, 29, 49, 51, 56, 58, 61, 63, 64, 65, 68, 77, 79, 80, 81, 87, 88, 89, and 94, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2 / 3 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2 / 3 protein by 50% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. In some embodiments, the compound is Compound 12, 14, 25, 26, 31, 32, 33, 37, 78, and 90, or a pharmaceutically acceptable form thereof.

[0381] In some embodiments of the methods of treating an inflammatory disease provided 117 NAI-1541502036v1herein, the method administering a compound or pharmaceutically acceptable form that modulates JNK activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by about 50% at 10 µM according to JNK Activation Assay. In some embodiments, the compound is Compound 8, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by about 50% or more at 10 µM according to JNK Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.

[0382] In some embodiments of the methods of treating an inflammatory disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates MAPK p38 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 by about 50% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or 118 NAI-1541502036v1more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 by about 50% or more at 10 µM according to MAPK p38 Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.

[0383] In some embodiments of the methods of treating an inflammatory disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates IL-6 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 75% or more at 10 µM according to IL-6 Quantification Assay. In some embodiments, the compound is selected from the group consisting of Compounds 4, 9, 10, 11, 16, 17, 19, 20, 92, and 94, or a pharmaceutically acceptable form thereof.

[0384] In some embodiments of the methods of treating an inflammatory disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates TNF-alpha activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 75% or more at 10 µM according to TNF-alpha Quantification Assay. In some embodiments, the compound is Compound 20 and 94, or a pharmaceutically acceptable form thereof.

[0385] In some embodiments, the inflammatory disease is inflammation-associated cancer development. As disclosed here, the compounds provided herein are useful in treatment of cancer. It is well recognized that the immune inflammatory state serves as a key mediator of the middle stages of tumor development. It is also well known that chronic inflammation can 119 NAI-1541502036v1predispose an individual to cancer. Chronic inflammation is caused by a variety of factors, including bacterial, viral, and parasitic infections. The longer the inflammation persists, the higher the risk of associated carcinogenesis. Anti-inflammatory cancer therapy prevents premalignant cells from turning fully cancerous or impedes existing tumors from spreading to distant sites in the body. Thus, in some embodiments, the compounds provided herein are useful in treating inflammatory cancers. Such cancers, and the chronic inflammatory conditions that predispose susceptible cells to neoplastic transformation, include gastric adenocarcinoma (gastritis), mucosa-associated lymphoid tissue (MALT) lymphoma (gastritis), bladder, liver and rectal carcinomas (schistosomiasis), cholangiocarcinoma and colon carcinoma (cholangitis), gall bladder cncer (chronic cholecystitis), ovarian and cervical carcinoma (pelvic inflammatory disease, chronic cervicitis), skin carcinoma (osteomyelitis), colorectal carcinoma (inflammatory bowel disease), esophageal carcinoma (reflux esophagitis, Barrett’s esophagus), bladder cancer (bladder inflammation (cystitis)), mesothelioma and lung carcinoma (asbestosis, silicosis), oral squamous cell carcinoma (gingivitis, lichen planus), pancreatic carcinoma (pancreatitis, protease mutation), vulvar squamous cell carcinoma (lichen sclerosis), salivary gland carcinoma (slaladenitis), lung carcinoma (bronchitis) and MALT lymphoma (Sjogren syndrome, Hashimoto’s thyroiditis). Shacter, et al., 2002, Oncology, 16(2), 217-26.

[0386] In certain embodiments, the compounds provided herein are useful in treating inflammatory diseases in the airways, such as nonspecific bronchial hyper-reactivity, chronic bronchitis, cystic fibrosis, and acute respiratory distress syndrome (ARDS).

[0387] In certain embodiments, the compounds provided herein are useful in treating asthma and idiopathic lung fibrosis or idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis, and interstitial lung disease. As known to one of skill in the art, the differentiation of fibroblasts into cell types called myofibroblasts occurs during wound healing, when the cells contribute to the deposition of extracellular matrix (ECM) in the transient process of wound repair. In chronic inflammatory diseases such as asthma, pathological tissue remodeling often occurs, and is mediated by the functions of increased numbers of myofibroblasts in the diseased tissue, see Hinz, B. et al. Am J Pathol.2007; 170: 1807–1816. In certain embodiments, the compounds provided herein prevent or reduce TGF-β-induced myofibroblast differentiation, as measured by the expression of alpha smooth muscle actin (α-SMA), a hallmark of myofibroblast differentiation (Serini, G. and Gabbiani, G.1999; Exp. Cell Res.250: 273-283). 120 NAI-1541502036v1

[0388] In certain embodiments, the compounds provided herein are useful in treating psoriasis, chronic plaque psoriasis, psoriatic arthritis, acanthosis, atopic dermatitis, various forms of eczema, contact dermatitis (includes allergic dermatitis), systemic sclerosis (scleroderma), wound healing, and drug eruption.

[0389] In some embodiments, the disease is inflammation, arthritis, rheumatoid arthritis, spondylarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, and other arthritic conditions, systemic lupus erthematosus (SLE), skin-related conditions, eczema, Sjögren's syndrome, burns, dermatitis, neuroinflammation, allergy pain, autoimmune myositis, neuropathic pain, fever, pulmonary disorders, lung inflammation, adult respiratory distress syndrome, pulmonary sarcoisosis, asthma, silicosis, chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD), cardiovascular disease, arteriosclerosis, myocardial infarction (including post-myocardial infarction indications), thrombosis, congestive heart failure, cardiac reperfusion injury, as well as complications associated with hypertension and / or heart failure such as vascular organ damage, restenosis, cardiomyopathy, stroke including ischemic and hemorrhagic stroke, reperfusion injury, renal reperfusion injury, ischemia including stroke and brain ischemia, and ischemia resulting from cardiac / coronary bypass, neurodegenerative disorders, liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, viral and bacterial infections, sepsis, septic shock, gram negative sepsis, malaria, meningitis, HIV infection, opportunistic infections, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), pneumonia, herpes virus, myalgias due to infection, influenza, autoimmune disease, graft vs. host reaction and allograft rejections, treatment of bone resorption diseases, osteoporosis, multiple sclerosis, acute gout, pneumonitis, myocarditis, pericarditis, myositis, eczema, alopecia, vitiligo, bullous skin diseases, atherosclerosis, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritis nodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, vasculitis with organ involvement, acute rejection of transplanted organs. endotoxaemia, systemic inflammatory 121 NAI-1541502036v1response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, postsurgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex, coronavirus or dry eye syndrome (or keratoconjunctivitis sicca (KCS)).

[0390] In certain embodiments, the compounds provided herein are useful in treating neuropathic and nociceptive pain, chronic or acute, such as, without limitation, allodynia, inflammatory pain, inflammatory hyperalgesia, post herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns, back pain, ocular pain, visceral pain, cancer pain, dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post operative pain, post stroke pain, and menstrual pain.

[0391] In certain embodiments, the compounds provided herein are useful in treating Alzheimer's disease (AD), mild cognitive impairment (MCI), age-associated memory impairment (AAMI), multiple sclerosis, Parkinson's disease, vascular dementia, senile dementia, AIDS dementia, Pick's disease, dementia caused by cerebrovascular disorders, corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, diminished CNS function associated with traumatic brain injury.

[0392] In some embodiments, the compounds provided herein are useful in treating Alzheimer's disease (AD), ankylosing spondylitis, arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis), asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus, erythematous (SLE), nephritis, Parkinson's disease, ulcerative colitis.

[0393] When used for the treatment of inflammatory disease, the compounds provided herein may be administered in dosages, routes of administration and / or to achieve pK profiles as described herein for the treatment of cancer.

[0394] In some embodiments, the inflammatory disease is inflammation-associated cancer development. As disclosed here, the compounds provided herein are useful in treatment of cancer. It is well recognized that the immune inflammatory state serves as a key mediator of the middle stages of tumor development. It is also well known that chronic inflammation can predispose an individual to cancer. Chronic inflammation is caused by a variety of factors, 122 NAI-1541502036v1including bacterial, viral, and parasitic infections. The longer the inflammation persists, the higher the risk of associated carcinogenesis. Anti-inflammatory cancer therapy prevents premalignant cells from turning fully cancerous or impedes existing tumors from spreading to distant sites in the body. Thus, in some embodiments, the compounds provided herein are useful in treating inflammatory cancers. Such cancers, and the chronic inflammatory conditions that predispose susceptible cells to neoplastic transformation, include gastric adenocarcinoma (gastritis), mucosa-associated lymphoid tissue (MALT) lymphoma (gastritis), bladder, liver and rectal carcinomas (schistosomiasis), cholangiocarcinoma and colon carcinoma (cholangitis), gall bladder cncer (chronic cholecystitis), ovarian and cervical carcinoma (pelvic inflammatory disease, chronic cervicitis), skin carcinoma (osteomyelitis), colorectal carcinoma (inflammatory bowel disease), esophageal carcinoma (reflux esophagitis, Barrett’s esophagus), bladder cancer (bladder inflammation (cystitis)), mesothelioma and lung carcinoma (asbestosis, silicosis), oral squamous cell carcinoma (gingivitis, lichen planus), pancreatic carcinoma (pancreatitis, protease mutation), vulvar squamous cell carcinoma (lichen sclerosis), salivary gland carcinoma (slaladenitis), lung carcinoma (bronchitis) and MALT lymphoma (Sjogren syndrome, Hashimoto’s thyroiditis). Shacter, et al., 2002, Oncology, 16(2), 217-26.

[0395] In certain embodiments, the compounds provided herein are useful in treating inflammatory diseases in the airways, such as nonspecific bronchial hyper-reactivity, chronic bronchitis, cystic fibrosis, and acute respiratory distress syndrome (ARDS).

[0396] In certain embodiments, the compounds provided herein are useful in treating asthma and idiopathic lung fibrosis or idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis, and interstitial lung disease. As known to one of skill in the art, the differentiation of fibroblasts into cell types called myofibroblasts occurs during wound healing, when the cells contribute to the deposition of extracellular matrix (ECM) in the transient process of wound repair. In chronic inflammatory diseases such as asthma, pathological tissue remodeling often occurs, and is mediated by the functions of increased numbers of myofibroblasts in the diseased tissue, see Hinz, B. et al. Am J Pathol.2007; 170: 1807–1816. In certain embodiments, the compounds provided herein prevent or reduce TGF-β-induced myofibroblast differentiation, as measured by the expression of alpha smooth muscle actin (α-SMA), a hallmark of myofibroblast differentiation (Serini, G. and Gabbiani, G.1999; Exp. Cell Res.250: 273-283).

[0397] In certain embodiments, the compounds provided herein are useful in treating 123 NAI-1541502036v1psoriasis, chronic plaque psoriasis, psoriatic arthritis, acanthosis, atopic dermatitis, various forms of eczema, contact dermatitis (includes allergic dermatitis), systemic sclerosis (scleroderma), wound healing, and drug eruption.

[0398] In some embodiments, the disease is inflammation, arthritis, rheumatoid arthritis, spondylarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, and other arthritic conditions, systemic lupus erthematosus (SLE), skin-related conditions, eczema, Sjögren's syndrome, burns, dermatitis, neuroinflammation, allergy pain, autoimmune myositis, neuropathic pain, fever, pulmonary disorders, lung inflammation, adult respiratory distress syndrome, pulmonary sarcoisosis, asthma, silicosis, chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD), cardiovascular disease, arteriosclerosis, myocardial infarction (including post-myocardial infarction indications), thrombosis, congestive heart failure, cardiac reperfusion injury, as well as complications associated with hypertension and / or heart failure such as vascular organ damage, restenosis, cardiomyopathy, stroke including ischemic and hemorrhagic stroke, reperfusion injury, renal reperfusion injury, ischemia including stroke and brain ischemia, and ischemia resulting from cardiac / coronary bypass, neurodegenerative disorders, liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative diseases, gastric ulcers, viral and bacterial infections, sepsis, septic shock, gram negative sepsis, malaria, meningitis, HIV infection, opportunistic infections, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), pneumonia, herpes virus, myalgias due to infection, influenza, autoimmune disease, graft vs. host reaction and allograft rejections, treatment of bone resorption diseases, osteoporosis, multiple sclerosis, acute gout, pneumonitis, myocarditis, pericarditis, myositis, eczema, alopecia, vitiligo, bullous skin diseases, atherosclerosis, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritis nodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, vasculitis with organ involvement, acute rejection of transplanted organs. endotoxaemia, systemic inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acute 124 NAI-1541502036v1lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, postsurgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex, coronavirus or dry eye syndrome (or keratoconjunctivitis sicca (KCS)).

[0399] In certain embodiments, the compounds provided herein are useful in treating neuropathic and nociceptive pain, chronic or acute, such as, without limitation, allodynia, inflammatory pain, inflammatory hyperalgesia, post herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns, back pain, ocular pain, visceral pain, cancer pain, dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post operative pain, post stroke pain, and menstrual pain.

[0400] In certain embodiments, the compounds provided herein are useful in treating Alzheimer's disease (AD), mild cognitive impairment (MCI), age-associated memory impairment (AAMI), multiple sclerosis, Parkinson's disease, vascular dementia, senile dementia, AIDS dementia, Pick's disease, dementia caused by cerebrovascular disorders, corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, diminished CNS function associated with traumatic brain injury.

[0401] In some embodiments, the compounds provided herein are useful in treating Alzheimer's disease (AD), ankylosing spondylitis, arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis), asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus, erythematous (SLE), nephritis, Parkinson's disease, ulcerative colitis. 3.7. PHARMACEUTICAL COMPOSITIONS

[0402] The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of compounds provided herein (e.g. compounds of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), and a pharmaceutically acceptable carrier, diluent or excipient.

[0403] The compounds can be formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for ophthalmic or parenteral administration, as well as transdermal patch preparation and dry powder 125 NAI-1541502036v1inhalers. Typically the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, Twelfth Edition 2021).

[0404] In the compositions, effective concentrations of one or more compounds or pharmaceutically acceptable salts is (are) mixed with a suitable pharmaceutical carrier or vehicle. In certain embodiments, the concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms and / or progression of a disease or disorder disclosed herein.

[0405] Typically, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

[0406] In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. Liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as known in the art. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0407] The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the subject treated. The therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in vivo systems described herein and then extrapolated therefrom for dosages for humans. In some embodiments, the active compound is administered in a method to achieve a therapeutically effective concentration of the drug. In 126 NAI-1541502036v1some embodiments, a companion diagnostic (see, e.g., Olsen D and Jorgensen JT, Front. Oncol., 2014 May 16, 4:105, doi: 10.3389 / fonc.2014.00105) is used to determine the therapeutic concentration and safety profile of the active compound in specific subjects or subject populations.

[0408] The concentration of active compound in the pharmaceutical composition will depend on absorption, tissue distribution, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of a disease or disorder disclosed herein.

[0409] In certain embodiments, a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng / mL to about 50-100 μg / mL. In some embodiments, the pharmaceutical compositions provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg and in certain embodiments, from about 10 to about 500 mg of the essential active ingredient or a combination of essential ingredients per dosage unit form.

[0410] The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[0411] Thus, effective concentrations or amounts of one or more of the compounds described herein or pharmaceutically acceptable salts thereof are mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions. Compounds are included in an amount effective for ameliorating one or more 127 NAI-1541502036v1symptoms of, or for treating, retarding progression, or preventing. The concentration of active compound in the composition will depend on absorption, tissue distribution, inactivation, excretion rates of the active compound, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art.

[0412] The compositions are intended to be administered by a suitable route, including but not limited to oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, mucosal, dermal, transdermal, buccal, rectal, topical, local, nasal or inhalation. For oral administration, capsules and tablets can be formulated. The compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.

[0413] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol, dimethyl acetamide or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampules, pens, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.

[0414] In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

[0415] Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.

[0416] The pharmaceut...

Claims

What is claimed is:

1. A compound of Formula I: R1R2Nor a pharmaceutically acceptable form thereof, wherein: Y is an imidazolyl; wherein the imidazolyl is optionally substituted with 1 R5substituent and optionally substituted with 1-2 R6substituents; H3COH3CO , ,O N NH NH N N NH NH , orR5and R6are each independently C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, C1-6heteroalkyl, halo, –NR9R10, C1-6alkoxy, C1-6haloalkoxy, –C(O)NR9R10, –(CO)R8, –(CO)OH, –(CO)OR8, or CN, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, and C1-6heteroalkyl are each independently optionally substituted with 1-3 R7substituents; 337 NAI-1541502036v1R7is independently selected from the group consisting of halo, CN, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, 3-6 membered heterocycloalkyl, –NR9R10, –(CO)R8, –(CO)OH, –(CO)OR8, –C(O)NR9R10, oxo, –OH, C1-6alkoxy, C3-6cycloalkoxy, C1-6haloalkoxy, or 5-6 membered heteroaryl; R8is C1-6alkyl, C3-6cycloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R7substituents; and R9and R10are each independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, -OH, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, or 5-10 membered heteroaryl, wherein the C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 R7substituents, or R9and R10are combined to form a 3-7 membered heterocycloalkyl including the nitrogen atom to which they are both attached.

2. The compound of claim 1, wherein Y is a C-linked imidazolyl that is substituted with 1 R5substituent at a nitrogen of the imidazolyl ring and optionally substituted with 1-2 R6substituents at carbons of the imidazolyl ring.

3. The compound of claim 1 or claim 2, wherein the compound is a compound of Formula IA: R1R2wherein m is 0, 1 or 2;or a pharmaceutically acceptable form thereof. 338 NAI-1541502036v14. The compound of any one of claims 1-3, wherein m is 0 and the compound is a compound of Formula IA(1): R1R2Nor a pharmaceutically acceptable form thereof.

5. The compound of claim 3, wherein m is 1.

6. The compound of claim 3, wherein m is 2. N ,OCH38. The compound of any one of claims 1-6, , OCH3OCH3OCH3O O HC3 O ,NH 9. The compound of any one of claims 1-6, wherein R1, CHO O N3,10. The compound of any one of claims 1-9, wherein R3.

11. The compound of any one of claims 1-9, wherein R3.340 NAI-1541502036v112. The compound of any one of claims 1-9, wherein R3 N N CF3.NN13. The compound of any one of claims 1-9, wherein R3.N 3 N 14. The compound of any one of claims 1-9, wherein R or15. A compound of Formula IB: R1R2or a pharmaceutically acceptable form thereof, wherein: OCH3OH3COH3CO;R4is hydrogen or C1-6alkyl; R5and R6are each independently C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7 heterocycloalkyl, C1-6 heteroalkyl, halo, –NR9R10, C1-6 alkoxy, C1-6haloalkoxy, –C(O)NR9R10, –(CO)R8, –(CO)OH, –(CO)OR8, or CN, 341 NAI-1541502036v1wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, and C1-6heteroalkyl are each independently optionally substituted with 1-3 R7substituents; R7is independently selected from the group consisting of halo, CN, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, 3-6 membered heterocycloalkyl, –NR9R10, –(CO)R8, –(CO)OH, –(CO)OR8, –C(O)NR9R10, oxo, –OH, C1-6alkoxy, C3-6cycloalkoxy, C1-6haloalkoxy, or 5-6 membered heteroaryl; R8is C1-6alkyl, C3-6cycloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R7substituents; R9and R10are each independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, -OH, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, or 5-10 membered heteroaryl, wherein the C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 R7substituents, or R9and R10are combined to form a 3-7 membered heterocycloalkyl including the nitrogen atom to which they are both attached; and m is 0, 1 or 2.

16. The compound of claim 15, wherein m is 0 and the compound is a compound of Formula IB(1): R1R2or a pharmaceutically acceptable form thereof. 342 NAI-1541502036v117. The compound of claim 15, wherein m is 1.

18. The compound of claim 17, wherein the compound is a compound of Formula IB(2): R1R2N or a pharmaceutically19. The compound of claim 15, wherein m is 2. OCH320. The compound of any one of claims 15-19, .O 21. The compound of any one of claims 15-19, .H3CO 22. The compound of any one of claims 15-19, .343 NAI-1541502036v1H3CONH 23. The compound of any one of claims 15-19, .

24. The compound of any one of claims 1-23, -CH2F, - CHF2, -CF3, -CH2CF3, -CF2CH3, or -CF2CF3.

25. The compound of any one of claims 1-24, wherein R2is methyl.

26. The compound of any one of claims 1-25, wherein R4is hydrogen or C1-6 alkyl.

27. The compound of any one of claims 1-26, wherein R4is hydrogen, methyl, ethyl, or isopropyl.

28. The compound of any one of claims 1-27, wherein R4is hydrogen.

29. The compound of any one of claims 1-28, wherein R5is C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6haloalkoxy, –C(O)NR9R10, –(CO)R8, or –C(O)OR8, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6 haloalkyl, aryl, C5-10 heteroaryl, C3-7 heterocycloalkyl, and C1-6 heteroalkyl are each independently optionally substituted with 1-3 R7substituents.

30. The compound of any one of claims 1-29, wherein R5is C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R7substituents.

31. The compound of any one of claims 1-30, wherein R5is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R7, wherein R7is -OH, C1-3 alkoxy, or C1-3 haloalkoxy. 344 NAI-1541502036v132. The compound of any one of claims 1-31, wherein R5is methyl, ethyl, or isopropyl.

33. The compound of any one of claims 1-32, wherein R5is methyl.

34. The compound of any one of claims 1-33, wherein R6is C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R7substituents.

35. The compound of any one of claims 1-34, wherein R6is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R7, wherein R7is -OH, C1-3alkoxy, or C1-3haloalkoxy.

36. The compound of any one of claims 1-35, wherein R6is methyl, ethyl, or isopropyl.

37. The compound of any one of claims 1-36, wherein R6is methyl.

38. The compound of any one of claims 1-37, wherein R7is independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, 3-6 membered heterocycloalkyl, –NR9R10, –(CO)R8, oxo, C1-6alkoxy, or C3-6cycloalkoxy.

39. The compound of any one of claims 1-38, wherein R7is independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, C3-5cycloalkyl, C1-4hydroxyalkyl, C1-4heteroalkyl, 3-5 membered heterocycloalkyl, –NR9R10, –(CO)R8, oxo, C1-4alkoxy, or C3-5cycloalkoxy.

40. The compound of any one of claims 1-39, wherein R7is independently selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, C2-3345 NAI-1541502036v1hydroxyalkyl, C2-4heteroalkyl, –NR9R10, –(CO)R8, oxo, methoxy, ethoxy, isopropoxy, cyclopropoxy, or cyclobutoxy.

41. The compound of any one of claims 1-40, wherein R8is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or C2-4heteroalkyl.

42. The compound of any one of claims 1-41, wherein R9and R10are each independently selected from the group consisting of hydrogen, C1-4alkyl, C3-5cycloalkyl, C1-4hydroxyalkyl, C1-4heteroalkyl, –OH, or C1-4alkoxy.

43. The compound of any one of claims 1-42, wherein R9and R10are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, or ethoxy.

44. The compound of any one of claims 1-43, wherein R9and R10are each independently selected from the group consisting of hydrogen or methyl.

45. The compound of any one of claims 1-44, wherein R9and R10are each hydrogen.

46. A compound of Formula II: R11R12or a pharmaceutically acceptable form thereof, wherein: Y is an imidazolyl; wherein the imidazolyl is optionally substituted with 1 R15substituent and optionally substituted with 1-2 R16substituents; OCH3OCH3OCH3,H3COCH OHCH3 O3O ;R15and R16are each independently C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, C1-6heteroalkyl, halo, –NR19R20, C1-6alkoxy, C1-6haloalkoxy, –C(O)NR19R20, –(CO)R18, –(CO)OH, –(CO)OR18, or CN, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, and C1-6heteroalkyl are each independently optionally substituted with 1-3 R17substituents; R17is independently selected from the group consisting of halo, CN, C1-6 alkyl, C3-6cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, 3-6 347 NAI-1541502036v1membered heterocycloalkyl, –NR19R20, –(CO)R18, –(CO)OH, –(CO)OR18, -C(O)NR19R20, oxo, –OH, C1-6alkoxy, C3-6cycloalkoxy, C1-6haloalkoxy, or 5-6 membered heteroaryl; R18is C1-6alkyl, C3-6cycloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R17substituents; and R19and R20are each independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, -OH, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, or 5-10 membered heteroaryl, wherein the C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-7heterocycloalkyl, aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 R17substituents, or R19and R20are combined to form a 3-7 membered heterocycloalkyl including the nitrogen atom to which they are both attached.

47. The compound of claim 46, wherein Y is a C-linked imidazolyl that is substituted with 1 R15substituent at a nitrogen of the imidazolyl ring and optionally substituted with 1-2 R16substituents at carbons of the imidazolyl ring.

48. The compound of claim 46 or claim 47, wherein the compound is a compound of Formula IIA: R11R12wherein m is 0, 1 or 2; or a pharmaceutically acceptable form thereof.

49. The compound of any one of claims 46-48, wherein m is 0 and the compound is a 348 NAI-1541502036v1compound of Formula IIA(1): R11R12Nor a pharmaceutically acceptable 50. The compound of any one of claims 46-48, wherein m is 1.

51. The compound of any one of claims 46-48, wherein m is 2.

52. The compound of claim 46 or claim 47, wherein the compound is a compound of Formula IIB: R11R12wherein m is 0, 1 or 2; or a pharmaceutically acceptable form thereof.

53. The compound of any one of claims 46, 47, or 52, wherein m is 0 and the compound is a compound of Formula IIB(1): R11R12or a pharmaceutically acceptable form thereof. 349 NAI-1541502036v154. The compound of any one of claims 46, 47, or 52, wherein m is 1.

55. The compound of claim 54, wherein the compound is a compound of Formula IIB(2): R11R12Nor a pharmaceutically acceptable form thereof.

56. The compound of any one of claims 46, 47, or 52, wherein m is 2. OCH3OCH357. The compound of any one of claims 46-56, , OCH3.H3CO 59. The compound of any one of claims 46-56, ,350 NAI-1541502036v1H3COCH3O O or60. The compound of any one of claims 46-59, wherein R12.

61. The compound of any one of claims 46-59, .N 62. The compound of any one of claims 46-59, ,orN 63. The compound of any one of claims 46-59, wherein R12.351 NAI-1541502036v1NN64. The compound of any one of claims 46-63, wherein R13or.N 65. The compound of any one of claims 46-63, wherein R13is .

66. The compound of any one of claims 46-63, wherein R13or67. The compound of any one of claims 46-63, wherein R1368. The compound of any one of claims 46-67, wherein R14is hydrogen or C1-6alkyl.

69. The compound of any one of claims 46-68, wherein R14is hydrogen, methyl, ethyl, or isopropyl.

70. The compound of any one of claims 46-69, wherein R14is hydrogen.

71. The compound of any one of claims 46-70, wherein R15is C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, C1-6heteroalkyl, C1-6alkoxy, C1-6haloalkoxy, –C(O)NR19R20, –(CO)R18, or –C(O)OR18, wherein the C1-6alkyl, C3-6352 NAI-1541502036v1cycloalkyl, C1-6haloalkyl, aryl, C5-10heteroaryl, C3-7heterocycloalkyl, and C1-6heteroalkyl are each independently optionally substituted with 1-3 R17substituents.

72. The compound of any one of claims 46-71, wherein R15is C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R17substituents.

73. The compound of any one of claims 46-72, wherein R15is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R17, wherein R17is -OH, C1-3alkoxy, or C1-3haloalkoxy.

74. The compound of any one of claims 46-73, wherein R15is methyl, ethyl, or isopropyl.

75. The compound of any one of claims 46-74, wherein R15is methyl.

76. The compound of any one of claims 46-75, wherein R16is C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, or C1-6heteroalkyl, wherein the C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, and C1-6heteroalkyl, are each independently optionally substituted with 1-3 R17substituents.

77. The compound of any one of claims 46-76, wherein R16is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R17, wherein R17is -OH, C1-3alkoxy, or C1-3haloalkoxy.

78. The compound of any one of claims 46-77, wherein R16is methyl, ethyl, or isopropyl.

79. The compound of any one of claims 46-78, wherein R16is methyl. 353 NAI-1541502036v180. The compound of any one of claims 46-79, wherein R17is independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C1-6hydroxyalkyl, C1-6heteroalkyl, 3-6 membered heterocycloalkyl, –NR19R20, –(CO)R18, oxo, C1-6alkoxy, or C3-6cycloalkoxy.

81. The compound of any one of claims 46-80, wherein R17is independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, C3-5cycloalkyl, C1-4hydroxyalkyl, C1-4heteroalkyl, 3-5 membered heterocycloalkyl, –NR19R20, –(CO)R18, oxo, C1-4alkoxy, or C3-5cycloalkoxy.

82. The compound of any one of claims 46-81, wherein R17is independently selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, C2-3hydroxyalkyl, C2-4heteroalkyl, –NR19R20, –(CO)R18, oxo, methoxy, ethoxy, isopropoxy, cyclopropoxy, or cyclobutoxy.

83. The compound of any one of claims 46-82, wherein R18is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or C2-4heteroalkyl.

84. The compound of any one of claims 46-83, wherein R19and R20are each independently selected from the group consisting of hydrogen, C1-4alkyl, C3-5cycloalkyl, C1-4hydroxyalkyl, C1-4heteroalkyl, –OH, or C1-4alkoxy.

85. The compound of any one of claims 46-84, wherein R19and R20are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, or ethoxy.

86. The compound of any one of claims 46-85, wherein R19and R20are each independently selected from the group consisting of hydrogen or methyl.

87. The compound of any one of claims 46-86, wherein R19and R20are each hydrogen. 354 NAI-1541502036v188. The compound of any one of claims 1-87, wherein the compound has a MW of no more than 1,000 g / mol.

89. The compound of any one of claims 1-88, wherein the compound has a MW of no more than 900 g / mol, no more than 800 g / mol, no more than 700 g / mol, no more than 600 g / mol, or no more than 500 g / mol.

90. The compound of any one of claims 1-89, wherein the compound has a MW of no more than 600 g / mol.

91. The compound of any one of claims 1-90, wherein the compound has a MW of no more than 500 g / mol.

92. The compound of any one of claims 1-91, wherein the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof, optionally wherein the compound is selected from the group consisting of 9, 10, 11, 16, 18, 19, 36, 37, 38, 39, 40, and 62, or a pharmaceutically acceptable form thereof, or optionally wherein the compound is selected from the group consisting of 36, 37, 38, 39, 40, and 62, or a pharmaceutically acceptable form thereof.

93. The compound of any one of claims 1-92, wherein the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, and 69, or a pharmaceutically acceptable form thereof.

94. The compound of any one of claims 1-92, wherein the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 25, 26, 27, 28, 355 NAI-1541502036v134, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, and 45, or a pharmaceutically acceptable form thereof.

95. The compound of any one of claims 1-92, wherein the compound is selected from the group consisting of Compounds 22, 23, 24, and 30, or a pharmaceutically acceptable form thereof.

96. The compound of any one of claims 1-92, wherein the compound is selected from the group consisting of Compounds 31, 32, 33, and 69, or a pharmaceutically acceptable form thereof.

97. The compound of any one of claims 1-92, wherein the compound is selected from the group consisting of Compounds 16, 17, 18, 19, 20, 21, 29, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, and 68, or a pharmaceutically acceptable form thereof.

98. The compound of any one of claims 1-92, wherein the compound is selected from the group consisting of Compounds 16, 17, 18, 19, 20, 21, 29, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, and 62, or a pharmaceutically acceptable form thereof.

99. The compound of any one of claims 1-92, wherein the compound is selected from the group consisting of Compounds 63, 64, and 65, or a pharmaceutically acceptable form thereof.

100. The compound of any one of claims 1-92, wherein the compound is selected from the group consisting of Compounds 66, 67, and 68, or a pharmaceutically acceptable form thereof.

101. The compound of any one of claims 1-100, wherein the pharmaceutically acceptable form of the compound is an isomer, isotopic variant, pharmaceutically acceptable salt, polymorph, or solvate of said compound. 356 NAI-1541502036v1102. The compound of any one of claims 1-101, wherein the pharmaceutically acceptable form of the compound is exclusive of a salt form.

103. The compound of any one of claims 1-102, wherein the isomer of the compound is a diastereomer or enantiomer of the compound.

104. The compound of any one of claims 1-103, wherein the compound is a tautomer of the compound.

105. The compound of any one of claims 1-104, wherein the compound is a racemate or a mixture of diasteromers.

106. The compound of any one of claims 1-104, wherein the compound is a single enantiomer or a single diastereomer.

107. The compound of claim 106, wherein the compound is a single enantiomer.

108. The compound of claim 107, wherein the compound is an (R)-enantiomer; optionally wherein the compound has an enantiomeric excess of greater than 10% of the (R)-enantiomer; optionally wherein the compound has an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (R)-enantiomer; optionally wherein the compound has an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (R)-enantiomer.

109. The compound of claim 107, wherein the compound is an (S)-enantiomer; optionally wherein the compound has an enantiomeric excess of greater than 10% of the (S)-enantiomer; optionally wherein the compound has an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or 357 NAI-1541502036v1more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (S)-enantiomer; optionally wherein the compound has an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (S)-enantiomer.

110. The compound of claim 106, wherein the compound is a single diastereomer; optionally wherein the compound is a (R) / (R)-, (R) / (S)-, (S) / (R)-, or (S) / (S)-single diastereomer.

111. The compound of claim 110, wherein the compound is an (R) / (R)-diastereomer; optionally wherein the compound has a diastereomeric excess of greater than 10% of the (R) / (R)-diastereomer; optionally wherein the compound has a diastereomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (R) / (R)-diastereomer; optionally wherein the compound has a diastereomeric of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (R) / (R)-diastereomer.

112. The compound of claim 110, wherein the compound is an (R) / (S)-diastereomer; optionally wherein the compound has a diastereomeric excess of greater than 10% of the (R) / (S)-diastereomer; optionally wherein the compound has a diastereomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (R) / (S)-diastereomer; optionally wherein the compound has a diastereomeric of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (R) / (S)-diastereomer.

113. The compound of claim 110, wherein the compound is an (S) / (R)-diastereomer; optionally wherein the compound has a diastereomeric excess of greater than 10% of the 358 NAI-1541502036v1(S) / (R)-diastereomer; optionally wherein the compound has a diastereomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (S) / (R)-diastereomer; optionally wherein the compound has a diastereomeric of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (S) / (R)-diastereomer.

114. The compound of claim 110, wherein the compound is an (S) / (S)-diastereomer; optionally wherein the compound has a diastereomeric excess of greater than 10% of the (S) / (S)-diastereomer; optionally wherein the compound has a diastereomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (S) / (S)-diastereomer; optionally wherein the compound has a diastereomeric of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (S) / (S)-diastereomer.

115. The compound of any one of claims 1-114, wherein the compound or pharmaceutically acceptable form thereof is a modulator of Ras superfamily activity according to a Ras Superfamily Activity Assay.

116. The compound of claim 115, wherein the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 µM according to a Ras Superfamily Activity Assay.

117. The compound of claim 116, wherein the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 9, 10, 11, 12, 13, 16, 18, 22, 23, 24, 27, 28, 32, 33, 36, 37, 38, 39, 40, 57, 62, 75, 84, 86, and 92, or a pharmaceutically acceptable form thereof. 359 NAI-1541502036v1118. The compound of any one of claims 1-117, wherein the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 according to Erk1 / 2 Phosphorylation Assay.

119. The compound of claim 118, wherein the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Erk1 / 2 Phosphorylation Assay.

120. The compound of claim 119, wherein the compound is selected from the group consisting of Compounds 19, 20, 21, 49, 51, 53, 56, 67, 68, 79, 80, 81, 82, 89, and 94, or a pharmaceutically acceptable form thereof.

121. The compound of any one of claims 1-117, wherein the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 according to Erk1 / 2 Phosphorylation Assay.

122. The compound of claim 121, wherein the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Erk1 / 2 Phosphorylation Assay.

123. The compound of claim 122, wherein the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 16, 18, 23, 27, 28, 36, 37, 38, 40, 54, 55, 57, 60, 61, 62, 75, and 83, or a pharmaceutically acceptable form thereof.

124. The compound of any one of claims 1-123, wherein the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt according to Akt Phosphorylation Assay. 360 NAI-1541502036v1125. The compound of claim 124, wherein the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Akt Phosphorylation Assay.

126. The compound of claim 125, wherein the compound is selected from the group consisting of Compounds 19, 20, 49, 51, 53, 56, 79, 80, 81, and 94, or a pharmaceutically acceptable form thereof.

127. The compound of any one of claims 1-123, wherein the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt according to Akt Phosphorylation Assay.

128. The compound of claim 127, wherein the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Akt Phosphorylation Assay.

129. The compound of claim 128, wherein the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, 22, 27, 28, 32, 36, 37, 38, 39, 40, 47, 54, 55, 57, 59, 60, 61, 62, 66, 67, 74, 75, 76, 83, 84, 86, 87, 88, and 91, or a pharmaceutically acceptable form thereof.

130. The compound of any one of claims 1-129, wherein the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 according to Phospho-Smad2 / 3 Inhibition Assay.

131. The compound of claim 130, wherein the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay. 361 NAI-1541502036v1132. The compound of claim 131, wherein the compound is selected from the group consisting of Compounds 19, 20, 21, 29, 49, 51, 56, 58, 61, 63, 64, 65, 68, 77, 79, 80, 81, 87, 88, 89, and 94, or a pharmaceutically acceptable form thereof.

133. The compound of any one of claims 1-129, wherein the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 according to Phospho-Smad2 / 3 Inhibition Assay.

134. The compound of claim 133, wherein the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to Phospho-Smad2 / 3 Inhibition Assay.

135. The compound of claim 134, wherein the compound is Compound 12, 14, 25, 26, 31, 32, 33, 37, 78, and 90, or a pharmaceutically acceptable form thereof.

136. The compound of any one of claims 1-135, wherein the compound or pharmaceutically acceptable form thereof inhibits JNK according to JNK Activation Assay.

137. The compound of claim 136, wherein the compound or pharmaceutically acceptable form thereof inhibits JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to JNK Activation Assay.

138. The compound of claim 137, wherein the compound is Compound 8, or a pharmaceutically acceptable form thereof.

139. The compound of any one of claims 1-135, wherein the compound or pharmaceutically acceptable form thereof activates JNK according to JNK Activation Assay. 362 NAI-1541502036v1140. The compound of claim 139, wherein the compound or pharmaceutically acceptable form thereof activates JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to JNK Activation Assay.

141. The compound of claim 140, wherein the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.

142. The compound of any one of claims 1-141, wherein the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 according to MAPK p38 Activation Assay.

143. The compound of claim 142, wherein the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to MAPK p38 Activation Assay.

144. The compound of claim 143, wherein the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 90% or more, or 95% or more at 10 µM according to MAPK p38 Activation Assay.

145. The compound of any one of claims 1-141, wherein the compound or pharmaceutically acceptable form thereof activates MAPK p38 according to MAPK p38 Activation Assay.

146. The compound of claim 145, wherein the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 µM according to MAPK p38 Activation Assay. 363 NAI-1541502036v1147. The compound of claim 146, wherein the compound is selected from the group consisting of Compounds 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.

148. The compound of any one of claims 1-147, wherein the compound or pharmaceutically acceptable form thereof inhibits IL-6 according to IL-6 Quantification Assay.

149. The compound of claim 148, wherein the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to IL-6 Quantification Assay.

150. The compound of claim 149, wherein the compound is selected from the group consisting of Compounds 4, 9, 10, 11, 16, 17, 19, 20, 92, and 94 or a pharmaceutically acceptable form thereof.

151. The compound of any one of claims 1-150, wherein the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha according to TNF-alpha Quantification Assay.

152. The compound of claim 151, wherein the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 µM according to TNF-alpha Quantification Assay.

153. The compound of claim 152, wherein the compound is Compound 20 and 94, or a pharmaceutically acceptable form thereof.

154. The compound of any one of claims 1-153, wherein the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 according to Proliferation Assay. 364 NAI-1541502036v1155. The compound of claim 154, wherein the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50value of 1 µM or less, 0.9 µM or less, 0.8 µM or less, 0.75 µM or less, 0.7 µM or less, 0.6 µM or less, 0.5 µM or less, 0.4 µM or less, 0.3 µM or less, 0.25 µM or less, 0.2 µM or less, 0.15 µM or less, 0.1 µM or less, 0.09 µM or less, 0.05 µM or less, or 0.03 µM or less, according to Proliferation Assay.

156. The compound of claim 155, wherein the compound is selected from the group consisting of Compounds 1, 3, 4, 9, 10, 11, 12, 13, 16, 18, 19, 22, 23, 28, 31, 32, 36, 37, 38, 39, 40, 47, 48, 49, 52, 57, 62, 65, 68, 75, 80, 81, 82, 83, 85, 87, and 94, or a pharmaceutically acceptable form thereof.

157. The compound of claim 155 or claim 156, wherein the compound is selected from the group consisting of Compounds 9, 10, 11, 16, 18, 19, 28, 36, 37, 38, 39, 40, 48, 57, 62, and 65, or a pharmaceutically acceptable form thereof.

158. The compound of any one of claims 155-157, wherein the compound is selected from the group consisting of Compounds 9, 10, 11, 36, 37, 38, 39, 40, 62, and 65, or a pharmaceutically acceptable form thereof.

159. The compound of any one of claims 1-158, wherein the compound or pharmaceutically acceptable form thereof has a kinetic solubility of 10 µM or more, 20 µM or more, 30 µM or more, 40 µM or more, 50 µM or more, 60 µM or more, 70 µM or more, 80 µM or more, 90 µM or more, 100 µM or more, 150 µM or more, or 200 µM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay.

160. The compound of claim 159, wherein the compound is selected from the group consisting of Compounds 9 and 11, or a pharmaceutically acceptable form thereof.

161. The compound of claim 159 or claim 160, wherein the compound is Compound 9, or a pharmaceutically acceptable form thereof. 365 NAI-1541502036v1162. The compound of any one of claims 1-161, wherein the compound or pharmaceutically acceptable form thereof has a half-life of 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, or 50 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay.

163. The compound of claim 162, wherein the compound is Compound 11, or a pharmaceutically acceptable form thereof.

164. The compound of any one of claims 1-163, wherein the compound or pharmaceutically acceptable form thereof inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, according to Proliferation Assay.

165. The compound of claim 164, wherein the compound or pharmaceutically acceptable form thereof inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC50value of 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay.

166. The compound of claim 164 or claim 165, wherein the compound or pharmaceutically acceptable form thereof inhibits proliferation in MM.R1 with an IC50value of 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay.

167. The compound of any one of claims 164-166, wherein the compound is selected from the group consisting of Compounds 9 and 11, or a pharmaceutically acceptable form thereof.

168. A pharmaceutical composition comprising the compound or pharmaceutically acceptable form thereof, of any one of claims 1-167, and a pharmaceutically acceptable carrier, excipient or diluent. 366 NAI-1541502036v1169. A method of modulating a Ras superfamily protein, comprising contacting the Ras superfamily protein with an effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof.

170. A method of modulating a Ras superfamily protein, comprising contacting the Ras superfamily protein with an effective amount of the pharmaceutical composition of claim 168.

171. The method of claim 169 or claim 170, wherein the Ras superfamily protein is present in a cell.

172. The method of any one of claims 169-171, wherein the method inhibits the Ras superfamily protein.

173. The method of any one of claims 169-172, wherein the Ras superfamily protein is a Ras protein, or a mutant thereof.

174. The method of claim 173, wherein the Ras protein is DIRAS I; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRASI; NKIRAS2; NRAS; RALA; RALB; RAPIA; RAPIB; RAP2A; RAP2B; RAP2C; RASDI; RASD2; RASLIOA; RASLIOB; RASLI IA; RASLIIB; RASL12; REMI; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2.

175. The method of claim 173 or claim 174, wherein the Ras protein is HRAS; KRAS; or NRAS, or a mutant thereof.

176. The method of any one of claims 173-175, wherein the Ras protein is a KRAS mutant.

177. The method of claim 176, wherein the KRAS mutant is a KRas G12D mutant, KRas G12C mutant, or KRas Q61H mutant. 367 NAI-1541502036v1178. The method of any one of claims 173-175, wherein the Ras protein is HRAS or a mutant thereof.

179. The method of any one of claims 173-175, wherein the Ras protein is NRAS or a mutant thereof.

180. The method of any one of claims 169-173, wherein the Ras superfamily protein is a Rac protein, or a mutant thereof.

181. The method of claim 180, wherein the Rac protein is RAC1; RAC2; RAC3; RHOG, or a mutant thereof.

182. The method of claim 180 or claim 181, wherein the Rac protein is wild-type RAC1.

183. The method of any one of claims 169-173, wherein the Ras superfamily protein is a Rho protein, or a mutant thereof.

184. The method of claim 183, wherein the Rho protein is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; CDC42, or a mutant thereof.

185. The method of claim 183 or claim 184, wherein the Rho protein is wild-type RHOA.

186. The method of any one of claims 169-173, wherein the Ras superfamily protein is a Cdc42 protein, or a mutant thereof.

187. The method of any one of claims 169-173, wherein the Ras superfamily protein is a Rheb protein, or a mutant thereof. 368 NAI-1541502036v1188. The method of any one of claims 169-187, wherein the contacting of the Ras superfamily protein takes place in a cell.

189. The method of claim 188, wherein the cell is in a subject.

190. The method of claim 188 or claim 189, wherein the cell is a mammalian cell.

191. The method of any one of claims 188-190, wherein the cell is a human cell.

192. The method of any one of claims 188-191, wherein the subject suffers from a cancer.

193. The method of any one of claim 169-192, wherein the modulation takes place in a subject suffering from a cancer.

194. The method of claim 192 or claim 193, wherein the cancer is a solid tumor or is a blood borne tumor (or a hematological cancer).

195. The method of any one of claims 192-194, wherein the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, esophageal carcinoma, mesothelioma, or multiple myeloma; optionally wherein the cancer is hepatocellular carcinoma, pancreatic cancer, glioblastoma, esophageal carcinoma, mesothelioma, or small cell lung cancer (SCLC).

196. The method of claim 195, wherein the cancer is pancreatic cancer.

197. The method of claim 195, wherein the cancer is colon cancer.

198. The method of claim 195, wherein the cancer is triple negative breast cancer. 369 NAI-1541502036v1199. The method of claim 195, wherein the cancer is multiple myeloma.

200. The method of any one of claims 192-199, wherein the cancer is a cancer dependent on a Ras superfamily protein.

201. The method of any one of claims 189-200, wherein the subject is a human.

202. A method of modulating caspase activity, comprising contacting the caspase with an effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof.

203. A method of modulating caspase activity, comprising contacting the caspase with an effective amount of the pharmaceutical composition of claim 168.

204. The method of claim 202 or claim 203, wherein the method activates the caspase.

205. The method of any one of claims 202-204, wherein the caspase is caspase 3, caspase 6, or caspase 9.

206. The method of any one of claims 202-205, wherein the contacting of the caspase takes place in a cell.

207. The method of claim 206, wherein the modulation caspase activity induces apoptosis of the cell.

208. The method of claim 206 or 207, wherein the cell is in a subject.

209. The method of any one of claims 206-208, wherein the cell is a mammalian cell.

210. The method of any one of claims 206-209, wherein the cell is a human cell. 370 NAI-1541502036v1211. The method of any one of claims 206-210, wherein the subject suffers from a cancer.

212. The method of any one of claims 202-211, wherein the modulation takes place in a subject suffering from a cancer.

213. The method of claim 211 or claim 212, wherein the cancer is a solid tumor or is a blood borne tumor (or a hematological cancer).

214. The method of any one of claims 211-213, wherein the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, esophageal carcinoma, mesothelioma, or multiple myeloma; optionally wherein the cancer is hepatocellular carcinoma, pancreatic cancer, glioblastoma, esophageal carcinoma, mesothelioma, or small cell lung cancer (SCLC).

215. The method of claim 214, wherein the cancer is pancreatic cancer.

216. The method of claim 214, wherein the cancer is colon cancer.

217. The method of claim 214, wherein the cancer is triple negative breast cancer.

218. The method of claim 214, wherein the cancer is multiple myeloma.

219. The method of any one of claims 208-218, wherein the subject is a human.

220. A method of inhibiting one or more proteasome ATPase, comprising contacting a proteasome ATPase with an effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof.

221. A method of inhibiting one or more AAA-ATPase of a 19S regulatory particle, 371 NAI-1541502036v1comprising contacting an AAA-ATPase with an effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof.

222. The method of claim 220 or 221, wherein the contacting takes place in a cell.

223. The method of claim 222, wherein the cell is in a subject.

224. The method of claim 222 or 223, wherein the cell is a mammalian cell.

225. The method of claim 222 or 223, wherein the cell is a human cell.

226. The method of any one of claims 223-225, wherein the subject is suffering from cancer.

227. The method of any one of claims 220-226, wherein the inhibition takes place in a subject suffering from a cancer.

228. The method of claim 226 or 227, wherein the cancer is a solid tumor or is a blood borne tumor (or a hematological cancer).

229. The method of any one of claims 226-228, wherein the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, esophageal carcinoma, mesothelioma, or multiple myeloma; optionally wherein the cancer is hepatocellular carcinoma, pancreatic cancer, glioblastoma, esophageal carcinoma, mesothelioma, or small cell lung cancer (SCLC)..

230. A method of treating cancer in a subject, comprising administering a therapeutically effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof, to the subject having cancer. 372 NAI-1541502036v1231. A method of treating cancer in a subject, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 168 to the subject having cancer.

232. The method of claim 230 or claim 231, wherein the cancer is a solid tumor or is a blood borne tumor (or a hematological cancer).

233. The method of any one of claims 230-232, wherein the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, esophageal carcinoma, mesothelioma, or multiple myeloma; optionally wherein the cancer is hepatocellular carcinoma, pancreatic cancer, glioblastoma, esophageal carcinoma, mesothelioma, or small cell lung cancer (SCLC).

234. The method of claim 233, wherein the cancer is pancreatic cancer.

235. The method of claim 233, wherein the cancer is colon cancer.

236. The method of claim 233, wherein the cancer is triple negative breast cancer.

237. The method of claim 233, wherein the cancer is multiple myeloma.

238. The method of any one of claims 230-237, wherein the cancer is a cancer dependent on a Ras superfamily protein.

239. The method of claim 238, wherein the Ras superfamily protein is a Ras protein, or a mutant thereof.

240. The method of claim 249, wherein the Ras protein is DIRAS I; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRASI; NKIRAS2; NRAS; RALA; RALB; RAPIA; RAPIB; RAP2A; RAP2B; RAP2C; RASDI; RASD2; RASLIOA; RASLIOB; RASLI 373 NAI-1541502036v1IA; RASLIIB; RASL12; REMI; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2.

241. The method of claim 240, wherein the Ras protein is HRAS; KRAS; or NRAS, or a mutant thereof.

242. The method of claim 241, wherein the Ras protein is a KRAS mutant.

243. The method of claim 242, wherein the KRAS mutant is a KRas G12D mutant, KRas G12C mutant, or KRas Q61H mutant.

244. The method of claim 241, wherein the Ras protein is HRAS or a mutant thereof.

245. The method of claim 241, wherein the Ras protein is NRAS or a mutant thereof.

246. The method of claim 238, wherein the Ras superfamily protein is a Rac protein, or a mutant thereof.

247. The method of claim 246, wherein the Rac protein is RAC1; RAC2; RAC3; RHOG, or a mutant thereof.

248. The method of claim 247, wherein the Rac protein is wild-type RAC1.

249. The method of claim 238, wherein the Ras superfamily protein is a Rho protein, or a mutant thereof.

250. The method of claim 249, wherein the Rho protein is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; CDC42, or a mutant thereof.

251. The method of claim 250, wherein the Rho protein is wild-type RHOA. 374 NAI-1541502036v1252. The method of claim 238, wherein the Ras superfamily protein is a Cdc42 protein, or a mutant thereof.

253. The method of claim 238, wherein the Ras superfamily protein is a Rheb protein, or a mutant thereof.

254. The method of any one of claims 230-253, wherein the administration activates caspase activity in a cancerous cell of the subject.

255. The method of claim 254, wherein the activation induces apoptosis of the cancerous cell.

256. The method of any one of claims 230-255, wherein the subject is a human.

257. A method of modulating Erk1 / 2 activity, comprising contacting an Erk1 / 2 protein with an effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof.

258. A method of modulating Erk1 / 2 activity, comprising contacting an Erk1 / 2 protein with an effective amount of the pharmaceutical composition of claim 168.

259. The method of claim 257 or claim 258, wherein the method inhibits phosphorylation of the Erk1 / 2 protein.

260. The method of claim 257 or claim 258, wherein the method activates phosphorylation of the Erk1 / 2 protein.

261. A method of modulating Akt activity, comprising contacting an Akt protein with an effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof. 375 NAI-1541502036v1262. A method of modulating Akt activity, comprising contacting an AKT protein with an effective amount of the pharmaceutical composition of claim 168.

263. The method of claim 261 or claim 262, wherein the method inhibits phosphorylation of the Akt protein.

264. The method of claim 261 or claim 262, wherein the method activates phosphorylation of the Akt protein.

265. A method of modulating Smad2 / 3 activity, comprising contacting a Smad2 / 3 protein with an effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof.

266. A method of modulating Smad2 / 3 activity, comprising contacting a Smad2 / 3 protein with an effective amount of the pharmaceutical composition of claim 168.

267. The method of claim 265 or claim 266, wherein the method inhibits phosphorylation of the Smad2 / 3 protein.

268. The method of claim 265 or claim 266, wherein the method activates phosphorylation of the Smad2 / 3 protein.

269. A method of modulating JNK activity, comprising contacting a JNK protein with an effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof.

270. A method of modulating JNK activity, comprising contacting a JNK protein with an effective amount of the pharmaceutical composition of claim 168.

271. The method of claim 269 or claim 270, wherein the method inhibits phosphorylation of the JNK protein. 376 NAI-1541502036v1272. The method of claim 269 or claim 270, wherein the method activates phosphorylation of the JNK protein.

273. A method of modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof.

274. A method of modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of the pharmaceutical composition of claim 168.

275. The method of claim 273 or claim 274, wherein the method inhibits phosphorylation of the MAPK p38 protein.

276. The method of claim 273 or claim 274, wherein the method activates phosphorylation of the MAPK p38 protein.

277. A method of modulating IL-6 activity, comprising contacting a IL-6 protein with an effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof.

278. A method of modulating IL-6 activity, comprising contacting a IL-6 protein with an effective amount of the pharmaceutical composition of claim 168.

279. The method of claim 277 or claim 278, wherein the method inhibits IL-6 activity.

280. A method of modulating TNF-alpha activity, comprising contacting a TNF-alpha protein with an effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof.

281. A method of modulating TNF-alpha activity, comprising contacting a TNF-alpha 377 NAI-1541502036v1protein with an effective amount of the pharmaceutical composition of claim 168.

282. The method of claim 280 or claim 281, wherein the method inhibits TNF-alpha activity.

283. A method of treating a fibrotic disease in a subject, comprising administering a therapeutically effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof, to the subject.

284. A method of treating a fibrotic disease in a subject, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 168 to the subject.

285. A method of treating an inflammatory disease in a subject, comprising administering a therapeutically effective amount of the compound of any one of claims 1-167, or pharmaceutically acceptable form thereof, to the subject.

286. A method of treating an inflammatory disease in a subject, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 168 to the subject. 378 NAI-1541502036v1

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