Compounds that interact with RAS superfamily proteins for the treatment of cancer, inflammatory diseases, RAS diseases, and fibrotic diseases

Abstract

Provided herein are compounds of formula I, or pharma- ceutically acceptable forms thereof, and pharmaceutical compositions comprising same. Also provided herein are methods of modulating the activity of a cellular target by administering to a subject a compound of formula I, or a pharma- ceutically 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 pharma- ceutically acceptable form thereof. [Case 1] TIFF2025512935000458.tif41165

Description

[Technical Field]

[0001] cross reference This application claims the benefit of priority from U.S. Provisional Application No. 63 / 384,905, filed November 23, 2022, and U.S. Provisional Application No. 63 / 329,141, filed April 8, 2022. Each of the foregoing related applications is incorporated herein by reference in its entirety.

[0002] Provided herein are compounds of Formula I, or pharmaceutically acceptable forms thereof, and pharmaceutical compositions comprising same. Also provided herein are 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. Summary of the Invention

[0003] 2. As used herein, compounds of formula I: [ka] or a pharmaceutically acceptable form thereof, wherein X is -NR 1A R 2A OR 2A and; Y is imidazolyl, pyridinyl, or an 8- to 10-membered fused heteroaryl; Imidazolyl has one R 6A Optionally substituted with a substituent, 1 to 2 R 7A optionally substituted with substituents; Pyridinyl or 8- to 10-membered fused heteroaryl is 1 to 4 R 7A optionally substituted with substituents; R 1A is hydrogen or C 1-6 alkyl, C 1-6 Alkyl is one to four R 8Aoptionally substituted with substituents; R 2A is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, C 3-7 Heterocycloalkyl, C 5-10 -membered aryl, -S(O)R 15A , -P(O)R 16A R 17A or 5-10 membered heteroaryl, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 10-membered heteroaryl each independently have 1 to 4 R 8A optionally substituted with a substituent, and optionally two independent R 8A the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; or R 1A and R 2A are combined to form a 3- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached, and optionally R 1A and R 2A is fused to a 5- or 6-membered heteroaryl; R 3A is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, aryl, 5-10 membered heteroaryl, -(CO)R 11A , or -C(O)NR 12A R 13A and C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, aryl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, aryl, or 5- to 10-membered heteroaryl, and the aryl and the 5- to 10-membered heteroaryl each independently have 1 to 4 R 10Aoptionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen or C 1-6 is alkyl; R 6A and R 7A are each independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, aryl, C 5-10 Heteroaryl, C 3-7 Heterocycloalkyl, C 1-6 Heteroalkyl, halo, -NR 12A R 13A , C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)NR 12A R 13A , -(CO)R 11A , -C(O)OR 14A , or CN, and C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, aryl, C 5-10 Heteroaryl, C 3-7 Heterocycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -NR 12A R 13A , -(CO)R 11A , -C(O)OR 14A , -C(O)NR 12A R 13A , oxo, -OH, C 1-6 Alkoxy, C3-6 Cycloalkoxy, C 1-6 each independently selected from the group consisting of haloalkoxy, 5-6 membered heteroaryl, biotinamide, or biotinylating substituents; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5- to 6-membered heteroaryl; 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, or 5- or 6-membered heteroaryl, each independently, has 1 to 3 R 8A optionally substituted with substituents; R 11A -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, C1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-7 each independently selected from the group consisting of heterocycloalkyl, aryl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-7 Heterocycloalkyl, aryl, and 5- to 10-membered heteroaryl are each selected from 1 to 3 R 8A optionally substituted with a substituent, or R 12A and R 13A combine to form a 3- to 7-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 14A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 15A is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 16A and R 17A is C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 heteroalkyl, each independently selected from the group consisting of C1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with a substituent, or R 16A and R 17A combine to form a 3- to 7-membered heterocycloalkyl containing the phosphorus atom to which they are both attached; X is OH or [ka] and Y is N-methylimidazolyl, and R 5A If is H, then R 3A and R 4A at least one of which is not unsubstituted phenyl is provided.

[0004] Also provided herein are compounds of formula II: [ka] or a pharmaceutically acceptable form thereof, wherein X is -NR 1A R 2A -OR 2A and; R 1A is hydrogen or C 1-6 is alkyl; R 2A is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, -S(O)R 15A , -P(O)R 16A R 17A or 5-6 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with a substituent, and optionally two independent R 8Athe substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; or R 1A and R 2A are combined to form a 3- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached, and optionally R 1A and R 2A is fused to a 5- or 6-membered heteroaryl; R 3A is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl, 5-10 membered heteroaryl, -(CO)R 11A , or -C(O)NR 12A R 13A and C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R 6A and R 7A are each independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, and C 1-6Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -NR 12A R 13A , -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 each independently selected from the group consisting of haloalkoxy, 5-6 membered heteroaryl, biotinamide, or biotinylating substituents; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5- to 6-membered heteroaryl; 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, or 5- or 6-membered heteroaryl, each independently, has 1 to 3 R 8A optionally substituted with substituents; R 11A is C 1-6 Alkyl, C 3-6Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, C 1-6 Alkoxy, or C 1-6 haloalkoxy, or R 12A and R 13A combine to form a 3- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 15A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 16A and R 17A is C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 heteroalkyl, each independently selected from the group consisting of C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with a substituent, or R 16A and R 17A combine to form a 3- to 7-membered heterocycloalkyl containing the phosphorus atom to which they are both attached; m is 0, 1 or 2; X is OH or [ka] and Y is N-methylimidazolyl, and R 5A If is H, then R 3A and R 4A at least one of which is not unsubstituted phenyl is provided.

[0005] Also provided herein are compounds of formula IIa: [ka] or a pharmaceutically acceptable form thereof, wherein R 1A is hydrogen; R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, -S(O)R 15A or 5-6 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with a substituent, and optionally two independent R 8A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 3A is C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl, 5-, 6-, or 9-membered heteroaryl, —(CO)R 11A , or -C(O)NR 12A R 13A and C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-6Heteroalkyl, phenyl, and 5-, 6-, or 9-membered heteroaryl each independently have 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5-, 6-, or 9-membered heteroaryl, and the phenyl and 5-, 6-, or 9-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R 6A is C 1-3 Alkyl or C 1-3 Heteroalkyl, C 1-3 Alkyl or C 1-3 The heteroalkyl is optionally substituted with biotinamide; R 7A is methyl; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -NR 12A R 13A , -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 each independently selected from the group consisting of haloalkoxy, 5-6 membered heteroaryl, biotinamide, or biotinylating substituents; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 11A R 12A or 5- to 6-membered heteroaryl; 1-6 Alkyl or C 1-6 The heteroalkyl is optionally substituted with biotinamide; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 alkoxy, or R 12A and R 13A combine to form a 5- or 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 15A is C 1-3 Alkyl, C 3-6 Cycloalkyl, or C 1-4 is heteroalkyl; R 16A and R 17A is C 1-3 Alkyl or C 1-3 alkoxy, or R 16A and R 17A combine to form a 5-membered heterocycloalkyl containing the phosphorus atom to which they are both attached; m is 0 or 1) is provided.

[0006] Also provided herein are compounds of formula IIa(1): [ka] or a pharmaceutically acceptable form thereof, wherein R 1A is hydrogen; R 2A is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from 1 to 3 R 8A optionally substituted with a substituent, and optionally two independent R 8A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 8A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -NR 12A R 13A , -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 selected from the group consisting of haloalkoxy, 5-6 membered heteroaryl, biotinamide, or biotinylating substituents; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 alkoxy, or R 12A and R 13A combine to form a 5- or 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 18A is C 1-3 Alkyl or C 3-6 cycloalkyl) is provided.

[0007] Also provided herein are compounds of formula IIb: [ka] or a pharmaceutically acceptable form thereof, wherein R 1A and R 2A are combined to form a 4- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached, and optionally R 1A and R 2A is fused to a 6-membered heteroaryl; R 3A is C 1-3 alkyl or phenyl, C 1-3 Alkyl and phenyl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is phenyl or 5-membered heteroaryl, and the aryl and 5-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R 6Aは、 is methyl; R7A is methyl; R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0 or 1; R 1A and R 2A is combined [ka] Forming 6A is methyl, m is 0, and R 5A If is H, then R 3A and R 4A at least one of which is not unsubstituted phenyl is provided.

[0008] Also provided herein are compounds of formula IIc: [ka] or a pharmaceutically acceptable form thereof, wherein R 2A is hydrogen C 1-6 heteroalkyl, or 6-membered heteroaryl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each have 1 to 3 R 8A optionally substituted with substituents; R 3A is C 1-3 alkyl or phenyl, C 1-3 alkyl or phenyl, each independently, 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- or 6-membered heteroaryl, and the phenyl and 5- or 6-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R 6A is methyl; R 7A is methyl; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0 or 1; R 2A is H and R 6A is methyl, m is 0, and R 5A If is H, then R 3A and R 4A at least one of which is not unsubstituted phenyl is provided.

[0009] Also provided herein are compounds of formula III: [ka] or a pharmaceutically acceptable form thereof, wherein X is NR 1A R 2A -OR 2A and; R 1A is hydrogen or C 1-6 is alkyl; R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with a substituent, and optionally two independent R 8A the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; or R 1A and R 2A combine to form a 3- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 3A is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen or C 1-6 is alkyl; R 6A and R 7A are each independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1 or 2) is provided.

[0010] Also provided herein are compounds of formula IIIa: [ka] or a pharmaceutically acceptable form thereof, wherein R 1A is hydrogen; R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R 8Aoptionally substituted with a substituent, and optionally two independent R 8A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 3A is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen or C 1-6 is alkyl; R 6A and R 7A are each independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1 or 2) is provided.

[0011] Also provided herein are compounds of formula IIIb: [ka] or a pharmaceutically acceptable form thereof, wherein R 1A and R 2A combine to form a 4- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 3A is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen or C 1-6 is alkyl; R 6A and R 7A are each independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1 or 2) is provided.

[0012] Also provided herein are compounds of formula IIIc: [ka] or a pharmaceutically acceptable form thereof, wherein R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with substituents; R 3A is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen or C 1-6 is alkyl; R 6A and R 7A are each independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1 or 2) is provided.

[0013] Also provided herein are compounds of formula IV: [ka] or a pharmaceutically acceptable form thereof, wherein X is -NR 1A R 2A -OR 2A and; R 1A is hydrogen or C 1-6 is alkyl; R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with a substituent, and optionally two independent R 8A the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; or R 1A and R 2A combine to form a 3- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 3A is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10Aoptionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen or C 1-6 is alkyl; R 7A is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, aryl, C 5-10 Heteroaryl, C 3-7 Heterocycloalkyl, C 1-6 Heteroalkyl, halo, -NR 12A R 13A , C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)NR 12A R 13A , -(CO)R 11A , -C(O)OR 14A , or CN, and C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, aryl, C 5-10 Heteroaryl, C 3-7 Heterocycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10AHalo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1, 2, 3 or 4) is provided.

[0014] Also provided herein are compounds of formula IVa: [ka] or a pharmaceutically acceptable form thereof, wherein R 1A is hydrogen; R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl, or 6-membered heteroaryl, C1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with a substituent, and optionally two independent R 8A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 3A is C 1-6 alkyl or phenyl, C 1-6 Alkyl and phenyl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is a 5-membered heteroaryl, and the 5-membered heteroaryl is a 5-membered heteroaryl having 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R 7A is methyl; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1, 2, 3 or 4) is provided.

[0015] Also provided herein are compounds of formula IVb: [ka] or a pharmaceutically acceptable form thereof, wherein R 1A and R 2A combine to form a 4- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 3A is C 1-6 alkyl or phenyl, C 1-6 Alkyl and phenyl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4Ais a 5-membered heteroaryl, and the 5-membered heteroaryl is a 5-membered heteroaryl having 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R 7A is methyl; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8Aoptionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1, 2, 3 or 4) is provided.

[0016] Also provided herein are compounds of formula IVc: [ka] or a pharmaceutically acceptable form thereof, wherein R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with substituents; R 3A is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10Athe substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R 7A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1, 2, 3 or 4) is provided.

[0017] Also, as used herein, 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, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118 8, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 , 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 2 12, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243 3, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274,A compound of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc is provided, selected from the group consisting of: 275, and 276, or a pharmaceutically acceptable form thereof.

[0018] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, wherein the compound is a modulator of Ras superfamily activity according to a Ras superfamily activity assay. In one embodiment, the compound, or a pharmaceutically acceptable form thereof, modulates Ras superfamily activity of one or more GTPases 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 one embodiment, the compound or a pharmaceutically acceptable form thereof modulates the Ras superfamily activity of one or more GTPases 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.

[0019] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, wherein the compound inhibits phosphorylation of Erkl / 2 according to an Erkl / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erkl / 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 an Erkl / 2 phosphorylation assay. In one embodiment, the compound or a 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 an Erk1 / 2 phosphorylation assay.

[0020] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, wherein the compounds activate phosphorylation of Erk1 / 2 according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a 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 100% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a 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 an Erk1 / 2 phosphorylation assay.

[0021] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, wherein the compound inhibits phosphorylation of Akt according to an Akt phosphorylation assay. In one embodiment, the compound or a 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 an Akt phosphorylation assay. In one embodiment, the compound or a 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 an Akt phosphorylation assay.

[0022] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, wherein the compound activates phosphorylation of Akt according to an Akt phosphorylation assay. In one embodiment, the compound or a 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 100% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a 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 greater than 100% at 10 μM according to an Akt phosphorylation assay.

[0023] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, wherein the compound inhibits phosphorylation of Smad2 / 3 according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a 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 a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a 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 a Phospho-Smad2 / 3 inhibition assay.

[0024] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable forms thereof, which activate phosphorylation of Smad2 / 3 according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a 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 100% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a 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 a Phospho-Smad2 / 3 inhibition assay.

[0025] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, wherein the compounds inhibit JNK according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by 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, or 95% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a 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 a JNK activation assay.

[0026] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, wherein the compounds activate JNK according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK at 10 μM by 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, or 100% or more according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK at 10 μM 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 according to a JNK activation assay.

[0027] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, wherein the compounds inhibit MAPK p38 according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by 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, or 95% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a 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 a MAPK p38 activation assay.

[0028] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, wherein the compounds activate MAPK p38 according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 at 10 μM by 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, or 100% or more according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 at 10 μM 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 according to a MAPK p38 activation assay.

[0029] Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, wherein the compound inhibits the proliferation of MiaPaca2 according to a proliferation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits the proliferation of MiaPaca2 according to a proliferation assay 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, or 0.1 μM or less.

[0030] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, wherein the compound inhibits IL-6 according to an IL-6 quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits IL-6 at 10 μM 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 according to an IL-6 quantification assay. In one embodiment, the compound or a 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 an IL-6 quantification assay.

[0031] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, wherein the compound inhibits TNF-alpha according to a TNF-alpha quantitation assay. In one embodiment, the compound or a 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 a TNF-alpha quantitation assay. In one embodiment, the compound or a 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 a TNF-alpha quantification assay.

[0032] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable forms thereof, having a half-life in mouse liver microsomes of 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, or 50 minutes or more according to a mouse liver microsome metabolic stability assay.

[0033] Also provided herein are compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable forms thereof, having a kinetic solubility of 10 μM or greater, 20 μM or greater, 30 μM or greater, 40 μM or greater, 50 μM or greater, 60 μM or greater, 70 μM or greater, 80 μM or greater, 90 μM or greater, 100 μM or greater, 150 μM or greater, or 200 μM or greater in pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay.

[0034] Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, that inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 according to a proliferation assay. In one embodiment, the compound, or a pharmaceutically acceptable form thereof, inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 according to a proliferation assay 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. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits proliferation of MM.R1 according to a proliferation assay with an IC50 value of 1 nM or less, 0.1 nM or less, or 0.01 nM or less.

[0035] Also provided herein are methods for modulating a Ras superfamily protein, comprising contacting the Ras superfamily protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0036] Also provided herein are methods for modulating a Ras superfamily protein, comprising contacting the Ras superfamily protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof.

[0037] Also provided herein are methods of modulating caspase activity, comprising contacting a caspase with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0038] Also provided herein are methods of modulating caspase activity, comprising contacting a caspase with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof.

[0039] Also provided herein are methods for modulating Erk1 / 2 activity, comprising contacting Erk1 / 2 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0040] Also provided herein are methods for modulating Erk1 / 2 activity, comprising contacting Erk1 / 2 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof.

[0041] 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, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0042] 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, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof.

[0043] Also provided herein are methods for modulating Smad2 / 3 activity, comprising contacting a Smad2 / 3 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0044] Also provided herein are methods for modulating Smad2 / 3 activity, comprising contacting a Smad2 / 3 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof.

[0045] 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, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0046] 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, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof.

[0047] 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, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0048] 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, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof.

[0049] Also provided herein is a method for modulating IL-6 activity, comprising contacting IL-6 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0050] Also provided herein is a method for modulating IL-6 activity, comprising contacting IL-6 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof.

[0051] 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, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0052] 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, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof.

[0053] Also provided herein is a method of treating cancer in a subject, comprising administering a therapeutically effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, to a subject with cancer. In some embodiments, the compound is Compound 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, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 20, 21, 22 7, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 0, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232,233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

[0054] Also provided herein is a method of treating cancer in a subject, comprising administering to a subject with cancer a pharmaceutical comprising a therapeutically effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0055] Also provided herein is a method of treating a fibrotic disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0056] Also provided herein is a method of treating a fibrotic disease in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0057] Also provided herein is a method of treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0058] Also provided herein is a method of treating an inflammatory disease in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0059] Also provided herein are pharmaceutical compositions provided herein that include a therapeutically effective amount of one or more of the compounds provided herein (e.g., a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc) and a pharmaceutically acceptable carrier, diluent, or excipient. DETAILED DESCRIPTION OF THE INVENTION

[0060] 3. 3.1.Definition To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0061] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for terms herein, those in this section prevail unless stated otherwise.

[0062] The singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0063] As used herein, a "subject" is an animal, such as a mammal, including a human, such as a patient.

[0064] As used herein, biological activity refers to the in vivo activity of a compound or the physiological response that occurs upon in vivo administration of a compound, composition, or other mixture. Biological activity thus encompasses the therapeutic effects and pharmacokinetic behavior of such compounds, compositions, and mixtures. Biological activity can be observed in in vitro systems designed to test for such activity.

[0065] As used herein, pharmaceutically acceptable derivatives of a compound include, but are not limited to, its salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, clathrates, solvates, or hydrates. Such derivatives can be easily prepared by those skilled in the art using known methods for such derivatization. The resulting compounds can be administered to animals or humans without substantial toxic effects, and either are pharmaceutically active or are prodrugs. Pharmaceutically acceptable salts include 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 and sodium; alkaline earth metal salts, including, but not limited to, barium, calcium, and magnesium; transition metal salts, including, but not limited to, zinc; and inorganic salts, including, but not limited to, sodium hydrogen phosphate and disodium phosphate; further, salts of mineral acids, including, but not limited to, hydrochlorides and sulfates; and salts of organic acids, including, but not limited to, acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate, mesylate, and fumarate. 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 the 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 the 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 1 to about 2, 3, or 4 solvent or water molecules.

[0066] As used herein, treatment refers to any procedure in which one or more of the symptoms of a disease or disorder are improved or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein, such as use to treat fibrotic diseases, such as DMD.

[0067] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any attenuation, whether permanent or temporary, persistent or transient, that can result from or be associated with administration of the composition.

[0068] As used herein, unless otherwise indicated, the terms "manage," "managing," and "management" include preventing the recurrence of a specified disease or disorder in a subject already suffering from the disease or disorder and / or prolonging the time a subject suffering from a disease or disorder remains in remission. The terms also include modulating the threshold, progression, and / or duration of the disease or disorder, or changing the way a subject responds to a disease or disorder.

[0069] 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, resulting in substantial tissue remodeling and the formation of permanent scar tissue. For example, in some embodiments, the fibrotic disease may be renal fibrosis, e.g., progressive kidney disease. In some embodiments, the fibrotic disease may be cardiovascular fibrosis, e.g., 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, e.g., idiopathic pulmonary fibrosis. In some embodiments, the fibrotic disease may be pulmonary fibrosis, e.g., 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 liver fibrosis, e.g., cirrhosis. In some embodiments, the fibrotic disease may be intestinal fibrosis, e.g., Crohn's disease. In some embodiments, the fibrotic disease can be fibrosis of the muscular system, e.g., Duchenne muscular dystrophy (DMD). In some embodiments, the fibrotic disease can be fibrosis of the brain, e.g., glial scar. In some embodiments, the fibrotic disease can be fibrosis of the joint, e.g., arteriosclerosis, knee fibrosis, or shoulder fibrosis. In some embodiments, the fibrotic disease can be fibrosis of the skin, e.g., keloid. In some embodiments, the fibrotic disease can be fibrosis of the bone marrow, e.g., myelofibrosis. In some embodiments, the fibrotic disease can be fibrosis of the heart, e.g., myocardial fibrosis. In some embodiments, the fibrotic disease can be fibrosis of soft tissue. In some embodiments, the fibrotic disease can be fibrosis of tendons. In some embodiments, the fibrotic disease can be fibrosis of lymph nodes. In some embodiments, the fibrotic disease can be fibrosis of the eye. In some embodiments, the fibrotic disease can be retroperitoneal. In some embodiments, the fibrotic disease can be scleroderma. In some embodiments, the fibrotic disease can be surgical scar.

[0070] As used herein, "Duchenne muscular dystrophy" ("DMD") refers to all forms of muscular dystrophy and Duchenne muscular dystrophy (DMD). For example, in some embodiments, DMD can be Becker muscular dystrophy (BMD), an intermediate clinical finding between DMD and BMD, or DMD-associated dilated cardiomyopathy (heart disease) with little or no clinical skeletal or voluntary muscle disease.

[0071] As used herein, IC 50 refers to a particular amount, concentration, or dosage of a test compound that achieves 50% inhibition of a maximal response in an assay that measures such response.

[0072] As used herein, K d refers to the measured equilibrium dissociation constant between a compound (or ligand) and a protein (or binding domain of a protein).

[0073] As used herein, "Smad2 / 3" collectively refers to Smad2 and Smad3, which are members of the receptor-regulated Smad (R-Smad) family of transcription factors.

[0074] As used herein, "MAPK" means mitogen-activated protein kinase, which includes the stress-activated MAPK protein, MAPK p38, or simply p38.

[0075] As used herein, "JNK" refers to the stress-activated MAPK protein c-Jun NH2-terminal kinase.

[0076] As used herein, "Ras superfamily" refers to a protein superfamily of small guanosine triphosphate (GTPase) enzymes consisting of five major families: Ras, Rho, Rab, Ran, and Arf, or variants thereof. Subfamilies of the five major families also include, for example, the Rac subfamily of the Rho major family.

[0077] 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 control 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, but not limited to, cell growth, cell differentiation, cell migration, lipid vesicle trafficking, fibrosis, inflammation, and apoptosis.

[0078] Studies have defined numerous subfamilies of the Ras superfamily, largely based on amino acid sequence homology, and these subfamilies are often designated in an abbreviated manner based on the most commonly studied member of the class.

[0079] The GTP-binding domains of one subfamily of the Ras superfamily, which share substantial sequence homology, are commonly referred to as the Ras family or Ras.

[0080] 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).

[0081] Another subfamily of GTP-binding domains of the Ras superfamily, which has substantial sequence homology, is commonly referred to as the Rho family, which includes proteins and groups of proteins designated Rho, Rac, and Cdc42.

[0082] Without being bound by theory, all Ras isoforms share sequence identity in all regions contributing to GDP / GTP binding, GTPase activity, and effector interactions, suggesting functional redundancy. However, studies have clearly demonstrated that each Ras isoform can function in a unique manner distinct from other Ras proteins in normal physiological processes and in pathogenesis (Quinlan et al., Future Oncol., 5:105-116 (2009)).

[0083] Without being bound by theory, several cell surface receptors activate Ras, including receptor tyrosine kinases (RTKs), growth factor receptors, cytokine receptors, and integrins.

[0084] Without being bound by theory, Ras proteins cycle between "on" and "off" conformations, 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, and by GTPase-activating proteins (GAPs), which accelerate Ras-mediated GTP hydrolysis to GDP.

[0085] Without being bound by theory, the region of Sos functional for nucleotide exchange with Ras spans approximately 500 residues and contains blocks of sequences that are conserved in Sos and other Ras-specific GEFs, such as Cdc25, Sdc25, and Ras guanine-nucleotide releasing factors (GRFs) (Boguske et al., Nature 366, 643-654 (1993)).

[0086] Without being bound by theory, upon activation, Ras initiates signal transduction in the "MAPK pathway" (also referred to as the Ras-RAF-MEK-MAPK / ERK1 / 2 pathway), which affects cell growth, differentiation, proliferation, apoptosis, and migration. The MAPK pathway functions through a series of interactions between kinases. Upon activation by Ras in the "on" (GTP-bound) state, a MAPK kinase kinase (MAPK3), e.g., Raf, MLK, or TAK, phosphorylates and activates a MAPK kinase, e.g., MEK, which then phosphorylates and increases the activity of one or more MAPKs, e.g., ERK1 / 2.

[0087] Without being bound by theory, Ras activation also initiates signaling in the "Akt pathway," which influences cell survival, proliferation, migration, anti-apoptosis, and cell cycle control. In its "on" (GTP-bound) state, Ras activates phosphoinositide 3-kinase (PI3K), which in turn induces the generation of phosphatidylinositol (3,4,5) trisphosphate (PIP3). These lipids serve as plasma membrane docking sites for proteins containing pleckstrin-homology (PH) domains, including Akt (also known as protein kinase B or PKB), and its upstream activator, PDK1. Three closely related isoforms of Akt (Akt1, Akt2, and Akt3) exist 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, which directly interact with and activate PI3K.

[0088] Without being bound by theory, Ras activation is also associated with signaling through other molecular pathways besides phosphoinositide 3-kinase (PI3K), such as Rac1 GEF and Ral-guanine nucleotide dissociation stimulator (GDS). PI3K is part of the PI3K / AKT / mTOR pathway, which controls intracellular signaling important for several cellular functions, e.g., survival, anti-apoptosis, and cell cycle control.

[0089] Without being bound by theory, Ras and its downstream pathways (including ERK1 / 2 and Akt) have been extensively studied and are causally associated with a variety of diseases, including certain cancers, inflammatory disorders, Ras-associated autoimmune leukocyte proliferative disorders, type II diabetes, and certain RASopathies.

[0090] Without being bound by theory, activation of MAPKs, particularly ERK1 / 2, is a component of the inflammatory response. Thus, compounds provided herein that are ERK1 / 2 inhibitors through inhibition of Ras and / or Ras superfamily members are useful in treating inflammatory diseases.

[0091] Without being bound by theory, activation of Akt is a component of the inflammatory response. Thus, compounds provided herein that are Akt inhibitors through the inhibition of Ras and / or Ras superfamily members are useful in the treatment of inflammatory diseases.

[0092] Without being bound by theory, there are multiple distinguishable pathways for aberrant Ras activation, including mutational activation of Ras itself, overactivation of the wild-type protein via upstream signaling, and loss of GAP function required to terminate the activity of the protein.

[0093] According to literature, one million deaths per year are attributable to mutations in K-Ras. (Frank McCormick. “K-Ras protein as a drug target.” Journal of Molecular Medicine (Berlin) 2016:94:253-258)

[0094] Without being bound by theory, Ras is causally associated with inflammatory diseases, including 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), 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 diseases (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; spondyloarthropathy; idiopathic pulmonary fibrosis; juvenile arthritis; psoriasis; psoriatic arthritis.

[0095] Without being bound by theory, Ras is causally linked to Ras-associated autoimmune leukoproliferative disorder, a non-malignant clinical syndrome first identified in a subset of patients with presumed autoimmune lymphoproliferative syndrome (ALPS). (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)

[0096] Without being bound by theory, Ras signaling is causally involved in RASopathies. Thus, compounds provided herein that inhibit the function of one or more members of the Ras superfamily are useful in treating RASopathies, including neurofibromatosis type 1, Noonan syndrome, and Costello syndrome.

[0097] 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 variants thereof.

[0098] As used herein, "Rho" or "Rho family" or "Rho subfamily" or "Rho group" means RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; RAC1; RAC2; RAC3; CDC42, or variants thereof.

[0099] As used herein, "Rac" or "Rac family" or "Rac subfamily" or "Rac group" means RAC1; RAC2; RAC3; RHOG, or variants thereof.

[0100] Without being bound by theory, the Rho subfamily of the Ras superfamily currently includes approximately 22 proteins, most of which scientists generally divide into subgroups, including those designated 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).

[0101] Without being bound by theory, the three most commonly studied members of the Rho subfamily are Cdc42, Rac1, and RhoA.

[0102] Without being bound by theory, the Cdc42 group includes Cdc42, TC10, TCL, Chip, and Wrch-1.

[0103] Without being bound by theory, the Rac family includes Rac1, Rac2, Rac3, and RhoG.

[0104] Without being bound by theory, the RhoA family includes RhoA, RhoB, and RhoC.

[0105] Without being bound by theory, other Rho subfamily GTPases that are 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.

[0106] Without being bound by theory, like other Ras superfamily proteins, Rho subfamily GTPases cycle between "on" and "off" conformations, conferred by the binding of GTP and GDP, respectively. Under physiological conditions, the transition between these two states is controlled 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 GTPase-activating proteins (GAPs), which accelerate Rho subfamily member-mediated GTP hydrolysis to GDP. Guanine nucleotide dissociation inhibitor (GDI) proteins form large complexes with Rho proteins and help prevent their diffusion within the membrane and into the cytosol, thus acting as anchors and enabling tight spatial control of Rho activation.

[0107] Without being bound by theory, Rho subfamily members are intracellular proteins that broadly influence numerous downstream pathways, including cytoskeletal organization, cell polarity, migration, transcription, and proliferation, and more particularly, membrane and vesicle trafficking, cell cycle, microtubule stability, actin membrane tethering, actin polymerization, myosin phosphorylation, API-dependent gene expression, cell adhesion, cell contractility, cell adhesion, and MTOC orientation (Martin Schwartz, "Rho Signaling 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).

[0108] Without being bound by theory, Rho subfamily-related 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. 2015 67(1):103-17).

[0109] Without being bound by theory, given their role in disease processes, Rho subfamily members have been identified as potential therapeutic molecular targets.

[0110] Without being bound by theory, Rho subfamily members have been identified as potential therapeutic molecules in cancer.

[0111] Without being bound by theory, Rho subfamily members have been identified as potential therapeutic molecules in fibrotic diseases.

[0112] As used herein, "GTP binding site" or "GTP binding domain" both refer to the region of a protein that binds GTP and the surrounding region of said protein to which another compound can bind, such binding blocking the ability of GTP to bind to said protein.

[0113] As used herein, "GDP-binding site" or "GDP-binding domain" both refer to the region of a protein that binds GDP and the surrounding region of the protein to which another compound can bind, such binding blocking the ability of GDP to bind to the protein.

[0114] As used herein, "guanosine-binding region" means the region of a protein that is part of the GDP-binding domain or GTP-binding domain, which mediates the interaction with the guanosine moiety of GDP or GTP.

[0115] As used herein, "metal region" means a region of a protein that is part of the GDP- or GTP-binding domain near the magnesium (Mg202) binding site.

[0116] As used herein, "alternative Tyr32 conformation" means the conformation of the GTP or GDP binding domain in the region of Tyr32 in the KRas crystal structure PDB code: 3gft compared to the KRas crystal structure PDB code: 4epr.

[0117] Without being bound by theory, as used herein, "apoptosis" refers to the process of programmed cell death, which plays an important role in physiology and pathology. It is activated during embryonic development and to eliminate unnecessary or damaged cells. Apoptosis also plays an important role in preventing cancer. Loss of apoptotic control allows tumor cells to survive longer, providing time for them to accumulate mutations that can increase invasiveness during cancer progression, stimulate angiogenesis, uncontrollable cell proliferation, and disrupt differentiation.

[0118] Without being bound by theory, with regard to apoptosis, it has been demonstrated that some members of the Ras superfamily of small GTPases have pro- and anti-apoptotic functions. Members of the Rho family of GTPases, such as Rho, Rac, and cdc42, can activate apoptosis via the JNK or p38 pathway. Meanwhile, members of the Ras and Rab families of GTPases have anti-apoptotic activity mediated by activating the PI3K / Akt / mTOR survival pathway, which prevents apoptosis and leads to increased cell proliferation. It has also 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-inhibitory effects, thereby promoting tumor progression.

[0119] 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 numerous cellular processes, including proliferation, embryonic development, and apoptosis. The JNK pathway is activated by environmental stresses (ionizing radiation, heat, oxidative stress, e.g., reactive oxygen species (ROS) and DNA damage), inflammatory cytokines, and growth factors. JNK activation often involves the Rho family of GTPases, including Rho, Cdc42, and Rac.

[0120] Without being bound by theory, JNK activates apoptotic signaling by upregulating proapoptotic genes through transactivation of c-Jun / AP1-dependent or p53 / 73 protein-dependent mechanisms. In these mitochondrial apoptotic protein-induced pathways, activated JNK directly regulates the activity of mitochondrial proapoptotic proteins through distinct phosphorylation events.

[0121] Without being bound by theory, another member of the MAPK signaling pathway is p38 MAPK (also referred to herein as MAPK p38), which enables cells to interpret a wide range of external signals and respond by activating downstream pathways that mediate several biological effects. This pathway also functions in the regulation of apoptosis and cytokine release by macrophages and neutrophils.

[0122] 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, such as Bax and Bak, regulate and mediate the intrinsic apoptotic process in which mitochondria contribute to cell death. Upon apoptotic stimuli, these proteins are activated at the outer mitochondrial membrane, oligomerize, and mediate its permeabilization. Permeabilization allows the release of cytochrome c from mitochondria, which in turn induces a series of biochemical reactions that lead to caspase activation and subsequent cell death.

[0123] Without being bound by theory, induction of apoptosis, such as that in mammalian cells, can be mediated by several mechanisms, including inhibition of the ubiquitin proteasome system (UPS). The UPS system is the major proteolytic pathway for the removal of cytoplasmic, nuclear, and membrane-associated proteins and has essential functions in homeostasis, including preventing the accumulation of misfolded or harmful proteins. Proteins targeted for degradation are selected by covalently tagging them with ubiquitin, typically lysine-48-linked tetraubiquitin chains, followed by proteolysis within the 26S proteasome. The 26S proteasome holoenzyme consists of a 19S regulatory particle (RP), which recognizes the ubiquitin signal and unfolds the target protein, and a 20S core particle (CP), which hydrolyzes unfolded polypeptides into short peptides of various lengths. Therefore, impairment of the UPS is associated with several pathological conditions, including cancer. Tumor cells can be characterized by loss of cell cycle checkpoint control and are often subjected to elevated stress levels due to hyperactivation of oncogenic signaling and / or adverse microenvironmental conditions. Therefore, transformed cells may be highly dependent on the correct function of the 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 received FDA approval for treating cancer patients with multiple myeloma. Three proteasome inhibitors, namely, Velcade (bortezomib), Kyprolis (carfilzomib), and Ninlaro (ixazomib), have been reported to target proteolytic sites within the 20S CP.

[0124] Without being bound by theory, as used herein, "caspase(s)" refers to one or more of a family of cysteine ​​proteases that cleave proteins after aspartic acid residues. All caspases are synthesized in cells as catalytically inactive zymogens and must undergo a cleavage activation process to generate large and small subunits that dimerize to generate the active enzyme. Caspases exist in a hierarchy that includes so-called upstream caspases 2, 8, 9, and 10 and downstream caspases 3, 6, and 7. Active caspase-9 initiates caspase cleavage, which activates downstream executioner caspases 3, 6, and 7, which cleave other cellular targets and initiate apoptosis. In some embodiments, the antiproliferative inhibitory activity of the compounds disclosed herein is mediated by the induction of apoptosis, as determined by an Annexin V apoptosis assay kit.

[0125] It should be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be in either the (R) or (S) configuration, or may be a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure or may be stereoisomeric or diastereomeric mixtures. Thus, one skilled in the art will recognize that administration of a compound in its (R) form is equivalent to administration of a compound in its (S) form for compounds that undergo epimerization in vivo.

[0126] As used herein, substantially pure means sufficiently homogeneous to be free of readily detectable impurities, as determined by standard analytical methods used by those skilled in the art to assess such purity, such as thin-layer chromatography (TLC), gel electrophoresis, high-performance liquid chromatography (HPLC), and mass spectrometry (MS), or sufficiently pure so that further purification does not detectably alter the enzymatic and biological activity of the substance. Methods for purifying compounds to produce substantially chemically pure compounds are known to those skilled in the art. However, a substantially chemically pure compound may be a mixture of stereoisomers. In such instances, further purification may increase the specific activity of the compound. The present 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 can 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, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included. For example, Formula A includes, but is not limited to, the following three tautomeric structures: [ka]

[0127] As used herein, abbreviations for any protecting groups, amino acids, and other compounds, unless otherwise indicated, refer to their common usage, recognized abbreviations, IUPAC-IUB Commission on Biochemical Nomenclature (see (1972) Biochem. 11:942-944), or IUPAC Nomenclature of Organic Chemistry (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).

[0128] As used herein, alkyl, alkenyl, and alkynyl carbon chains, unless otherwise specified, contain 1 to 20 carbons or 1 to 16 carbons and are straight or branched. Alkenyl carbon chains of 2 to 20 carbons, in certain embodiments, contain 1 to 8 double bonds, and alkenyl carbon chains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 double bonds. Alkynyl carbon chains of 2 to 20 carbons, in certain embodiments, contain 1 to 8 triple bonds, and 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)(quin)quinyl" refers to an alkyl group containing at least one double bond and at least one triple bond.

[0129] As used herein, "heteroalkyl" refers to a group containing one or more oxygen, sulfur, or -NR- and -N groups in the hydrocarbon chain. + refers to a straight-chain or branched aliphatic hydrocarbon group interrupted by a substituted or unsubstituted nitrogen atom containing an RR- group, wherein the nitrogen substituent(s) is alkyl, aryl, aralkyl, heteroaryl, heterocycloaralkyl, S(=O)R', or COR', where R' is alkyl, aryl, aralkyl, heteroaryl, heterocycloaralkyl, -OY, or -NYY', and Y and Y' are each independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, having in one embodiment 1 to about 20 atoms in the chain, and in another embodiment 1 to 12 atoms in the chain.

[0130] As used herein, "cycloalkyl" refers to a saturated monocyclic or polycyclic ring system of 3 to 10 carbon atoms in certain embodiments and 3 to 6 carbon atoms in other embodiments; cycloalkenyl and cycloalkynyl refer to monocyclic or polycyclic ring systems containing at least one double bond and at least one triple bond, respectively. Cycloalkenyl and cycloalkynyl groups can contain 3 to 10 carbon atoms in certain embodiments, with cycloalkenyl groups containing 4 to 7 carbon atoms in further embodiments and cycloalkynyl groups containing 8 to 10 carbon atoms in further embodiments. The ring systems of cycloalkyl, cycloalkenyl, and cycloalkynyl groups can be composed of one ring or two or more rings, which may be combined together in a fused, bridged, or spiro-connected fashion. "Cycloalk(en)(quin)quinyl" 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.

[0131] As used herein, "carbocyclic" refers to a monocyclic or polycyclic ring system in which all of the atoms comprising the ring are carbon atoms, e.g., benzene or cyclopropane. In some embodiments, the carbocyclic ring is unsaturated or partially saturated.

[0132] 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, from 1 to 3 or 4 substituents, wherein the substituents are as defined herein.

[0133] As used herein, "aryl" refers to an aromatic monocyclic or polycyclic group containing 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.

[0134] As used herein, "heteroaryl" refers, in certain embodiments, to a monocyclic or polycyclic aromatic ring system having about 5 to about 15 members, wherein one or more, in one embodiment, one to three, of the atoms in the ring system are heteroatoms, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, or sulfur. A heteroaryl group may optionally be fused to a benzene ring. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, and isoquinolinyl. In certain embodiments, a heteroaryl may optionally be fused to a heterocycloalkyl ring. In certain embodiments, a heteroaryl may be a partially saturated heteroaryl, e.g., a phenyl ring fused to a heterocycloalkyl ring, e.g., a phenyl ring fused to a tetrahydrofuryl ring.

[0135] As used herein, "heterocycloalkyl," "heterocyclyl," or "heterocyclic" refers to a monocyclic or polycyclic non-aromatic ring system, in one embodiment 3-10 members, in another embodiment 4-7 members, and in a further embodiment 5-6 members, in which one or more, in one embodiment 1-3, of the atoms in the ring system are heteroatoms, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, or sulfur. In embodiments in which the heteroatom(s) is nitrogen, the nitrogen is optionally substituted with hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heterocycloaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acyl, guanidino, amidino, sulfonyl, or the nitrogen may be quaternized to form an ammonium group, with the substituents selected as above. In some embodiments, the heterocyclyl ring is saturated. In some embodiments, the heterocyclyl ring is unsaturated or partially saturated.

[0136] 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, from 1 to 3 or 4 substituents, wherein the substituents are as defined herein.

[0137] As used herein, "aralkyl" or "arylalkyl" refers to an alkyl group in which one of the alkyl's hydrogen atoms is replaced by an aryl group.

[0138] As used herein, "heterocycloaralkyl" refers to an alkyl group in which one of the alkyl's hydrogen atoms is replaced by a heteroaryl group.

[0139] As used herein, "halo," "halogen," or "halide" refers to F, Cl, Br, or I.

[0140] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by hydrogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl, and 1-chloro-2-fluoroethyl.

[0141] As used herein, "haloalkoxy" refers to RO where R is a haloalkyl group.

[0142] As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a hydroxyl group (-OH).

[0143] As used herein, "cycloalkoxy" refers to the group --OR where R is a cycloalkyl group.

[0144] As used herein, "carboxy" refers to a divalent radical, --C(O)O--.

[0145] As used herein, "aminocarbonyl" refers to -C(O)NH2.

[0146] As used herein, "alkylaminocarbonyl" refers to -C(O)NHR where R is alkyl, including lower alkyl. As used herein, "dialkylaminocarbonyl" refers to -C(O)NR'R where R' and R are independently alkyl, including lower alkyl; and "carboxamido" refers to a group of the formula -NR'COR where R' and R are independently alkyl, including lower alkyl.

[0147] As used herein, "arylalkylaminocarbonyl" refers to -C(O)NRR', where 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.

[0148] As used herein, "arylaminocarbonyl" refers to --C(O)NHR, where R is aryl, including lower aryl, such as phenyl.

[0149] As used herein, "hydroxycarbonyl" refers to --COOH.

[0150] As used herein, "alkoxycarbonyl" refers to --C(O)OR, where R is alkyl, including lower alkyl.

[0151] As used herein, "aryloxycarbonyl" refers to --C(O)OR, where R is aryl, including lower aryl, such as phenyl.

[0152] As used herein, "alkoxy" and "alkylthio" refer to RO- and RS-, where R is alkyl, including lower alkyl.

[0153] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, where R is aryl, including lower aryl, such as phenyl.

[0154] Where the number of any given substituent is not specified (e.g., "haloalkyl"), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens.

[0155] As used herein, a "cyclic structure" can be a cycloalkyl, carbocyclic, heterocyclic, aryl, or heteroaryl group.

[0156] As used herein, abbreviations for any protecting groups, amino acids, and other compounds, unless otherwise indicated, refer to their common usage, recognized abbreviations, IUPAC-IUB Commission on Biochemical Nomenclature (see (1972) Biochem. 11:942-944), or IUPAC Nomenclature of Organic Chemistry (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).

[0157] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., in reference to a mammalian subject, e.g., a human subject, and in one embodiment, a human.

[0158] The terms "treat," "treating," and "treatment" mean reducing or abolishing a disorder, disease, or condition, or one or more of the symptoms associated with a disorder, disease, or condition; or reducing or eliminating the cause(s) of the disorder, disease, or condition itself.

[0159] The terms "prevent," "preventing," and "prevention" are meant to include methods of delaying the onset of and / or preventing 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.

[0160] The term "therapeutically effective amount" refers to an amount of a compound sufficient to prevent 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 an amount of a compound sufficient to elicit a biological or medical response in a biological molecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, as desired 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., single dose administration) or divided and administered over time (i.e., sequential administration or administration of multiple sub-doses). Single dose administration, sequential administration, or administration of multiple sub-doses can be repeated, for example, to maintain the level of the compound in a biological molecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human.

[0161] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable substance, composition, or vehicle, e.g., a liquid or solid filler, diluent, solvent, or encapsulating substance. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication commensurate with a reasonable benefit / risk ratio. 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 See Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC, 2009.

[0162] As used herein, "pharmaceutically acceptable forms" of the compounds disclosed herein include, but are not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopologues (i.e., isotopically labeled derivatives) of the compounds disclosed herein. In one embodiment, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopologues (i.e., isotopically labeled derivatives) of the compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc disclosed herein.

[0163] The term "about" or "approximately" refers to 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.

[0164] The term "weight percent" 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 components in a composition equals 100%.

[0165] The terms "active ingredient" and "active substance" refer to a compound administered to a subject alone or in combination with one or more pharmaceutically acceptable excipients to treat, prevent, or ameliorate one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient" and "active substance" may be an optically active isomer or isotopic variant of a compound described herein.

[0166] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a chemical compound, or pharmaceutical composition thereof, that is administered to a subject to treat, prevent, or ameliorate one or more symptoms of a condition, disorder, or disease.

[0167] In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomeric excess of about 50% or greater, about 70% or greater, about 80% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, or about 99.8% or greater. In certain embodiments, the compound contains about 95% or greater of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the subject racemate.

[0168] In describing an optically active compound, the prefixes R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction in which a plane of polarized light is rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs of optical rotation (+) and (-) do not relate to the absolute configuration R and S of the molecule.

[0169] The term "racemate" is understood to refer to an equimolar mixture of a pair of enantiomers, which does not exhibit optical activity. The chemical name or formula of a racemate is distinguished from 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.

[0170] Racemic compounds disclosed herein that contain two asymmetric centers of known relative configuration are named using the configuration 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 the enantiomers (1R,3S)-1-bromo-3-chlorocyclohexane and (1S,3R)-1-bromo-3-chlorocyclohexane. [ka]

[0171] The lowercase r / s stereo descriptor is used to describe pseudo-asymmetric centers according to the Cahn-Ingold-Prelog rule (see RS Cahn, CK 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, the following compound B is named (1s,4s)-1-bromo-4-chlorocyclohexane. [ka]

[0172] The compound names contained herein were generated from the corresponding chemical structures using ChemDraw® versions 20.0.0.38, 20.1.0.112, and 22.2.0.3348. In the event of a discrepancy between a chemical structure and a name disclosed herein, the structure shall prevail.

[0173] The term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such a compound. In certain embodiments, an "isotopic variant" of a compound is an isotope of hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), fluorine-18( 18 F), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-36( 36 Cl), and chlorine-37( 37 In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., is non-radioactive. In the compounds provided herein, any hydrogen may be replaced with, for example, 2 H, or any carbon can be, for example, 13 C, or any nitrogen, for example, 15 N, and any oxygen 18 It is understood that the isotopic variant may be O. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of deuterium. In some embodiments, a pharmaceutically acceptable derivative of a compound is an isotopic variant.

[0174] 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, present in stoichiometric or non-stoichiometric amounts. 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 one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0175] 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 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 a variant thereof."

[0176] 3.2. Compounds As used herein, compounds of formula I: [ka] or a pharmaceutically acceptable form thereof, wherein X is -NR 1A R 2A OR 2A and; Y is imidazolyl, pyridinyl, or an 8- to 10-membered fused heteroaryl; Imidazolyl has one R 6AOptionally substituted with a substituent, 1 to 2 R 7A optionally substituted with substituents; Pyridinyl or 8- to 10-membered fused heteroaryl is 1 to 4 R 7A optionally substituted with substituents; R 1A is hydrogen or C 1-6 alkyl, C 1-6 Alkyl is one to four R 8A optionally substituted with substituents; R 2A is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, C 3-7 Heterocycloalkyl, C 5-10 -membered aryl, -S(O)R 15A , -P(O)R 16A R 17A or 5-10 membered heteroaryl, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 10-membered heteroaryl each independently have 1 to 4 R 8A optionally substituted with a substituent, and optionally two independent R 8A the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; or R 1A and R 2A are combined to form a 3- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached, and optionally R 1A and R 2A is fused to a 5- or 6-membered heteroaryl; R 3A is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, aryl, 5-10 membered heteroaryl, -(CO)R 11A , or -C(O)NR 12A R 13A and C 1-6Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, aryl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, aryl, or 5- to 10-membered heteroaryl, and the aryl and the 5- to 10-membered heteroaryl each independently have 1 to 4 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen or C 1-6 is alkyl; R 6A and R 7A are each independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, aryl, C 5-10 Heteroaryl, C 3-7 Heterocycloalkyl, C 1-6 Heteroalkyl, halo, -NR 12A R 13A , C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)NR 12A R 13A , -(CO)R 11A , -C(O)OR 14A , or CN, and C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, aryl, C 5-10 Heteroaryl, C 3-7 Heterocycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -NR 12A R 13A , -(CO)R 11A , -C(O)OR 14A , -C(O)NR 12A R 13A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 each independently selected from the group consisting of haloalkoxy, 5-6 membered heteroaryl, biotinamide, or biotinylating substituents; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5- to 6-membered heteroaryl; 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, or 5- or 6-membered heteroaryl, each independently, has 1 to 3 R 8A optionally substituted with substituents; R 11A -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-7 each independently selected from the group consisting of heterocycloalkyl, aryl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-7 Heterocycloalkyl, aryl, and 5- to 10-membered heteroaryl are each selected from 1 to 3 R 8A optionally substituted with a substituent, or R 12A and R 13A combine to form a 3- to 7-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 14A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 15A is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6Cycloalkyl, C 1-6 Alkoxy, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 16A and R 17A is C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 heteroalkyl, each independently selected from the group consisting of C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with a substituent, or R 16A and R 17A combine to form a 3- to 7-membered heterocycloalkyl containing the phosphorus atom to which they are both attached; X is OH or [ka] and Y is N-methylimidazolyl, and R 5A If is H, then R 3A and R 4A at least one of which is not unsubstituted phenyl is provided.

[0177] In some embodiments, compounds of formula I are those in which Y is one R 6A optionally substituted with a substituent and 1 to 2 R 7A In some embodiments, compounds of Formula I are those in which Y is an imidazolyl optionally substituted with a substituent. ... 6A Substituted by a substituent and 1 to 2 R on the carbon of the imidazolyl ring 7A In some embodiments, the compound of formula I is a compound of formula Ia: [ka] or a pharmaceutically acceptable form thereof. In some embodiments, the compound of formula I is a compound of formula Ib: [ka] or a pharmaceutically acceptable form thereof. In some embodiments, compounds of Formula I are those in which Y is selected from 1 to 4 R 7A In some embodiments, the compound of formula I is a compound of formula Ib: [ka] or a pharmaceutically acceptable form thereof.

[0178] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is R 4A and R 5A In some embodiments, the compound is such that no more than one of R 5A is hydrogen, methyl, ethyl, or isopropyl. In some embodiments, the compound is 5A is like hydrogen.

[0179] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is R 6A But C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, aryl, C 5-10 Heteroaryl, C 3-7 Heterocycloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)NR 12A R 13A , -(CO)R 11A , or -C(O)OR 14A and C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, aryl, C 5-10Heteroaryl, C 3-7 Heterocycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A In some embodiments, the compound is R 6A But C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A In some embodiments, the compound is R 6A is methyl, ethyl, or isopropyl, and methyl, ethyl, and isopropyl are each independently selected from 1 to 3 R 8A and optionally substituted with R 8A But -OH, C 1-3 Alkoxy, or C 1-3 In some embodiments, the compound is R 6A is methyl, ethyl, or isopropyl. In some embodiments, the compound is 6A is methyl.

[0180] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is R 7A But C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8AIn some embodiments, the compound is R 7A is methyl, ethyl, or isopropyl, and methyl, ethyl, and isopropyl are each independently selected from 1 to 3 R 8A and optionally substituted with R 8A But -OH, C 1-3 Alkoxy, or C 1-3 In some embodiments, the compound is R 7A is methyl, ethyl, or isopropyl. In some embodiments, the compound is 7A is methyl. In some embodiments, the compound is such that m is 4. In some embodiments, the compound is such that m is 3. In some embodiments, the compound is such that m is 2. In some embodiments, the compound is such that m is 1. In some embodiments, the compound is such that m is 0.

[0181] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is a compound wherein X is -OR 2A In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is such that X is —NR 1A R 2A In some embodiments, the compound is such that X is -NR 1A R 2A and R 1A and R 2A are such that they combine to form a 3-6 membered heterocycloalkyl containing the nitrogen atom to which they are both attached. In some embodiments, the compound is 1A is hydrogen or C 1-3 In some embodiments, the compound is R 1A is methyl, ethyl, or isopropyl. In some embodiments, the compound is 1Ais hydrogen. In some embodiments, the compound is 2A But C 1-4 Alkyl, C 4-5 Cycloalkyl, C 1-4 heteroalkyl, or 5-6 membered heteroaryl, C 1-4 Alkyl, C 4-5 Cycloalkyl, C 1-4 heteroalkyl, or 5- or 6-membered heteroaryl, each independently, 1 to 3 R 8A In some embodiments, the compound is R 2A is a 5- to 6-membered heteroaryl, each independently representing 1 to 3 1R 8A optionally substituted with a substituent, and optionally two independent R 8A The substituents are such that they combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached. In some embodiments, the compound is R 2A is a 5- to 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl, each independently consisting of 1 to 3 R 8A In some embodiments, the 5-6 membered heteroaryl is a 5-6 membered cycloalkyl fused to the 5-6 membered heteroaryl, each of which comprises two independent R 8A In some embodiments, the 5-6 membered heteroaryl is substituted with two independent R groups that combine to form a 5-6 membered heterocycloalkyl fused to the 5-6 membered heteroaryl, each containing the atom(s) to which it is bonded. 8A In some embodiments, two R 8A The substituents combine to form a pyrazolo[5,1-b]oxazolyl ring. In some embodiments, two R 8AThe substituents combine to form a 2,3-dihydropyrazolo[5,1-b]oxazolyl ring. In some embodiments, the 5-6 membered heteroaryl is pyrazolyl. In some embodiments, the compound is R 8A But C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -NR 12A R 13A , -(CO)R 11A , Oxo, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, or C 3-6 In some embodiments, the compound is such that R 8A But C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-5 Cycloalkyl, -NR 12A R 13A , -(CO)R 11A , Oxo, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, 3- to 5-membered heterocycloalkyl, C 1-4 Alkoxy, or C 3-5 In some embodiments, the compound is such that R 8A Methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -NR 12A R 13A , -(CO)R 11A , Oxo, C 2-3 Hydroxyalkyl, C 2-4 such that the alkyl group is independently selected from the group consisting of heteroalkyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, or cyclobutoxy.

[0182] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is a compound wherein X is —OH, —NH 2 , [ka] TIFF2025512935000028.tif223165TIFF2025512935000029.tif223165TIFF2025512935000030.tif130165.

[0183] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is a compound wherein X is -OH, -NH 2、 [ka] TIFF2025512935000032.tif228165TIFF2025512935000033.tif223165TIFF2025512935000034.tif68165.

[0184] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is R 3A But C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Heteroalkyl, phenyl, 5-6 membered heteroaryl, -(CO)R 11A , or -C(O)NR 12A R 13A and C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 heteroalkyl, phenyl, or 5- to 6-membered heteroaryl, each independently, 1 to 3 R 9A In some embodiments, the compound is R 9A But C 1-4 Alkyl, C 3-5 Cycloalkyl, -(CO)R 11A , C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, 4-6 membered heterocycloalkyl, C 1-4 Alkoxy, or C 3-5 In some embodiments, the compound is such that R9A is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -(CO)R 11A , C 2-3 Hydroxyalkyl, C 2-4 In some embodiments, the compounds are such that R is independently selected from the group consisting of heteroalkyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, imidazolyl, or piperidinyl. 3A is -CH3, unsubstituted phenyl, (4-methoxy)-phenyl, isopropyl, cyclopropyl, [ka] In some embodiments, the compound is such that R 3A is -CH3, unsubstituted phenyl, isopropyl, cyclopropyl, [ka] It is as if.

[0185] In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is R 4A is phenyl or 5- to 10-membered heteroaryl, and each of the phenyl or 5- to 10-membered heteroaryl is independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A The substituents are such that they combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached. In some embodiments, the compound is R 4A However, 1 to 3 R 10A In some embodiments, the compound is R 4A However, 1 to 3 R 10A In some embodiments, the compound is a 5- to 6-membered heteroaryl optionally substituted with a substituent. 10A But, Halo, CN, C 1-6 Alkyl, C 3-6Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A In some embodiments, the compound is such that R 10A But, Halo, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, 3- to 5-membered heterocycloalkyl, -OH, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, C 1-4 Haloalkoxy, or -NR 12A R 13A In some embodiments, the compound is such that R 10A halo, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, C 1-3 Haloalkyl, C 2-3 Hydroxyalkyl, C 2-4 Heteroalkyl, -OH, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, C 1-4 Haloalkoxy, or -NR 12A R 13A In some embodiments, the compound is such that R 12A and R 13A But hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, -OH, or C 1-4 In some embodiments, the compound is such that R 12A and R13A are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, or ethoxy. 12A and R 13A are each independently selected from the group consisting of hydrogen or methyl. In some embodiments, the compound is 12A and R 13A are hydrogen atoms.

[0186] In some embodiments, the compound is R 4A is hydrogen, unsubstituted phenyl, [ka] In some embodiments, the compound is such that R 4A is hydrogen, unsubstituted phenyl, [ka] It is as if.

[0187] In some embodiments, the compound of formula I is a compound of formula II: [ka] or a pharmaceutically acceptable form thereof, wherein X is -NR 1A R 2A -OR 2A and; R 1A is hydrogen or C 1-6 is alkyl; R 2A is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, -S(O)R 15A , -P(O)R 16A R 17A or 5-6 membered heteroaryl, C 1-6 Alkyl, C3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with a substituent, and optionally two independent R 8A the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; or R 1A and R 2A are combined to form a 3- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached, and optionally R 1A and R 2A is fused to a 5- or 6-membered heteroaryl; R 3A is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl, 5-10 membered heteroaryl, -(CO)R 11A , or -C(O)NR 12A R 13A and C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R 6A and R 7A are each independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6Haloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -NR 12A R 13A , -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 each independently selected from the group consisting of haloalkoxy, 5-6 membered heteroaryl, biotinamide, or biotinylating substituents; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5- to 6-membered heteroaryl; 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6haloalkoxy, or 5- or 6-membered heteroaryl, each independently, has 1 to 3 R 8A optionally substituted with substituents; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, C 1-6 Alkoxy, or C 1-6 haloalkoxy, or R 12A and R 13A combine to form a 3- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 15A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 16A and R 17A is C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 heteroalkyl, each independently selected from the group consisting of C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 Heteroalkyl is each independently 1 to 3 R8A optionally substituted with a substituent, or R 16A and R 17A combine to form a 3- to 7-membered heterocycloalkyl containing the phosphorus atom to which they are both attached; m is 0, 1 or 2; X is OH or [ka] and Y is N-methylimidazolyl, and R 5A If is H, then R 3A and R 4A at least one of which is not unsubstituted phenyl is.

[0188] In some embodiments, the compound of Formula I is a compound of Formula IIa: [ka] or a pharmaceutically acceptable form thereof, wherein R 1A is hydrogen; R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, -S(O)R 15A or 5-6 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with a substituent, and optionally two independent R 8A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 3A is C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl, 5-, 6-, or 9-membered heteroaryl, —(CO)R 11A, or -C(O)NR 12A R 13A and C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl, and 5-, 6-, or 9-membered heteroaryl each independently have 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5-, 6-, or 9-membered heteroaryl, and the phenyl and 5-, 6-, or 9-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R 6A is C 1-3 Alkyl or C 1-3 Heteroalkyl, C 1-3 Alkyl or C 1-3 The heteroalkyl is optionally substituted with biotinamide; R 7A is methyl; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -NR 12A R 13A , -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 each independently selected from the group consisting of haloalkoxy, 5-6 membered heteroaryl, biotinamide, or biotinylating substituents; R 10A Halo, CN, C 1-6 Alkyl, C3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 11A R 12A or 5- to 6-membered heteroaryl; 1-6 Alkyl or C 1-6 The heteroalkyl is optionally substituted with biotinamide; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 alkoxy, or R 12A and R 13A combine to form a 5- or 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 15A is C 1-3 Alkyl, C 3-6 Cycloalkyl, or C 1-4 is heteroalkyl; R 16A and R 17A is C 1-3 Alkyl or C 1-3 alkoxy, or R 16A and R 17Acombine to form a 5-membered heterocycloalkyl containing the phosphorus atom to which they are both attached; m is 0 or 1) is.

[0189] In some embodiments, the compound of Formula IIa is R 1A and R 2A together with the nitrogen to which they are attached, -NH 2、 [ka] It has the structure TIFF2025512935000043.tif223165TIFF2025512935000044.tif223165TIFF2025512935000045.tif99165; R 3A is -CH3, unsubstituted phenyl, isopropyl, cyclopropyl, [ka] and; R 4A is hydrogen, unsubstituted phenyl, [ka] and; R 5A is hydrogen; R 6A is methyl, -CH2CH2NH2, or [ka] and; R 7A is methyl; m is 0 or 1.

[0190] In some embodiments, the compound of Formula IIa is R 1A and R 2A together with the nitrogen to which they are attached, -NH 2、 [ka] It has the structure TIFF2025512935000050.tif228165TIFF2025512935000051.tif192165TIFF2025512935000052.tif68165; R 3A is -CH3, unsubstituted phenyl, isopropyl, cyclopropyl, [ka] and; R 4A is hydrogen, unsubstituted phenyl, [ka] and R 5A is hydrogen; R 6A is methyl, -CH2CH2NH2, or [ka] and; m is such that it is 0.

[0191] In some embodiments, the compound of Formula I is a compound of Formula IIa(1): [ka] or a pharmaceutically acceptable form thereof, wherein R 1A is hydrogen; R 2A is a 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from 1 to 3 R 8A optionally substituted with a substituent, and optionally two independent R 8A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 8A Halo, CN, C 1-6Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -NR 12A R 13A , -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 selected from the group consisting of haloalkoxy, 5-6 membered heteroaryl, biotinamide, or biotinylating substituents; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 alkoxy, or R 12A and R 13A combine to form a 5- or 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 18A is C 1-3 Alkyl or C 3-6 cycloalkyl) is.

[0192] In some embodiments, the compound of formula IIa(1) is R 18A is methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, the compound of formula IIa(1) is such that R 18Ais methyl. In some embodiments, the compound of formula IIa(1) is such that R 18A is ethyl. In some embodiments, the compound of formula IIa(1) is such that R 18A is isopropyl. In some embodiments, the compound of formula IIa(1) is such that R 18A is cyclopropyl.

[0193] In some embodiments, the compound of formula IIa(1) is R 8A But C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkoxy, or C 3-6 Cycloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl.

[0194] In some embodiments, the compound of formula IIa(1) is R 2A is pyridyl, pyrimidyl, pyrazyl, or pyrazolyl, and the pyridyl, pyrimidyl, pyrazyl, or pyrazolyl is selected from the group consisting of 1 to 3 R 8A optionally substituted with a substituent, and optionally two independent R 8A The substituents are such that they combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached. In some embodiments, the compound of Formula IIa(1) is R 2A But 1-2 R 8A In some embodiments, the compound of formula IIa(1) is R 2A but, [ka] In some embodiments, the compound of formula IIa(1) is such that R 2A But 1-2 R 8AIn some embodiments, the compound of formula IIa(1) is R 2A but, [ka] In some embodiments, the compound of formula IIa(1) is such that R 2A But 1-2 R 8A In some embodiments, the compound of formula IIa(1) is pyrazyl optionally substituted with a substituent. 2A But 1-2 R 8A In some embodiments, the compound of formula IIa(1) is R 2A but, [ka] In some embodiments, the compound of formula IIa(1) is such that two independent R 8A The substituents are such that they combine to form a 5-membered cycloalkyl or 5-membered heterocycloalkyl containing the atom(s) to which each is attached.

[0195] In some embodiments, the compound of formula IIa(1) is R 1A and R 2A but together with the nitrogen to which they are attached, [ka] In some embodiments, the compound of formula IIa(1) has the structure: 1A and R 2A but together with the nitrogen to which they are attached, [ka] It has the following structure.

[0196] In some embodiments, the compound of Formula IIa(1) is selected from the group consisting of compounds 6, 57, 58, 62, 63, 64, 68, 84, 91, 100, 102, 104, 107, 124, 126, 136, 137, 141, 142, 143, 144, 145, 157, 221, 222, 226, 235, 238, 252, 255, 260, 265, 267, and 268. In some embodiments, the compound of Formula IIa(1) is selected from the group consisting of compounds 6, 84, 100, 102, 104, 124, 221, 222, 235, 238, 252, 255, 260, and 267.

[0197] In some embodiments, the compound of Formula I is a compound of Formula IIb: [ka] or a pharmaceutically acceptable form thereof, wherein R 1A and R 2A are combined to form a 4- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached, and optionally R 1A and R 2A is fused to a 6-membered heteroaryl; R 3A is C 1-3 alkyl or phenyl, C 1-3 Alkyl and phenyl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is phenyl or 5-membered heteroaryl, and the aryl and 5-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R 6Aは、 is methyl; R7A is methyl; R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0 or 1; R 1A and R 2A is combined [ka] Forming 6A is methyl, m is 0, and R 5A If is H, then R 3A and R 4A at least one of which is not unsubstituted phenyl is.

[0198] In some embodiments, the compound of Formula IIb is R 1A and R 2A But combined, [ka] Forming; R 3A is —CH3, unsubstituted phenyl, (4-methoxy)-phenyl, or isopropyl; R 4A but, [ka] and; R 5A is hydrogen; R 6A is methyl; m is such that it is 0.

[0199] In some embodiments, the compound of Formula IIb is R 1A and R 2A But combined, [ka] Forming; R 3A is —CH or unsubstituted phenyl; R 4A but, [ka] and; R 5A is hydrogen; R 6A is methyl; m is such that it is 0.

[0200] In some embodiments, the compound of Formula I is a compound of Formula IIc: [ka] or a pharmaceutically acceptable form thereof, wherein R 2A is hydrogen C 1-6 heteroalkyl, or 6-membered heteroaryl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each have 1 to 3 R 8A optionally substituted with substituents; R 3A is C 1-3 alkyl or phenyl, C 1-3 alkyl or phenyl, each independently, 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- or 6-membered heteroaryl, and the phenyl and 5- or 6-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R 6A is methyl; R 7A is methyl; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0 or 1; R 2A is H and R 6A is methyl, m is 0, and R 5A If is H, then R3A and R 4A at least one of which is not unsubstituted phenyl is.

[0201] In some embodiments, the compound of Formula IIc is R 2A But together with the oxygen to which they are bound, OH, [ka] having the structure R 3A is —CH or unsubstituted phenyl; R 4A is hydrogen, unsubstituted phenyl, [ka] and; R 5A is hydrogen; R 6A is methyl; m is such that it is 0.

[0202] In some embodiments, the compound of formula I is a compound of formula III: [ka] or a pharmaceutically acceptable form thereof, wherein X is NR 1A R 2A -OR 2A and; R 1A is hydrogen or C 1-6 is alkyl; R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R8A optionally substituted with a substituent, and optionally two independent R 8A the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; or R 1A and R 2A combine to form a 3- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 3A is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen or C 1-6 is alkyl; R 6A and R 7A are each independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1 or 2) is.

[0203] In some embodiments, the compound of Formula I is a compound of Formula IIIa: [ka] or a pharmaceutically acceptable form thereof, wherein R 1A is hydrogen; R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with a substituent, and optionally two independent R 8A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 3A is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen or C 1-6 is alkyl; R 6A and R 7A are each independently 1-6Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8Aoptionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1 or 2) is.

[0204] In some embodiments, the compound of Formula I is a compound of Formula IIIb: [ka] or a pharmaceutically acceptable form thereof, wherein R 1A and R 2A combine to form a 4- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 3A is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen or C 1-6 is alkyl; R 6A and R 7Aare each independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1 or 2) is.

[0205] In some embodiments, the compound of Formula I is a compound of Formula IIIc: [ka] or a pharmaceutically acceptable form thereof, wherein R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with substituents; R 3A is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10Athe substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen or C 1-6 is alkyl; R 6A and R 7A are each independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1 or 2) is.

[0206] In some embodiments, the compound of formula I is a compound of formula IV: [ka] or a pharmaceutically acceptable form thereof, wherein X is -NR 1A R 2A -OR 2A and; R 1A is hydrogen or C 1-6 is alkyl; R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with a substituent, and optionally two independent R 8Athe substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; or R 1A and R 2A combine to form a 3- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 3A is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen or C 1-6 is alkyl; R 7A is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, aryl, C 5-10 Heteroaryl, C 3-7 Heterocycloalkyl, C 1-6 Heteroalkyl, halo, -NR 12A R 13A , C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)NR 12A R 13A , -(CO)R 11A , -C(O)OR 14A , or CN, and C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, aryl, C5-10 Heteroaryl, C 3-7 Heterocycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1, 2, 3 or 4) is.

[0207] In some embodiments, the compound of Formula I is a compound of Formula IVa: [ka] or a pharmaceutically acceptable form thereof, wherein R 1A is hydrogen; R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl, or 6-membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with a substituent, and optionally two independent R 8A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 3A is C 1-6 alkyl or phenyl, C 1-6 Alkyl and phenyl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is a 5-membered heteroaryl, and the 5-membered heteroaryl is a 5-membered heteroaryl having 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R7A is methyl; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1, 2, 3 or 4) is.

[0208] In some embodiments, the compound of formula IVa is R 1A and R 2A but together with the nitrogen to which they are attached, [ka] having the structure R 3A is -CH3 or phenyl; R 4A but, [ka] and; R 5A is hydrogen; R 7A is methyl. m is such that it is 0.

[0209] In some embodiments, the compound of Formula I is a compound of Formula IVb: [ka] or a pharmaceutically acceptable form thereof, wherein R 1A and R 2A combine to form a 4- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R 3A is C 1-6 alkyl or phenyl, C 1-6 Alkyl and phenyl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is a 5-membered heteroaryl, and the 5-membered heteroaryl is a 5-membered heteroaryl having 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10Athe substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R 7A is methyl; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1, 2, 3 or 4) is.

[0210] In some embodiments, the compound of formula IVb is R 1A and R 2A But combined, [ka] Forming; R 3A is -CH3 or phenyl; R 4A but, [ka] and; R 5A is hydrogen; R 7A is methyl. m is such that it is 0.

[0211] In some embodiments, the compound of Formula I is a compound of Formula IVc: [ka] or a pharmaceutically acceptable form thereof, wherein R 2A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl and 5- to 6-membered heteroaryl each independently have 1 to 3 R 8A optionally substituted with substituents; R 3A is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl, or 5- to 10-membered heteroaryl; C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R 9A optionally substituted with substituents; R 4A is hydrogen, phenyl, or 5- to 10-membered heteroaryl, and the phenyl and the 5- to 10-membered heteroaryl are each independently selected from 1 to 3 R 10A optionally substituted with a substituent, and optionally two independent R 10A the substituents, when combined, form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R 5A is hydrogen; R 7A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 8A and R 9A Halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 haloalkoxy, and 5-6 membered heteroaryl; R 10A Halo, CN, C 1-6 Alkyl, C 3-6Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3- to 6-membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or 5-6 membered heteroaryl; R 11A is C 1-6 Alkyl, C 3-6 Cycloalkyl, or C 1-6 Heteroalkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl, and C 1-6 Heteroalkyl is each independently 1 to 3 R 8A optionally substituted with substituents; R 12A and R 13A is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH, or C 1-6 each independently selected from the group consisting of alkoxy; m is 0, 1, 2, 3 or 4) is.

[0212] In some embodiments, the compound of formula IVc is R 2A is hydrogen; R 3A is -CH3; R 4A but, [ka] and; R 5A is hydrogen; R 7A is methyl. m is such that it is 0.

[0213] In one embodiment, the compound of Formula I, Ia, II, or IIb is a compound in which Y, X, R 1A , R 2A , R 3A , R 4A , and R 5A The combination of substituents is [ka] It is something that does not form a

[0214] In one embodiment, the compound of Formula I, Ia, II, or IIb is [ka] is.

[0215] In one embodiment, the compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc has a molecular weight (MW) of 1000 g / mol or less. In one embodiment, the compound has a MW of 900 g / mol or less, 800 g / mol or less, 700 g / mol or less, 600 g / mol or less, or 500 g / mol or less. In one embodiment, the compound has a MW of 900 g / mol or less. In one embodiment, the compound has a MW of 800 g / mol or less. In one embodiment, the compound has a MW of 700 g / mol or less. In one embodiment, the compound has a MW of 600 g / mol or less. In one embodiment, the compound has a MW of 500 g / mol or less. In one embodiment, the compound has a MW of 450 g / mol or less.

[0216] In one embodiment, the compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc is selected from the group consisting of Compound 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, 94, 95, 96, 97, 98, 9 9, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130 , 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 1 93, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224 4, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255,256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

[0217] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, is a modulator of Ras superfamily activity according to a Ras superfamily activity assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPases by 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, or 95% or more at 20 μM according to a Ras superfamily activity assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof modulates the Ras superfamily activity of one or more GTPases 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 one embodiment, the compound or a pharmaceutically acceptable form thereof modulates the Ras superfamily activity of one or more GTPases by 45% or more at 20 μM according to a Ras superfamily activity assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof modulates the Ras superfamily activity of one or more GTPases by 50% or more at 20 μM according to a Ras superfamily activity assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof modulates the Ras superfamily activity of one or more GTPases by 75% or more at 20 μM according to a Ras superfamily activity assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof modulates the Ras superfamily activity of one or more GTPases by 90% or more at 20 μM according to a Ras superfamily activity assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof modulates the Ras superfamily activity of one or more GTPases by 95% or more at 20 μM according to a Ras superfamily activity assay.In one embodiment, the compound or a pharmaceutically acceptable form thereof modulates the Ras superfamily activity of one or more GTPases by about 50% to about 60% at 20 μM according to a Ras superfamily activity assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof modulates the Ras superfamily activity of one or more GTPases by about 60% to about 70% at 20 μM according to a Ras superfamily activity assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof modulates the Ras superfamily activity of one or more GTPases by about 70% to about 80% at 20 μM according to a Ras superfamily activity assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof modulates the Ras superfamily activity of one or more GTPases by about 80% to about 90% at 20 μM according to a Ras superfamily activity assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPases by about 90% to about 100% at 20 μM according to a Ras superfamily activity assay.In one embodiment, the compound is selected from the group consisting of compounds 6, 17, 22, 32, 34, 37, 42, 43, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98 , 99, 100, 101, 102, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 1 54, 156, 157, 158, 165, 166, 167, 169, 170, 172, 173, 174, 175, 176, 177, 178, 179, 186, 187, 188, 196, 200, 202, 208, 211, 212, 213, 214, 215, 216, 217, 220, 221, 222, 223, 224, 226, 227, 228, 229, 230, 231, 232, 233 3, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 254, 255, 256, 257, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, and 276, or a pharmaceutically acceptable form thereof.In one embodiment, the compound is selected from the group consisting of compounds 6, 17, 22, 37, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 149, 150, 151, 152, 153 , 154, 156, 157, 158, 165, 166, 169, 170, 173, 175, 176, 177, 178, 179, 186, 187, 188, 196, 202, 208, 211, 212, 213, 214, 215, 216, 217, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 2 36, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 254, 255, 256, 257, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, and 276, or a pharmaceutically acceptable form thereof.

[0218] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, inhibits phosphorylation of Erkl / 2 according to an Erkl / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erkl / 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 an Erkl / 2 phosphorylation assay. In one embodiment, the compound or a 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 an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 50% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 75% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 80% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 85% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 90% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by 95% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by about 50% to about 60% at 10 μM according to an Erk1 / 2 phosphorylation assay.In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by about 60% to about 70% at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by about 70% to about 80% at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by about 80% to about 90% at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 by about 90% to about 100% at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound is selected from the group consisting of compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 36, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof.

[0219] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, activates phosphorylation of Erkl / 2 according to an Erkl / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erkl / 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 100% or more at 10 μM according to an Erkl / 2 phosphorylation assay. In one embodiment, the compound or a 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 an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 50% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 75% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 85% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 90% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 95% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by 100% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by about 50% to about 60% at 10 μM according to an Erk1 / 2 phosphorylation assay.In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by about 60% to about 70% at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by about 70% to about 80% at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by about 80% to about 90% at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 by about 90% to about 100% at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erkl / 2 by about 100% or more at 10 μM according to an Erkl / 2 phosphorylation assay. In one embodiment, the compound is selected from the group consisting of compounds 49, 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 130, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 21 7, 178, 179, 183, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharmaceutically acceptable form thereof.In one embodiment, the compound is selected from the group consisting of compounds 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177 , 178, 179, 183, 190, 191, 192, 193, 194, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharmaceutically acceptable form thereof.

[0220] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, inhibits phosphorylation of Akt according to an Akt phosphorylation assay. In one embodiment, the compound or a 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 an Akt phosphorylation assay. In one embodiment, the compound or a 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 an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 75% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 85% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 90% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 95% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 50% to about 60% at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 60% to about 70% at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 70% to about 80% at 10 μM according to an Akt phosphorylation assay.In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 80% to about 90% at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 90% to about 100% at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound is selected from the group consisting of compounds 17, 20, 23, 25, 29, 30, 31, 32, 33, 34, 42, 203, 209, 210, 219, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In one embodiment, the compound.

[0221] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, activates phosphorylation of Akt according to an Akt phosphorylation assay. In one embodiment, the compound or a 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 100% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a 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 an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Akt by 75% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Akt by 85% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Akt by 90% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Akt by 95% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Akt by 100% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 50% to about 60% at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 60% to about 70% at 10 μM according to an Akt phosphorylation assay.In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 70% to about 80% at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 80% to about 90% at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 90% to about 100% at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 100% or more at 10 μM according to an Akt phosphorylation assay. In one embodiment, the compound is Compound 1, 2, 18, 19, 21, 47, 48, 49, 50, 51, 57, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 93, 94, 95, 96, 97, 98, 100, 101, 102, 103, 104, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 122, 124, 125, 126, 127, 128, 129, 130, 135, 136, 137, 138, 143, 145, 149, 151, 156, 157 , 158, 165, 166, 169, 170, 173, 174, 175, 176, 178, 179, 187, 190, 191, 192, 193, 194, 195, 196, 204, 205, 207, 208, 213, 217, 218, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234 , 235, 237, 238, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 254, 255, 256, 257, 259, 260, 263, 264, 265, 266, 267, 268, 275, and 276, or a pharmaceutically acceptable form thereof.

[0222] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, inhibits phosphorylation of Smad2 / 3 according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a 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 a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a 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 a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 50% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 75% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 80% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 85% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 90% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by 95% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay.In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by about 50% to about 60% at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by about 60% to about 70% at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by about 70% to about 80% at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by about 80% to about 90% at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 by about 90% to about 100% at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound is selected from the group consisting of compounds 27, 29, 30, 31, 32, 33, 36, 43, 44, 47, 51, 52, 55, 59, 85, 96, 97, 98, 99, 116, 141, 144, 156, 203, 205, 207, 208, 209, 210, 211, 214, 219, 230, 269, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of compounds 29, 30, 31, 32, 33, 36, 44, 47, 59, 85, 97, 98, 99, 116, 141, 144, 156, 203, 205, 207, 208, 209, 210, 211, 214, 219, 230, 269, 272, 273, and 274, or a pharmaceutically acceptable form thereof.

[0223] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, activates phosphorylation of Smad2 / 3 according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a 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 100% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a 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 a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 50% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 75% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 85% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 90% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 95% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by 100% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay.In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 50% to about 60% at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 60% to about 70% at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 70% to about 80% at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 80% to about 90% at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 90% to about 100% at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Smad2 / 3 by about 100% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In one embodiment, the compound is selected from the group consisting of compounds 56, 63, 84, 88, 89, 90, 95, 100, 101, 103, 104, 106, 108, 109, 111, 112, 113, 114, 129, 166, 173, 179, 183, 186, 216, 241, 247, 248, 250, 255, 256, 257, and 266, or a pharmaceutically acceptable form thereof.

[0224] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, inhibits JNK according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by 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, or 95% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a 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 a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by 25% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by 30% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by 50% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by 75% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by 85% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by 90% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by 95% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by about 50% to about 60% at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by about 60% to about 70% at 10 μM according to a JNK activation assay.In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by about 70% to about 80% at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by about 80% to about 90% at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits JNK by about 90% to about 100% at 10 μM according to a JNK activation assay. In one embodiment, the compound is selected from the group consisting of compounds 29, 30, 32, 33, and 34, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of compounds 29, 32, 33, and 34, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of compounds 29, 32, and 34, or a pharmaceutically acceptable form thereof.

[0225] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, activates JNK according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK at 10 μM by 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55%, 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 100% or more according to a JNK activation assay. In one embodiment, the compound or a 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 a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by 25% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by 30% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by 50% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by 75% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by 85% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by 90% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by 95% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by 100% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by about 50% to about 60% at 10 μM according to a JNK activation assay.In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by about 60% to about 70% at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by about 70% to about 80% at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by about 80% to about 90% at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by about 90% to about 100% at 10 μM according to a JNK activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates JNK by about 100% or more at 10 μM according to a JNK activation assay. In one embodiment, the compound is selected from the group consisting of compounds 1, 2, 3, 4, 6, 7, 8, 9, 11, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of compounds 3, 4, 6, 7, 11, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of compounds 3, 6, 7, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof.

[0226] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, inhibits MAPK p38 according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by 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, or 95% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a 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 a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by 25% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by 30% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by 50% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by 75% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by 85% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by 90% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by about 50% to about 60% at 10 μM according to a MAPK p38 activation assay.In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by about 60% to about 70% at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by about 70% to about 80% at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by about 80% to about 90% at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by about 90% to about 100% at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MAPK p38 by 95% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound is selected from the group consisting of compounds 29, 30, 32, 33, 34, 46, 47, 188, 196, 197, 203, 205, 207, 208, 209, 210, 212, 213, 214, 215, 217, and 220, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of compounds 29, 32, 33, 34, 46, 207, and 209, or a pharmaceutically acceptable form thereof.

[0227] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, activates MAPK p38 according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 at 10 μM by 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, or 100% or more according to a MAPK p38 activation assay. In one embodiment, the compound or a 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 a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by 25% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by 30% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by 75% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by 85% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by 90% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by 95% or more at 10 μM according to a MAPK p38 activation assay.In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by 100% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by about 50% to about 60% at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by about 60% to about 70% at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by about 70% to about 80% at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by about 80% to about 90% at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by about 90% to about 1000% at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof activates MAPK p38 by about 100% or more at 10 μM according to a MAPK p38 activation assay. In one embodiment, the compound is selected from the group consisting of compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, 93, and 218, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof.In one embodiment, the compound is selected from the group consisting of compounds 1, 2, 3, 7, 8, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof.

[0228] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, inhibits MiaPaca2 proliferation according to a proliferation assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay 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, or 0.1 μM or less. In one embodiment, the compound or a pharmaceutically acceptable form thereof is administered to inhibit MiaPaca2 proliferation according to a proliferation assay at a concentration 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, or 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. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of 1.25 μM or less. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of 1 μM or less. In six embodiments, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of 1 μM or less. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of 0.5 μM or less.In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation in a proliferation assay with an IC50 value of 0.4 μM or less. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation in a proliferation assay with an IC50 value of 0.3 μM or less. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation in a proliferation assay with an IC50 value of 0.25 μM or less. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation in a proliferation assay with an IC50 value of 0.20 μM or less. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation in a proliferation assay with an IC50 value of 0.15 μM or less. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation in a proliferation assay with an IC50 value of 0.10 μM or less. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 1.25 μM to about 1.1 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 1.1 μM to about 1 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 1.0 μM to about 0.9 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.9 μM to about 0.8 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.8 μM to about 0.75 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.75 μM to about 0.7 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.7 μM to about 0.6 μM.In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.6 μM to about 0.5 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.5 μM to about 0.4 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.4 μM to about 0.3 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.3 μM to about 0.25 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.25 μM to about 0.2 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.2 μM to about 0.15 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.15 μM to about 0.1 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.1 μM to about 0.01 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.01 μM to about 0.001 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of about 0.001 μM to about 0.0001 μM. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits MiaPaca2 proliferation according to a proliferation assay with an IC50 value of less than about 0.0001 μM.In one embodiment, the compound is compound 6, 13, 22, 26, 29, 30, 32, 33, 34, 42, 45, 46, 48, 49, 50, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 68, 72, 73, 74, 76, 78, 79, 81, 82, 83, 84, 86, 89, 91, 93, 94, 95 , 96, 97, 98, 100, 101, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 199, 199, 199, 199, 190, 1 0, 141, 142, 143, 144, 145, 146, 149, 156, 157, 158, 165, 169, 170, 173, 174, 175, 176, 196, 203, 209, 210, 213, 214, 217, 219, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234 4, 235, 236, 237, 238, 239, 240, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 255, 257, 263, 264, 265, 266, 267, 268, 269, 270, 271, 274, and 276, or a pharmaceutically acceptable form thereof.In one embodiment, the compound is compound 6, 13, 22, 26, 29, 30, 32, 33, 34, 42, 48, 49, 50, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 68, 72, 73, 74, 76, 78, 79, 81, 82, 83, 84, 86, 89, 91, 93, 94, 95, 96, 97, 98, 100, 101, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 122, 123, 124, 125, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141 , 142, 143, 144, 145, 146, 149, 156, 157, 158, 165, 169, 170, 173, 174, 175, 176, 196, 203, 209, 210, 213, 217, 219, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235 , 236, 237, 238, 239, 240, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 255, 257, 263, 264, 265, 266, 267, 268, 269, 270, 271, 274, and 276, or a pharmaceutically acceptable form thereof.In one embodiment, the compound is selected from the group consisting of compounds 6, 13, 22, 32, 34, 48, 49, 50, 53, 54, 55, 56, 57, 58, 59, 62, 63, 64, 65, 68, 73, 74, 76, 78, 79, 81, 82, 83, 84, 86, 89, 91, 93, 94, 95, 96, 97, 98, 100, 101, 102, 104, 106, 107, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 122, 123, 124, 125, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 156, 157, 158, 165, 169, 170, 174, 175, 196, 209, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 243, 244, 245, 246, 247, 248, 249, 250, 252, 255, 257, 263, 264, 265, 266, 267, 268, 270, 271, 274, and 276, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of compounds 6, 48, 49, 50, 53, 54, 55, 57, 58, 62, 63, 64, 65, 68, 73, 76, 79, 82, 84, 89, 91, 94, 95, 97, 98, 100, 102, 104, 106, 107, 110, 112, 113, 114, 115, 117, 118, 120, 122, 123, 124, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141 , 142, 143, 144, 145, 156, 157, 158, 165, 169, 170, 196, 221, 222, 224, 226, 227, 228, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 243, 244, 245, 248, 249, 250, 252, 255, 257, 263, 265, 266, 267, and 268, or a pharmaceutically acceptable form thereof.

[0229] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, inhibits IL-6 according to an IL-6 quantification assay. In one embodiment, the compound or a 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 an IL-6 quantification assay. In one embodiment, the compound or a 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 an IL-6 quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits IL-6 by 50% or more at 10 μM according to an IL-6 quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits IL-6 by 75% or more at 10 μM according to an IL-6 quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits IL-6 by 85% or more at 10 μM according to an IL-6 quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits IL-6 by 90% or more at 10 μM according to an IL-6 quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits IL-6 by 95% or more at 10 μM according to an IL-6 quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits IL-6 by about 50% to about 60% at 10 μM according to an IL-6 quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits IL-6 by about 60% to about 70% at 10 μM according to an IL-6 quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits IL-6 by about 70% to about 80% at 10 μM according to an IL-6 quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits IL-6 by about 80% to about 90% at 10 μM according to an IL-6 quantification assay.In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits IL-6 by about 90% to about 100% at 10 μM according to an IL-6 quantification assay. In one embodiment, the compound is selected from the group consisting of Compounds 1, 4, 6, 13, 19, 20, 22, 23, 27, 29, 30, 31, 32, 33, 34, 40, 42, 45, 46, 67, 81, 82, 85, 86, 89, 93, 99, 104, 105, 111, 113, 143, 149, 160, 161, 163, 164, 166, 173, 175, 176, 177, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 227, 229, 30, 31, 32, 33, 34, 40, 42, 45, 46, 92, 193, 194, 196, 199, 201, 203, 204, 206, 207, 208, 209, 210, 217, 219, 238, 247, 248, 249, 250, 257, 260, 263, 264, 265, 268, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof.

[0230] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, inhibits TNF-alpha according to a TNF-alpha quantitation assay. In one embodiment, the compound or a 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 a TNF-alpha quantitation assay. In one embodiment, the compound or a 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 a TNF-alpha quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits TNF-alpha by 50% or more at 10 μM according to a TNF-alpha quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits TNF-alpha by 75% or more at 10 μM according to a TNF-alpha quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits TNF-alpha by 85% or more at 10 μM according to a TNF-alpha quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits TNF-alpha by 90% or more at 10 μM according to a TNF-alpha quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits TNF-alpha by 95% or more at 10 μM according to a TNF-alpha quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits TNF-alpha by about 50% to about 60% at 10 μM according to a TNF-alpha quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits TNF-alpha by about 60% to about 70% at 10 μM according to a TNF-alpha quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits TNF-alpha by about 70% to about 80% at 10 μM according to a TNF-alpha quantification assay.In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits TNF-alpha by about 80% to about 90% at 10 μM according to a TNF-alpha quantification assay. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits TNF-alpha by about 90% to about 100% at 10 μM according to a TNF-alpha quantification assay. In one embodiment, the compound is selected from the group consisting of compounds 4, 23, 29, 30, 31, 32, 33, 42, 45, 46, 93, 99, 149, 166, 196, 203, 207, 209, 210, 219, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof.

[0231] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a 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 a pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay. In one embodiment, the compound has a kinetic solubility of 10 μM or more in a pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay. In one embodiment, the compound has a kinetic solubility of 20 μM or more in a pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay. In one embodiment, the compound has a kinetic solubility of 30 μM or greater in a pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay. In one embodiment, the compound has a kinetic solubility of 40 μM or greater in a pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay. In one embodiment, the compound has a kinetic solubility of 50 μM or greater in a pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay. In one embodiment, the compound has a kinetic solubility of 60 μM or greater in a pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay. In one embodiment, the compound has a kinetic solubility of 70 μM or greater in a pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay. In one embodiment, the compound has a kinetic solubility of 80 μM or greater in a pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay. In one embodiment, the compound has a kinetic solubility of 90 μM or greater in a pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay. In one embodiment, the compound has a kinetic solubility of 100 μM or greater in a pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay. In one embodiment, the compound has a kinetic solubility of 150 μM or greater in a pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay.In one embodiment, the compound has a kinetic solubility of 200 μM or greater in pH 7.4 buffer containing 2% DMSO according to a kinetic solubility assay. In one embodiment, the compound is selected from the group consisting of compounds 53, 55, 57, 58, 84, 91, 100, 102, 116, 118, 124, 137, 141, 142, 145, 158, 221, 222, 255, and 267, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of compounds 91, 102, 118, and 255, or a pharmaceutically acceptable form thereof.

[0232] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a 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 a mouse liver microsome metabolic stability assay. In one embodiment, the compound has a half-life of 10 minutes or more in mouse liver microsomes according to a mouse liver microsome metabolic stability assay. In one embodiment, the compound has a half-life of 20 minutes or more in mouse liver microsomes according to a mouse liver microsome metabolic stability assay. In one embodiment, the compound has a half-life of 30 minutes or more in mouse liver microsomes according to a mouse liver microsome metabolic stability assay. In one embodiment, the compound has a half-life of 40 minutes or more in mouse liver microsomes according to a mouse liver microsome metabolic stability assay. In one embodiment, the compound has a half-life of 50 minutes or more in mouse liver microsomes according to a mouse liver microsome metabolic stability assay. In one embodiment, the compound is selected from the group consisting of compounds 6, 102, 104, 124, 126, 128, 129, 137, 141, 142, 144, 145, 156, 157, 224, 226, 227, 235, 238, 248, 255, 265, and 267, or a pharmaceutically acceptable form thereof.

[0233] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 according to a proliferation assay. In one embodiment, the compound inhibits the proliferation of NCI-H358 according to a proliferation assay. In one embodiment, the compound inhibits the proliferation of A375 according to a proliferation assay. In one embodiment, the compound inhibits the proliferation of GP2d according to a proliferation assay. In one embodiment, the compound inhibits the proliferation of MM.R1 according to a proliferation assay. In one embodiment, the compound inhibits proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 according to a proliferation assay with an IC 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. 50 In one embodiment, the compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 cells according to a proliferation assay with an IC value of 50 nM or less. 50 In one embodiment, the compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 cells according to a proliferation assay with an IC value of 40 nM or less. 50 In one embodiment, the compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 cells according to a proliferation assay with an IC value of 30 nM or less. 50 In one embodiment, the compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 cells according to a proliferation assay with an IC value of 20 nM or less. 50 In one embodiment, the compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 cells according to a proliferation assay with an IC value of 10 nM or less. 50 In one embodiment, the compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 cells according to a proliferation assay with an IC value of 1 nM or less. 50In one embodiment, the compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 cells according to a proliferation assay with an IC value of 1 nM or less. 50 In one embodiment, the compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 cells according to a proliferation assay with an IC value of 1 nM or less. 50 In one embodiment, the compound inhibits MM.R1 proliferation according to a proliferation assay with an IC value of 1 nM or less, 0.1 nM or less, or 0.01 nM or less. 50 In one embodiment, the compound inhibits MM.R1 proliferation according to a proliferation assay with an IC value of 1 nM or less. 50 In one embodiment, the compound inhibits MM.R1 proliferation according to a proliferation assay with an IC value of 1 nM or less. 50 In one embodiment, the compound inhibits MM.R1 proliferation according to a proliferation assay with an IC value of 1 nM or less. 50 In one embodiment, the compound is selected from the group consisting of compounds 6, 58, 84, 100, 102, 104, 124, 221, 222, 235, 238, 252, 255, and 267, or a pharmaceutically acceptable form thereof.

[0234] In one embodiment, a pharmaceutically acceptable form of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc is an isomer, isotopic variant, pharmaceutically acceptable salt, polymorph, or solvate of the compound. In one embodiment, a pharmaceutically acceptable form of the compound excludes a salt form. In one embodiment, an isomer of a compound is a diastereomer or enantiomer of the compound.

[0235] In one embodiment, the compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc is a tautomer of the compound.

[0236] In one embodiment, the compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc is a racemate or a mixture of diastereomers.

[0237] In one embodiment, a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc is a single enantiomer or a single diastereomer.

[0238] In one embodiment, the compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc is the (R) enantiomer. In one embodiment, the compound has an enantiomeric excess of the (R) enantiomer of greater than 10%. In one embodiment, the compound has an enantiomeric excess of the (R) enantiomer 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. In one embodiment, the compound has an enantiomeric excess of the (R) enantiomer of 15% or more. In one embodiment, the compound has an enantiomeric excess of the (R) enantiomer of 25% or greater. In one embodiment, the compound has an enantiomeric excess of the (R) enantiomer of 50% or greater. In one embodiment, the compound has an enantiomeric excess of the (R) enantiomer of 75% or greater. In one embodiment, the compound has an enantiomeric excess of the (R) enantiomer of 90% or greater. In one embodiment, the compound has an enantiomeric excess of the (R) enantiomer of 95% or greater. In one embodiment, the compound has an enantiomeric excess of the (R) enantiomer of 98% or greater. In one embodiment, the compound has an enantiomeric excess of the (R) enantiomer of 99% or greater. In one embodiment, 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.

[0239] In one embodiment, the compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc is the (S) enantiomer. In one embodiment, the compound has an enantiomeric excess of the (S) enantiomer of greater than 10%. In one embodiment, the compound has an enantiomeric excess of the (S) enantiomer 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. In one embodiment, the compound has an enantiomeric excess of the (S) enantiomer of 15% or more. In one embodiment, the compound has an enantiomeric excess of the (S) enantiomer of 25% or greater. In one embodiment, the compound has an enantiomeric excess of the (S) enantiomer of 50% or greater. In one embodiment, the compound has an enantiomeric excess of the (S) enantiomer of 75% or greater. In one embodiment, the compound has an enantiomeric excess of the (S) enantiomer of 90% or greater. In one embodiment, the compound has an enantiomeric excess of the (S) enantiomer of 95% or greater. In one embodiment, the compound has an enantiomeric excess of the (S) enantiomer of 98% or greater. In one embodiment, the compound has an enantiomeric excess of the (S) enantiomer of 99% or greater. In one embodiment, 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.

[0240] 3.3. Methods of Modulating the Activity of Cellular Targets Provided herein are methods for modulating a Ras superfamily protein, comprising contacting the Ras superfamily protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof. Also provided herein are methods for modulating a Ras superfamily protein, comprising contacting the Ras superfamily protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, as disclosed herein below, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof. In some embodiments, the compound is Compound 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, 94, 95, 96, 97, 98, 99, 100, 105, 106, 107, 108, 109, 110, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 20, 21, 22, 23, 24, 25, 26, 27 0, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 10 2, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 199, 199, 100, 101, 10 42, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181,182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 33, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

[0241] In some embodiments of the methods provided herein, the Ras superfamily protein is present in a cell.

[0242] In some embodiments, the method comprises contacting a Ras superfamily protein with a compound or a pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily proteins by 45% or more at 20 μM according to a Ras superfamily activity assay. In some embodiments, the method comprises contacting a Ras superfamily protein with a compound or a 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 compound 6, 17, 22, 32, 34, 37, 42, 43, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 1 8, 99, 100, 101, 102, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 156, 157, 158, 165, 166, 167, 169, 170, 172, 173, 174, 175, 176, 177, 178, 179, 186, 187, 188, 196, 200, 202, 208, 211, 212, 213, 214, 215, 216, 217, 220, 221, 222, 223, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 33, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 254, 255, 256, 257, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, and 276, or a pharmaceutically acceptable form thereof.In some embodiments, the compound is Compound 6, 17, 22, 37, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98 , 99, 100, 101, 102, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 209, 2010, 2011, 209, 20 3, 154, 156, 157, 158, 165, 166, 169, 170, 173, 175, 176, 177, 178, 179, 186, 187, 188, 196, 202, 208, 211, 212, 213, 214, 215, 216, 217, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 254, 255, 256, 257, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, and 276, or a pharmaceutically acceptable form thereof.

[0243] In some embodiments, the methods provided herein inhibit a Ras superfamily protein.

[0244] 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; RASLIIA; 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, a KRas G12C mutant, or a 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.

[0245] In some embodiments of the methods provided herein, Ras superfamily protein is Rac protein or its mutant.In some embodiments, Rac protein is RAC1;RAC2;RAC3;RHOG or its mutant.In some embodiments, Rac protein is wild-type RAC1.

[0246] 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.

[0247] In some embodiments of the methods provided herein, the Ras superfamily protein is a Cdc42 protein, or a variant thereof.

[0248] In some embodiments of the methods provided herein, the Ras superfamily protein is a Rheb protein, or a variant thereof.

[0249] In some embodiments of the methods provided herein, the contacting of the Ras superfamily protein occurs 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 is suffering from cancer. In some embodiments, the subject is human.

[0250] In some embodiments of the methods provided herein, the modulation is performed in a subject suffering from cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a blood-borne tumor (or blood 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, endometrial cancer, skin cancer (melanoma), cervical cancer, urinary tract cancer, glioblastoma, 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 a cancer dependent on a Ras superfamily protein.

[0251] Provided herein are methods of modulating caspase activity, comprising contacting a caspase with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof. Also provided herein are methods of modulating caspase activity, comprising contacting a caspase with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, as disclosed herein below, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof. In some embodiments, the compound is Compound 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, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150 0, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192,193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238 , 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

[0252] In some embodiments, the methods provided herein activate a caspase, hi some embodiments, the caspase is caspase 3, caspase 6, or caspase 9.

[0253] In some embodiments of the methods provided herein, the caspase contacting occurs in a cell. In some embodiments, 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 is afflicted with cancer. In some embodiments, the modulation occurs in a subject afflicted with cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a blood-borne tumor (or blood 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, endometrial cancer, skin cancer (melanoma), cervical cancer, urinary tract cancer, glioblastoma, 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 subject is human.

[0254] Provided herein are methods for modulating Erk1 / 2 activity, comprising contacting an Erk1 / 2 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof. Also provided herein are methods for modulating Erk1 / 2 activity, comprising contacting an Erk1 / 2 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, as disclosed herein below, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof. In some embodiments, the compound is Compound 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, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 7, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188,189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236 , 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276 or a pharmaceutically acceptable form thereof.

[0255] In certain embodiments of the methods of modulating Erk1 / 2 activity described herein, the method inhibits phosphorylation of Erk1 / 2 protein. In some embodiments, the method comprises contacting Erk1 / 2 protein with a compound, or a pharmaceutically acceptable form thereof, that inhibits phosphorylation of Erk1 / 2 protein by 80% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In some embodiments, the method comprises contacting Erk1 / 2 protein with a compound, or a pharmaceutically acceptable form thereof, that inhibits phosphorylation of Erk1 / 2 protein by 85% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In some embodiments, the compound is selected from the group consisting of compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 36, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof.

[0256] In certain embodiments of the methods of modulating Erk1 / 2 activity described herein, the method activates phosphorylation of Erk1 / 2 protein. In some embodiments, the method comprises contacting Erk1 / 2 protein with a compound, or a pharmaceutically acceptable form thereof, that activates phosphorylation of Erk1 / 2 protein by 45% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In some embodiments, the method comprises contacting Erk1 / 2 protein with a compound, or a pharmaceutically acceptable form thereof, that activates phosphorylation of Erk1 / 2 protein by 50% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In some embodiments, the compound is compound 49, 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 130, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 77, 178, 179, 183, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharmaceutically acceptable form thereof.In some embodiments, the compound is Compound 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 7, 178, 179, 183, 190, 191, 192, 193, 194, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharmaceutically acceptable form thereof.

[0257] In some embodiments of the methods provided herein, the contacting of the Erk1 / 2 protein is performed 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.

[0258] Provided herein are methods of modulating Akt activity, comprising contacting an Akt protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof. 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, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, as disclosed herein below, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof. In some embodiments, the compound is Compound 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, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107 7, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 , 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191,192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 38, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

[0259] In certain embodiments of the methods of modulating Akt activity described herein, the method inhibits phosphorylation of Akt protein. In some embodiments, the method comprises contacting Akt protein with a compound, or a pharmaceutically acceptable form thereof, that inhibits phosphorylation of Akt protein by 85% or more at 10 μM according to an Akt phosphorylation assay. In some embodiments, the compound is selected from the group consisting of compounds 17, 20, 23, 25, 29, 30, 31, 32, 33, 34, 42, 203, 209, 210, 219, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof.

[0260] In certain embodiments of the methods of modulating Akt activity described herein, the method activates phosphorylation of an Akt protein. In some embodiments, the method comprises contacting an Akt protein with a compound or a pharmaceutically acceptable form thereof that activates phosphorylation of the Akt protein by 50% or more at 10 μM according to an Akt phosphorylation assay. In some embodiments, the compound is Compound 1, 2, 18, 19, 21, 47, 48, 49, 50, 51, 57, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 93, 94, 95 , 96, 97, 98, 100, 101, 102, 103, 104, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 122, 124, 125, 126, 127, 128, 129, 130, 135, 136, 137, 138, 143, 145, 149, 151, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 2 7, 158, 165, 166, 169, 170, 173, 174, 175, 176, 178, 179, 187, 190, 191, 192, 193, 194, 195, 196, 204, 205, 207, 208, 213, 217, 218, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234 4, 235, 237, 238, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 254, 255, 256, 257, 259, 260, 263, 264, 265, 266, 267, 268, 275, and 276, or a pharmaceutically acceptable form thereof.

[0261] In some embodiments of the methods provided herein, the contacting of the Akt protein occurs 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.

[0262] Provided herein are methods for modulating Smad2 / 3 activity, comprising contacting a Smad2 / 3 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof. Also provided herein are methods for modulating Smad2 / 3 activity, comprising contacting a Smad2 / 3 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, as disclosed herein below, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof. In some embodiments, the compound is Compound 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, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 20, 21, 22 2, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 5, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146 , 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187,188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 36, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

[0263] In certain embodiments of the methods of modulating Smad2 / 3 activity described herein, the method inhibits phosphorylation of Smad2 / 3 protein. In some embodiments, the method comprises contacting Smad2 / 3 protein with a compound, or a pharmaceutically acceptable form thereof, that inhibits phosphorylation of Smad2 / 3 protein by 80% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In some embodiments, the method comprises contacting Smad2 / 3 protein with a compound, or a pharmaceutically acceptable form thereof, that inhibits phosphorylation of Smad2 / 3 protein by 85% or more. In some embodiments, the compound is selected from the group consisting of compounds 27, 29, 30, 31, 32, 33, 36, 43, 44, 47, 51, 52, 55, 59, 85, 96, 97, 98, 99, 116, 141, 144, 156, 203, 205, 207, 208, 209, 210, 211, 214, 219, 230, 269, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of compounds 29, 30, 31, 32, 33, 36, 44, 47, 59, 85, 97, 98, 99, 116, 141, 144, 156, 203, 205, 207, 208, 209, 210, 211, 214, 219, 230, 269, 272, 273, and 274, or a pharmaceutically acceptable form thereof.

[0264] In certain embodiments of the methods of modulating Smad2 / 3 activity described herein, the method activates phosphorylation of Smad2 / 3 protein. In some embodiments, the method comprises contacting Smad2 / 3 protein with a compound or a pharmaceutically acceptable form thereof that activates phosphorylation of Smad2 / 3 protein by 50% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay. In some embodiments, the compound is selected from the group consisting of compounds 56, 63, 84, 88, 89, 90, 95, 100, 101, 103, 104, 106, 108, 109, 111, 112, 113, 114, 129, 166, 173, 179, 183, 186, 216, 241, 247, 248, 250, 255, 256, 257, and 266, or a pharmaceutically acceptable form thereof.

[0265] In some embodiments of the methods provided herein, the contacting of the Smad2 / 3 protein is performed 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.

[0266] Provided herein are methods for modulating JNK activity, comprising contacting a JNK protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof. Also provided herein are methods for modulating JNK activity, comprising contacting a JNK protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, as disclosed herein below, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof. In some embodiments, the compound is Compound 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, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107 7, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 , 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191,192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 38, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

[0267] In certain embodiments of the methods of modulating JNK activity described herein, the method inhibits phosphorylation of a JNK protein. In some embodiments, the method comprises contacting a JNK protein with a compound, or a pharmaceutically acceptable form thereof, that inhibits phosphorylation of the JNK protein by 30% or more according to a JNK activation assay. In some embodiments, the method comprises contacting a JNK protein with a compound, or a pharmaceutically acceptable form thereof, that inhibits phosphorylation of the JNK protein by 75% or more according to a JNK activation assay. In some embodiments, the method comprises contacting a JNK protein with a compound, or a pharmaceutically acceptable form thereof, that inhibits phosphorylation of the JNK protein by about 100% according to a 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 selected from the group consisting of compounds 29, 32, 33, and 34, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of compounds 29, 32, and 34, or a pharmaceutically acceptable form thereof.

[0268] In certain embodiments of the methods of modulating JNK activity described herein, the method activates phosphorylation of a JNK protein. In some embodiments, the method comprises contacting a JNK protein with a compound, or a pharmaceutically acceptable form thereof, that activates phosphorylation of the JNK protein by 30% or more according to a JNK activation assay. In some embodiments, the method comprises contacting a JNK protein with a compound, or a pharmaceutically acceptable form thereof, that activates phosphorylation of the JNK protein by 75% or more according to a JNK activation assay. In some embodiments, the method comprises contacting a JNK protein with a compound, or a pharmaceutically acceptable form thereof, that activates phosphorylation of the JNK protein by about 100% or more according to a JNK activation assay. In some embodiments, the compound is selected from the group consisting of compounds 1, 2, 3, 4, 6, 7, 8, 9, 11, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of compounds 3, 4, 6, 7, 11, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of compounds 3, 6, 7, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof.

[0269] In some embodiments of the methods provided herein, the contacting of the JNK protein occurs 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.

[0270] Provided herein are methods for modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof. Also provided herein are methods for modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, as disclosed herein below, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof. In some embodiments, the compound is Compound 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, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186,187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235 , 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

[0271] In certain embodiments of the methods of modulating MAPK p38 described herein, the method inhibits phosphorylation of MAPK p38 protein. In some embodiments, the method comprises contacting MAPK p38 with a compound, or a pharmaceutically acceptable form thereof, that inhibits phosphorylation of MAPK p38 by 30% or more at 10 μM according to a MAPK p38 activation assay. In some embodiments, the method comprises contacting MAPK p38 with a compound, or a pharmaceutically acceptable form thereof, that inhibits phosphorylation of MAPK p38 by about 100% at 10 μM according to a MAPK p38 activation assay. In some embodiments, the compound is selected from the group consisting of compounds 29, 30, 32, 33, 34, 46, 47, 188, 196, 197, 203, 205, 207, 208, 209, 210, 212, 213, 214, 215, 217, and 220, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of compounds 29, 32, 33, 34, 46, 207, and 209, or a pharmaceutically acceptable form thereof.

[0272] In certain embodiments of the methods of modulating MAPK p38 described herein, the method activates phosphorylation of MAPK p38 protein. In some embodiments, the method comprises contacting MAPK p38 with a compound, or a pharmaceutically acceptable form thereof, that activates phosphorylation of MAPK p38 by 30% or more at 10 μM according to a MAPK p38 activation assay. In some embodiments, the method comprises contacting MAPK p38 with a compound, or a pharmaceutically acceptable form thereof, that activates phosphorylation of MAPK p38 by 75% or more at 10 μM according to a MAPK p38 activation assay. In some embodiments, the method comprises contacting MAPK p38 with a compound, or a pharmaceutically acceptable form thereof, that activates phosphorylation of MAPK p38 by about 100% or more at 10 μM according to a MAPK p38 activation assay. In some embodiments, the compound is selected from the group consisting of compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, 93, and 218, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of compounds 1, 2, 3, 7, 8, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof.

[0273] In some embodiments of the methods provided herein, the contacting of the MAPK p38 protein is performed 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.

[0274] Provided herein are methods for modulating IL-6 activity, comprising contacting an IL-6 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof. Also provided herein are methods for modulating IL-6 activity, comprising contacting an IL-6 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, as disclosed herein below, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof. In some embodiments, the compound is Compound 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, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 20, 21, 22 3, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190,191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237 , 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

[0275] In certain embodiments of the methods for modulating IL-6 activity described herein, the method inhibits IL-6 activity. In some embodiments, the method comprises contacting IL-6 protein with a compound, or a pharmaceutically acceptable form thereof, that inhibits IL-6 activity by 75% or more at 10 μM according to an IL-6 quantification assay. In some embodiments, the compound is Compound 1, 4, 6, 13, 19, 20, 22, 23, 27, 29, 30, 31, 32, 33, 34, 40, 42, 45, 46, 67, 81, 82, 85, 86, 89, 93, 99, 104, 105, 111, 113, 143, 149, 160, 161, 163, 164, 166, 173, 175, 176, 177, 192, 193, 194, 196, 199, 201, 203, 204, 206, 207, 208, 209, 210, 217, 219, 238, 247, 248, 249, 250, 257, 260, 263, 264, 265, 268, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof.

[0276] In some embodiments of the methods provided herein, the contacting of the IL-6 protein is performed 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.

[0277] 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, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a 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 compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, as disclosed herein below, or a pharmaceutical composition comprising a pharmaceutically acceptable form thereof. In some embodiments, the compound is Compound 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, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186,187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235 , 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

[0278] In certain embodiments of the methods of modulating IL-6 activity described herein, the method inhibits TNF-alpha activity. In some embodiments, the method comprises contacting TNF-alpha protein with a compound, or a pharmaceutically acceptable form thereof, that inhibits TNF-alpha activity by 75% or more at 10 μM according to a TNF-alpha quantification assay. In some embodiments, the compound is selected from the group consisting of compounds 4, 23, 29, 30, 31, 32, 33, 42, 45, 46, 93, 99, 149, 166, 196, 203, 207, 209, 210, 219, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof.

[0279] In some embodiments of the methods provided herein, the contacting of the TNF-alpha protein occurs 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] 3.4. Methods of Treating Cancer Without being bound by theory, cancer is primarily characterized by an increase in the number of abnormal cells derived from a given normal tissue, the invasion of adjacent tissues by these abnormal cells, or the lymphatic or blood-mediated spread of malignant cells to regional lymph nodes and distant sites. Clinical data and molecular biology studies indicate that cancer is a multistep process beginning with small preneoplastic changes that, under certain conditions, can progress to neoplasia. Neoplastic lesions can evolve clonally and develop increased capacities for invasion, growth, metastasis, and heterogeneity, especially under conditions where neoplastic cells evade host immune surveillance. (Roitt, I., Brostoff, J., and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993))

[0281] Without being bound by theory, the various stages of tumor progression can be generally described as follows:

[0282] a) Tumor evolution begins when cells within a normal population maintain genetic mutations that magnify their tendency to proliferate.

[0283] b) Although such genetically altered cells and their progeny continue to appear normal, they proliferate excessively, resulting in a condition called hyperplasia. Altered cells may also secrete signaling elements or other molecules that cause changes in their local cellular and extracellular environment (including, but not limited to, immune system responses to them). Such environmental effects may in turn affect the survival, proliferation, and further mutations of the altered cells. After some time (months or years), very small numbers of these altered cells may maintain additional mutations with subsequent loss of control of cell growth and further potential effects on their environment.

[0284] c) The progeny of these cells not only proliferate excessively but also appear abnormal in shape and orientation. The tissue is now said to exhibit a condition called dysplasia. After some time, one or more additional mutations may further alter cell behavior and the cells' interactions with their environment.

[0285] d) Affected, genetically altered cells become more abnormal in growth and appearance. When a tumor mass does not invade through any boundaries between tissues, it is called an in situ tumor. This tumor may remain contained indefinitely, but some cells may acquire more and more mutations.

[0286] e) Malignant or invasive tumors occur when genetic changes allow the tumor mass to invade underlying tissues and shed cells into the blood or lymph. These cells can then introduce new tumor loci (metastases) throughout the body.

[0287] Without being bound by theory, metastasis represents the end product of a multistep cell biological process termed the invasion-metastasis cascade, which involves the spread of cancer cells to anatomically distant organ sites and their subsequent adaptation to foreign tissue microenvironments. Each of these events is induced by the acquisition of genetic and / or epigenetic changes within tumor cells and the recruitment of non-neoplastic stromal cells, which together provide the initial metastatic cells with the traits required to generate macroscopic metastases. (Volastyan, S., et al., Cell, 2011, vol. 147, 275-292)

[0288] Without being bound by theory, a wide variety of cancers affect different tissues throughout the body, which are well documented 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, pancreas, prostate, breast, brain, and intestine. Other human tumors, including leukemia and myeloma, originate from cells involved in the formation of immune cells and other blood cells.

[0289] The incidence of cancer continues to rise as the general population ages, new cancers occur, and susceptible populations grow. Therefore, there is a great need for new methods and compositions that can be used to treat subjects with cancer.

[0290] Without being bound by theory, current cancer therapies may involve surgery, chemotherapy, hormonal therapy, biological therapy, targeted therapy, immunotherapy, and / or radiation therapy to eradicate neoplastic cells in patients (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).

[0291] Without being bound by theory, such therapies may be used independently or in combination. The choice of therapy will depend on the history and nature of the cancer, the condition of the patient, and, in the circumstances, the anticipated efficacies and adverse effects of the therapeutic agents and methods being considered.

[0292] 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 are not tumor-specific, have broad systemic effects, are toxic, and can cause significant, often dangerous, side effects, including severe nausea, myelosuppression, and immunosuppression.

[0293] Without being bound by theory, even when using a combination of chemotherapy drugs, many tumor cells are resistant or become resistant to chemotherapy drugs.In fact, cells that are resistant to a specific chemotherapy drug used in a treatment protocol often turn out to be resistant to other drugs, even if these drugs act by a different mechanism than the drug used in the specific treatment.This phenomenon is called multidrug resistance.Due to drug resistance, many cancers are refractory to standard chemotherapy treatment protocols.

[0294] Thus, there is a significant need for alternative compounds, compositions and methods for treating, preventing and managing cancer.

[0295] Without being bound by theory, while surgical resection and adjuvant therapy can cure well-defined primary tumors, metastatic disease is largely incurable due to its systemic nature and the resistance of disseminated tumor cells to existing therapeutic agents. This explains why over 90% of cancer-related mortality is attributable to metastases rather than the primary tumors from which these malignancies arise.

[0296] Provided herein are methods of treating cancer in a subject, comprising administering a therapeutically effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof, to a subject with cancer. Also provided herein are methods of treating cancer in a subject, comprising administering a therapeutically effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, as disclosed herein below, or a pharmaceutically acceptable form thereof, to a subject with cancer. In some embodiments, the compound is Compound 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, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 7, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188,189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236 , 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

[0297] In some embodiments of the methods of treating cancer provided herein, the method involves administering a compound or a pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily proteins. In some embodiments, the compound or a pharmaceutically acceptable form thereof modulates the Ras superfamily activity of one or more GTPases 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 a pharmaceutically acceptable form thereof inhibits the activity of one or more Ras superfamily proteins. In some embodiments, the compound or a pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily proteins by 45% or more at 20 μM according to Ras superfamily activity. In some embodiments, the compound or a pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily proteins by 50% or more at 20 μM according to Ras superfamily activity.In some embodiments, the compound is compound 6, 17, 22, 32, 34, 37, 42, 43, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 1 8, 99, 100, 101, 102, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 156, 157, 158, 165, 166, 167, 169, 170, 172, 173, 174, 175, 176, 177, 178, 179, 186, 187, 188, 196, 200, 202, 208, 211, 212, 213, 214, 215, 216, 217, 220, 221, 222, 223, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 33, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 254, 255, 256, 257, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, and 276, or a pharmaceutically acceptable form thereof.In some embodiments, the compound is Compound 6, 17, 22, 37, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98 , 99, 100, 101, 102, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 209, 2010, 2011, 209, 20 3, 154, 156, 157, 158, 165, 166, 169, 170, 173, 175, 176, 177, 178, 179, 186, 187, 188, 196, 202, 208, 211, 212, 213, 214, 215, 216, 217, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 254, 255, 256, 257, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, and 276, or a pharmaceutically acceptable form thereof.

[0298] In some embodiments of the methods of treating cancer provided herein, the method involves administering a compound or a pharmaceutically acceptable form thereof that modulates Erk1 / 2 activity. In some embodiments, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 protein. In some embodiments, the compound or a 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 an Erk1 / 2 phosphorylation assay. In some embodiments, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 protein by 80% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In some embodiments, the compound or a pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 protein by 85% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In some embodiments, the compound is selected from the group consisting of compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 36, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erkl / 2 proteins. In some embodiments, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erkl / 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 100% or more at 10 μM according to an Erkl / 2 phosphorylation assay.In some embodiments, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 protein by 45% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In some embodiments, the compound or a pharmaceutically acceptable form thereof activates phosphorylation of Erk1 / 2 protein by 50% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In some embodiments, the compound is compound 49, 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 130, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 77, 178, 179, 183, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is Compound 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 7, 178, 179, 183, 190, 191, 192, 193, 194, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharmaceutically acceptable form thereof.

[0299] In some embodiments of the method...

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable form thereof, X is -NR １Ａ R ２Ａ OR ２Ａ and Y is imidazolyl, pyridinyl, or an 8-10 membered fused heteroaryl; The imidazolyl is one R ６Ａ Optionally substituted with a substituent, 1 to 2 R ７Ａ is optionally substituted with a substituent; The pyridinyl or the 8- to 10-membered fused heteroaryl is selected from 1 to 4 R ７Ａ is optionally substituted with a substituent; R １Ａ is hydrogen or C １－６ alkyl, １－６ Alkyl is 1 to 4 R ８Ａ is optionally substituted with a substituent; R ２Ａ is hydrogen, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Heteroalkyl, C ３－７ Heterocycloalkyl, C ５－１０ aryl, -S(O) ２ R １５Ａ , -P(O)R １６Ａ R １７Ａ or 5-10 membered heteroaryl, １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Heteroalkyl and 5- to 10-membered heteroaryl each independently represent 1 to 4 R ８Ａ Optionally substituted with a substituent, optionally with two independent R ８Ａ The substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; or R １Ａ and R ２Ａ are combined to form a 3-6 membered heterocycloalkyl containing the nitrogen atom to which they are both attached, and optionally R １Ａ and R ２Ａ said 3- to 6-membered heterocycloalkyl formed by is fused to a 5- to 6-membered heteroaryl; R ３Ａ is C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Heteroalkyl, aryl, 5- to 10-membered heteroaryl, -(CO)R １１Ａ or -C(O)NR １２Ａ R １３Ａ and said C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Heteroalkyl, aryl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R ９Ａ is optionally substituted with a substituent; R ４Ａ is hydrogen, aryl, or 5- to 10-membered heteroaryl, each of the aryl and 5- to 10-membered heteroaryl independently being selected from 1 to 4 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ５Ａ is hydrogen or C １－６ is alkyl; R ６Ａ and R ７Ａ are each independently １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, aryl, C ５－１０ Heteroaryl, C ３－７ Heterocycloalkyl, C １－６ Heteroalkyl, halo, -NR １２Ａ R １３Ａ , C １－６ Alkoxy, C １－６ Haloalkoxy, —C(O)NR １２Ａ R １３Ａ , -(CO)R １１Ａ , -C(O)OR １４Ａ or CN, １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, aryl, C ５－１０ Heteroaryl, C ３－７ Heterocycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R ８Ａ and R ９Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, -NR １２Ａ R １３Ａ , -(CO)R １１Ａ , -C(O)OR １４Ａ , -C(O)NR １２Ａ R １３Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ each independently selected from the group consisting of haloalkoxy, 5-6 membered heteroaryl, biotinamide, or a biotinylating substituent; R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl, １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3-6 membered heterocycloalkyl, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ haloalkoxy, or 5- to 6-membered heteroaryl each independently represent 1 to 3 R ８Ａ is optionally substituted with a substituent; R １１Ａ is -OH, C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, C １－６ Alkoxy, C １－６ Haloalkoxy, C ３－７ heterocycloalkyl, aryl, or 5- to 10-membered heteroaryl; １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ３－７ Heterocycloalkyl, aryl, and 5- to 10-membered heteroaryl each have 1 to 3 R ８Ａ Optionally substituted with a substituent, or R １２Ａ and R １３Ａ combine to form a 3- to 7-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R １４Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １５Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Alkoxy, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Alkoxy, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １６Ａ and R １７Ａ is C １－６ Alkyl, C １－６ Alkoxy, or C １－６ heteroalkyl; １－６ Alkyl, C １－６ Alkoxy, and C １－６ Heteroalkyl is each independently one to three R ８Ａ Optionally substituted with a substituent, or R １６Ａ and R １７Ａ combine to form a 3- to 7-membered heterocycloalkyl containing a phosphorus atom to which they are both attached; X is OH or 【Chemistry 2】 Y is N-methylimidazolyl; R ５Ａ is H, then R ３Ａ and R ４Ａ at least one of is not unsubstituted phenyl.

2. Y is one R ６Ａ Optionally substituted with a substituent and 1 to 2 R ７Ａ The compound of claim 1 which is an imidazolyl optionally substituted with a substituent.

3. Y is a nitrogen atom of the imidazolyl ring. ６Ａ substituted with a substituent and 1 to 2 R ７Ａ is a C-linked imidazolyl optionally substituted with a substituent; A compound according to claim 1 or claim 2.

4. The compound is a compound of formula Ia: 【Chemistry 3】 or a pharma- ceutically acceptable form thereof.

5. The compound is a compound of formula Ib: 【Chemistry 4】 or a pharma- ceutically acceptable form thereof.

6. Y is 1 to 4 R ７Ａ The compound of claim 1 which is pyridinyl optionally substituted with a substituent.

7. The compound is a compound of formula Ic: 【Chemistry 5】 7. The compound of claim 1 or claim 6, or a pharma- ceutically acceptable form thereof.

8. Y is 1 to 4 R ７Ａ The compound of claim 1 which is an 8-10 membered fused heteroaryl optionally substituted with a substituent.

9. X is -OR ２Ａ The compound according to any one of claims 1 to 8,

10. X is -NR １Ａ R ２Ａ The compound according to any one of claims 1 to 8,

11. Compound of Formula II: 【Chemistry 6】 or a pharma- ceutically acceptable form thereof, X is -NR １Ａ R ２Ａ Or -OR ２Ａ and R １Ａ is hydrogen or C １－６ is alkyl; R ２Ａ is hydrogen, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Heteroalkyl, -S(O) ２ R １５Ａ , -P(O)R １６Ａ R １７Ａ or 5-6 membered heteroaryl, １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl and 5- to 6-membered heteroaryl each independently represent 1 to 3 R ８Ａ Optionally substituted with a substituent, optionally with two independent R ８Ａ The substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; or R １Ａ and R ２Ａ are combined to form a 3-6 membered heterocycloalkyl containing the nitrogen atom to which they are both attached, and optionally R １Ａ and R ２Ａ said 3- to 6-membered heterocycloalkyl formed by is fused to a 5- to 6-membered heteroaryl; R ３Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl, phenyl, 5- to 10-membered heteroaryl, -(CO)R １１Ａ or -C(O)NR １２Ａ R １３Ａ and said C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R ９Ａ is optionally substituted with a substituent; R ４Ａ is hydrogen, phenyl, or 5- to 10-membered heteroaryl, each of the phenyl and 5- to 10-membered heteroaryl independently being selected from 1 to 3 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ５Ａ is hydrogen; R ６Ａ and R ７Ａ are each independently １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R ８Ａ and R ９Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, -NR １２Ａ R １３Ａ , -(CO)R １１Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ each independently selected from the group consisting of haloalkoxy, 5-6 membered heteroaryl, biotinamide, or a biotinylating substituent; R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl, １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3-6 membered heterocycloalkyl, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ haloalkoxy, or 5- to 6-membered heteroaryl each independently represent 1 to 3 R ８Ａ is optionally substituted with a substituent; R １１Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, C １－６ Alkoxy, or C １－６ haloalkoxy, or R １２Ａ and R １３Ａ combine to form a 3- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R １５Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １６Ａ and R １７Ａ is C １－６ Alkyl, C １－６ Alkoxy, or C １－６ heteroalkyl; １－６ Alkyl, C １－６ Alkoxy, and C １－６ Heteroalkyl is each independently one to three R ８Ａ Optionally substituted with a substituent, or R １６Ａ and R １７Ａ combine to form a 3- to 7-membered heterocycloalkyl containing a phosphorus atom to which they are both attached; m is 0, 1 or 2; X is OH or 【Chemistry 7】 Y is N-methylimidazolyl; R ５Ａ is H, then R ３Ａ and R ４Ａ at least one of is not unsubstituted phenyl.

12. Compound of Formula IIa: 【Chemistry 8】 or a pharma- ceutically acceptable form thereof, R １Ａ is hydrogen; R ２Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl, -S(O) ２ R １５Ａ or 5-6 membered heteroaryl, １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl and 5- to 6-membered heteroaryl each independently represent 1 to 3 R ８Ａ Optionally substituted with a substituent, optionally with two independent R ８Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ３Ａ is C １－３ Alkyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl, phenyl, 5-, 6- or 9-membered heteroaryl, -(CO)R １１Ａ or -C(O)NR １２Ａ R １３Ａ and said C １－３ Alkyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl, phenyl, and 5-, 6-, or 9-membered heteroaryl each independently represent 1 to 3 R ９Ａ is optionally substituted with a substituent; R ４Ａ is hydrogen, phenyl, or 5-, 6-, or 9-membered heteroaryl, each of which is independently selected from 1 to 3 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ５Ａ is hydrogen; R ６Ａ is C １－３ Alkyl or C １－３ Heteroalkyl, wherein C １－３ Alkyl or C １－３ The heteroalkyl is optionally substituted with biotinamide; R ７Ａ is methyl; R ８Ａ and R ９Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, -NR １２Ａ R １３Ａ , -(CO)R １１Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ each independently selected from the group consisting of haloalkoxy, 5-6 membered heteroaryl, biotinamide, or a biotinylating substituent; R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １１Ａ R １２Ａ or 5-6 membered heteroaryl, １－６ Alkyl or C １－６ The heteroalkyl is optionally substituted with biotinamide; R １１Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, or C １－６ alkoxy, or R １２Ａ and R １３Ａ combine to form a 5- or 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R １５Ａ is C １－３ Alkyl, C ３－６ Cycloalkyl, or C １－４ is heteroalkyl; R １６Ａ and R １７Ａ is C １－３ Alkyl or C １－３ alkoxy, or R １６Ａ and R １７Ａ combine to form a 5-membered heterocycloalkyl containing the phosphorus atom to which they are both attached; m is 0 or 1).

13. R １Ａ and R ２Ａ together with the nitrogen to which they are attached form -NH ２、 【Chemistry 9】 【change】 【change】 【change】 having the structure R ３Ａ is -CH ３ , unsubstituted phenyl, isopropyl, cyclopropyl, 【Chemistry 10】 and R ４Ａ is hydrogen, unsubstituted phenyl, 【Chemistry 11】 and R ５Ａ is hydrogen; R ６Ａ is methyl, -CH ２ CH ２ N.H. ２ ,or 【Chemistry 12】 and R ７Ａ is methyl; m is 0 or 1; 13. The compound of claim 12.

14. R １Ａ and R ２Ａ together with the nitrogen to which they are attached form -NH ２、 【Chemistry 13】 【change】 【change】 【change】 having the structure R ３Ａ is -CH ３ , unsubstituted phenyl, isopropyl, cyclopropyl, 【Chemistry 14】 and R ４Ａ is hydrogen, unsubstituted phenyl, 【Chemistry 15】 and R ５Ａ is hydrogen; R ６Ａ is methyl, -CH ２ CH ２ N.H. ２ ,or 【Chemistry 16】 and m is 0; 13. The compound of claim 12.

15. Compound of Formula IIb: 【Chemistry 17】 or a pharma- ceutically acceptable form thereof, R １Ａ and R ２Ａ are combined to form a 4-6 membered heterocycloalkyl containing the nitrogen atom to which they are both attached, and optionally R １Ａ and R ２Ａ said 4-6 membered heterocycloalkyl formed by is fused to a 6 membered heteroaryl; R ３Ａ is C １－３ alkyl or phenyl, １－３ Alkyl and phenyl each independently represent 1 to 3 R ９Ａ is optionally substituted with a substituent; R ４Ａ is phenyl or 5-membered heteroaryl, and the aryl and 5-membered heteroaryl each independently represent 1 to 3 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ５Ａ is hydrogen; R ６Ａは、 methyl; R ７Ａ is methyl; R ９Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —(CO)R １１Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ haloalkoxy, or 5-6 membered heteroaryl; R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl; R １１Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, or C １－６ each independently selected from the group consisting of alkoxy; m is 0 or 1; R １Ａ and R ２Ａ Combined 【Chemistry 18】 Forming ６Ａ is methyl, m is 0, R ５Ａ is H, then R ３Ａ and R ４Ａ at least one of is not unsubstituted phenyl.

16. R １Ａ and R ２Ａ are combined, 【Chemistry 19】 Forming R ３Ａ is -CH ３ , unsubstituted phenyl, (4-methoxy)-phenyl, or isopropyl; R ４Ａ teeth, 【Chemistry 20】 and R ５Ａ is hydrogen; R ６Ａ is methyl; m is 0; 16. The compound of claim 15.

17. R １Ａ and R ２Ａ are combined, 【Chemistry 21】 Forming R ３Ａ is -CH ３ or unsubstituted phenyl; R ４Ａ teeth, 【Chemical 22】 and R ５Ａ is hydrogen; R ６Ａ is methyl; m is 0; 16. The compound of claim 15.

18. Compound of Formula IIc: 【Chemistry 23】 or a pharma- ceutically acceptable form thereof, R ２Ａ is hydrogen C １－６ heteroalkyl, or 6-membered heteroaryl, １－６ Heteroalkyl and 5- to 6-membered heteroaryl each have 1 to 3 R ８Ａ is optionally substituted with a substituent; R ３Ａ is C １－３ alkyl or phenyl, １－３ Alkyl or phenyl each independently represent 1 to 3 R ９Ａ is optionally substituted with a substituent; R ４Ａ is hydrogen, phenyl, or 5- or 6-membered heteroaryl, each of which is independently selected from 1 to 3 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ５Ａ is hydrogen; R ６Ａ is methyl; R ７Ａ is methyl; R ８Ａ and R ９Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —(CO)R １１Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ haloalkoxy, or 5-6 membered heteroaryl; R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl; R １１Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, or C １－６ each independently selected from the group consisting of alkoxy; m is 0 or 1; R ２Ａ is H, and R ６Ａ is methyl, m is 0, R ５Ａ is H, then R ３Ａ and R ４Ａ at least one of is not unsubstituted phenyl.

19. R ２Ａ together with the oxygen to which they are attached, OH, 【Chemistry 24】 having the structure R ３Ａ is -CH ３ or unsubstituted phenyl; R ４Ａ is hydrogen, unsubstituted phenyl, 【Chemistry 25】 and R ５Ａ is hydrogen; R ６Ａ is methyl; m is 0; 19. The compound of claim 18.

20. Compound of Formula III: 【Chemistry 26】 or a pharma- ceutically acceptable form thereof, X is NR １Ａ R ２Ａ Or -OR ２Ａ and R １Ａ is hydrogen or C １－６ is alkyl; R ２Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ heteroalkyl, or 5- to 6-membered heteroaryl, １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl and 5- to 6-membered heteroaryl each independently represent 1 to 3 R ８Ａ Optionally substituted with a substituent, optionally with two independent R ８Ａ The substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; or R １Ａ and R ２Ａ combine to form a 3- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R ３Ａ is C １－６ Alkyl, C １－６ heteroalkyl, phenyl, or 5- to 10-membered heteroaryl, １－６ Alkyl, C １－６ Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R ９Ａ is optionally substituted with a substituent; R ４Ａ is hydrogen, phenyl, or 5- to 10-membered heteroaryl, each of the phenyl and 5- to 10-membered heteroaryl independently being selected from 1 to 3 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ５Ａ is hydrogen or C １－６ is alkyl; R ６Ａ and R ７Ａ are each independently １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R ８Ａ and R ９Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —(CO)R １１Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ haloalkoxy, or 5-6 membered heteroaryl; R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl; R １１Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, or C １－６ each independently selected from the group consisting of alkoxy; m is 0, 1 or 2).

21. Compound of Formula IIIa: 【Chemistry 27】 or a pharma- ceutically acceptable form thereof, R １Ａ is hydrogen; R ２Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ heteroalkyl, or 5- to 6-membered heteroaryl, １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl and 5- to 6-membered heteroaryl each independently represent 1 to 3 R ８Ａ Optionally substituted with a substituent, optionally with two independent R ８Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ３Ａ is C １－６ Alkyl, C １－６ heteroalkyl, phenyl, or 5- to 10-membered heteroaryl, １－６ Alkyl, C １－６ Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R ９Ａ is optionally substituted with a substituent; R ４Ａ is hydrogen, phenyl, or 5- to 10-membered heteroaryl, each of the phenyl and 5- to 10-membered heteroaryl independently being selected from 1 to 3 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ５Ａ is hydrogen or C １－６ is alkyl; R ６Ａ and R ７Ａ are each independently １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R ８Ａ and R ９Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —(CO)R １１Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ haloalkoxy, or 5-6 membered heteroaryl; R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl; R １１Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, or C １－６ each independently selected from the group consisting of alkoxy; m is 0, 1 or 2).

22. Compound of formula IIIb: 【Chemistry 28】 or a pharma- ceutically acceptable form thereof, R １Ａ and R ２Ａ combine to form a 4-6 membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R ３Ａ is C １－６ Alkyl, C １－６ heteroalkyl, phenyl, or 5- to 10-membered heteroaryl, １－６ Alkyl, C １－６ Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R ９Ａ is optionally substituted with a substituent; R ４Ａ is hydrogen, phenyl, or 5- to 10-membered heteroaryl, each of the phenyl and 5- to 10-membered heteroaryl independently being selected from 1 to 3 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ５Ａ is hydrogen or C １－６ is alkyl; R ６Ａ and R ７Ａ are each independently １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R ８Ａ and R ９Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —(CO)R １１Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ haloalkoxy, or 5-6 membered heteroaryl; R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl; R １１Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, or C １－６ each independently selected from the group consisting of alkoxy; m is 0, 1 or 2).

23. Compound of formula IIIc: 【Chemical 29】 or a pharma- ceutically acceptable form thereof, R ２Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ heteroalkyl, or 5- to 6-membered heteroaryl, １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl and 5- to 6-membered heteroaryl each independently represent 1 to 3 R ８Ａ is optionally substituted with a substituent; R ３Ａ is C １－６ Alkyl, C １－６ heteroalkyl, phenyl, or 5- to 10-membered heteroaryl, １－６ Alkyl, C １－６ Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R ９Ａ is optionally substituted with a substituent; R ４Ａ is hydrogen, phenyl, or 5- to 10-membered heteroaryl, each of the phenyl and 5- to 10-membered heteroaryl independently being selected from 1 to 3 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ５Ａ is hydrogen or C １－６ is alkyl; R ６Ａ and R ７Ａ are each independently １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R ８Ａ and R ９Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —(CO)R １１Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ haloalkoxy, or 5-6 membered heteroaryl; R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl; R １１Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, or C １－６ each independently selected from the group consisting of alkoxy; m is 0, 1 or 2).

24. Compound of Formula IV: 【Chemistry 30】 or a pharma- ceutically acceptable form thereof, X is -NR １Ａ R ２Ａ Or -OR ２Ａ and R １Ａ is hydrogen or C １－６ is alkyl; R ２Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ heteroalkyl, or 5- to 6-membered heteroaryl, １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl and 5- to 6-membered heteroaryl each independently represent 1 to 3 R ８Ａ Optionally substituted with a substituent, optionally with two independent R ８Ａ The substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; or R １Ａ and R ２Ａ combine to form a 3- to 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R ３Ａ is C １－６ Alkyl, C １－６ heteroalkyl, phenyl, or 5- to 10-membered heteroaryl, １－６ Alkyl, C １－６ Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R ９Ａ is optionally substituted with a substituent; R ４Ａ is hydrogen, phenyl, or 5- to 10-membered heteroaryl, each of the phenyl and 5- to 10-membered heteroaryl independently being selected from 1 to 3 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ５Ａ is hydrogen or C １－６ is alkyl; R ７Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, aryl, C ５－１０ Heteroaryl, C ３－７ Heterocycloalkyl, C １－６ Heteroalkyl, halo, -NR １２Ａ R １３Ａ , C １－６ Alkoxy, C １－６ Haloalkoxy, —C(O)NR １２Ａ R １３Ａ , -(CO)R １１Ａ , -C(O)OR １４Ａ or CN, １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, aryl, C ５－１０ Heteroaryl, C ３－７ Heterocycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R ８Ａ and R ９Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —(CO)R １１Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ haloalkoxy, or 5-6 membered heteroaryl; R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl; R １１Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, or C １－６ each independently selected from the group consisting of alkoxy; m is 0, 1, 2, 3 or 4).

25. Compound of formula IVa: 【Chemistry 31】 or a pharma- ceutically acceptable form thereof, R １Ａ is hydrogen; R ２Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ heteroalkyl, or 6-membered heteroaryl, １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl and 6-membered heteroaryl each independently represent 1 to 3 R ８Ａ Optionally substituted with a substituent, optionally with two independent R ８Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ３Ａ is C １－６ alkyl or phenyl, １－６ Alkyl and phenyl each independently represent 1 to 3 R ９Ａ is optionally substituted with a substituent; R ４Ａ is a 5-membered heteroaryl, said 5-membered heteroaryl being selected from 1 to 3 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ５Ａ is hydrogen; R ７Ａ is methyl; R ８Ａ and R ９Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —(CO)R １１Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ haloalkoxy, or 5-6 membered heteroaryl; R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl; R １１Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, or C １－６ each independently selected from the group consisting of alkoxy; m is 0, 1, 2, 3 or 4).

26. R １Ａ and R ２Ａ together with the nitrogen to which they are attached, 【Chemistry 32】 having the structure R ３Ａ is -CH ３ or unsubstituted phenyl; R ４Ａ teeth, 【Chemical 33】 and R ５Ａ is hydrogen; R ７Ａ is methyl; 26. The compound of claim 25, wherein m is 0.

27. Compound of formula IVb: 【Chemical 34】 or a pharma- ceutically acceptable form thereof, R １Ａ and R ２Ａ combine to form a 4-6 membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R ３Ａ is C １－６ alkyl or phenyl, １－６ Alkyl and phenyl each independently represent 1 to 3 R ９Ａ is optionally substituted with a substituent; R ４Ａ is a 5-membered heteroaryl, said 5-membered heteroaryl being selected from 1 to 3 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ５Ａ is hydrogen; R ７Ａ is methyl; R ８Ａ and R ９Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —(CO)R １１Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ haloalkoxy, or 5-6 membered heteroaryl; R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl; R １１Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, or C １－６ each independently selected from the group consisting of alkoxy; m is 0, 1, 2, 3 or 4).

28. R １Ａ and R ２Ａ are combined, 【Chemistry 35】 Forming R ３Ａ is -CH ３ or phenyl; R ４Ａ teeth, 【Chemical 36】 and R ５Ａ is hydrogen; R ７Ａ is methyl; 28. The compound of claim 27, wherein m is 0.

29. Compound of formula IVc: 【Chemical 37】 or a pharma- ceutically acceptable form thereof, R ２Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ heteroalkyl, or 5- to 6-membered heteroaryl, １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Heteroalkyl and 5- to 6-membered heteroaryl each independently represent 1 to 3 R ８Ａ is optionally substituted with a substituent; R ３Ａ is C １－６ Alkyl, C １－６ heteroalkyl, phenyl, or 5- to 10-membered heteroaryl, １－６ Alkyl, C １－６ Heteroalkyl, phenyl, and 5- to 10-membered heteroaryl each independently represent 1 to 3 R ９Ａ is optionally substituted with a substituent; R ４Ａ is hydrogen, phenyl, or 5- to 10-membered heteroaryl, each of the phenyl and 5- to 10-membered heteroaryl independently being selected from 1 to 3 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ５Ａ is hydrogen; R ７Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R ８Ａ and R ９Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —(CO)R １１Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ haloalkoxy, or 5-6 membered heteroaryl; R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl; R １１Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, or C １－６ each independently selected from the group consisting of alkoxy; m is 0, 1, 2, 3 or 4).

30. R ２Ａ is hydrogen; R ３Ａ is -CH ３ and R ４Ａ teeth, 【Chemical Formula 38】 and R ５Ａ is hydrogen; R ７Ａ is methyl; 30. The compound of claim 29, wherein m is 0.

31. R ４Ａ and R ５Ａ The compound of any one of claims 1 to 30, wherein not more than one of is hydrogen.

32. R ５Ａ The compound according to any one of claims 1 to 31, wherein is hydrogen, methyl, ethyl, or isopropyl.

33. R ５Ａ The compound according to any one of claims 1 to 32, wherein is hydrogen.

34. R ６Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, aryl, C ５－１０ Heteroaryl, C ３－７ Heterocycloalkyl, C １－６ Heteroalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, —C(O)NR １２Ａ R １３Ａ , -(CO)R １１Ａ or -C(O)OR １４Ａ and said C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, aryl, C ５－１０ Heteroaryl, C ３－７ Heterocycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ The compound according to any one of claims 1 to 33, which is optionally substituted with a substituent.

35. R ６Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ The compound according to any one of claims 1 to 34, which is optionally substituted with a substituent.

36. R ６Ａ is methyl, ethyl, or isopropyl, and each of the methyl, ethyl, and isopropyl groups independently represents 1 to 3 R ８Ａ and optionally substituted with R ８Ａ is -OH, C １－３ Alkoxy, or C １－３ The compound of any one of claims 1 to 35, which is a haloalkoxy.

37. R ６Ａ The compound according to any one of claims 1 to 36, wherein is methyl, ethyl, or isopropyl.

38. R ６Ａ The compound according to any one of claims 1 to 37, wherein is methyl.

39. R ７Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ The compound according to any one of claims 1 to 38, which is optionally substituted with a substituent.

40. R ７Ａ is methyl, ethyl, or isopropyl, and each of the methyl, ethyl, and isopropyl groups independently represents 1 to 3 R ８Ａ and optionally substituted with R ８Ａ is -OH, C １－３ Alkoxy, or C １－３ The compound of any one of claims 1 to 39 which is a haloalkoxy.

41. R ７Ａ The compound according to any one of claims 1 to 40, wherein is methyl, ethyl, or isopropyl.

42. R ７Ａ The compound according to any one of claims 1 to 41, wherein is methyl.

43. The compound according to any one of claims 1 to 42, wherein m is 1.

44. The compound according to any one of claims 1 to 42, wherein m is 0.

45. X is nitrogen and R １Ａ and R ２Ａ are combined to form a 3-6 membered heterocycloalkyl containing the nitrogen atom to which they are both attached, and optionally R １Ａ and R ２Ａ 45. The compound of any one of claims 1 to 44, wherein the 3- to 6-membered heterocycloalkyl formed by is fused to a 5- to 6-membered heteroaryl.

46. R １Ａ is hydrogen or C １－３ The compound according to any one of claims 1 to 44, which is alkyl.

47. R １Ａ is methyl, ethyl, or isopropyl.

48. R １Ａ The compound according to any one of claims 1 to 46, wherein is hydrogen.

49. R ２Ａ is C １－４ Alkyl, C ４－５ Cycloalkyl, C １－４ heteroalkyl, or 5- to 6-membered heteroaryl, １－４ Alkyl, C ４－５ Cycloalkyl, C １－４ Heteroalkyl, or 5- to 6-membered heteroaryl, each independently, has 1 to 3 R ８Ａ Optionally substituted with a substituent, optionally with two independent R ８Ａ 49. The compound of any one of claims 1-44, or 46-48, wherein the substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl containing the atom(s) to which each is attached.

50. R ２Ａ is a 5-6 membered heteroaryl, each independently being selected from 1 to 3 R ８Ａ Optionally substituted with a substituent, optionally with two independent R ８Ａ 50. The compound of any one of claims 1-44, or 46-49, wherein the substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl containing the atom(s) to which each is attached.

51. R ２Ａ is a 5- to 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, or thiadiazolyl, each independently consisting of 1 to 3 R ８Ａ 51. The compound of any one of claims 1 to 44, or 46 to 50, optionally substituted with a substituent.

52. The 5- to 6-membered heteroaryl may each be selected from two independent R ８Ａ 52. The compound of claim 51, which is substituted with a substituent.

53. The 5- to 6-membered heteroaryl is selected from two independent R ８Ａ 52. The compound of claim 51, which is substituted with a substituent.

54. The two R ８Ａ 54. The compound of claim 53, wherein the substituents combine to form a 2,3-dihydropyrazolo[5,1-b]oxazolyl ring.

55. 55. The compound of claim 54, wherein the 5-6 membered heteroaryl is pyrazolyl.

56. R ８Ａ is C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, -NR １２Ａ R １３Ａ , -(CO)R １１Ａ , Oxo, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3-6 membered heterocycloalkyl, C １－６ Alkoxy, C ３－６ 52. The compound of claim 51, independently selected from the group consisting of cycloalkoxy, biotinamide, or biotinylation substituents.

57. R ８Ａ is C １－４ Alkyl, C １－４ Haloalkyl, C ３－５ Cycloalkyl, -NR １２Ａ R １３Ａ , -(CO)R １１Ａ , Oxo, C １－４ Hydroxyalkyl, C １－４ Heteroalkyl, 3- to 5-membered heterocycloalkyl, C １－４ Alkoxy, C ３－５ 57. The compound of claim 51 or claim 56, independently selected from the group consisting of cycloalkoxy, biotinamide, or biotinylation substituents.

58. R ８Ａ is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -NR １２Ａ R １３Ａ , -(CO)R １１Ａ , Oxo, C ２－３ Hydroxyalkyl, C ２－４ 58. The compound of any one of claims 51-57, independently selected from the group consisting of heteroalkyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, or cyclobutoxy.

59. X is -OH, -NH ２、 【Chemical 39】 【change】 【change】 【change】 The compound according to any one of claims 1 to 58,

60. X is -OH, -NH ２、 【Chemistry 40】 【change】 【change】 【change】 60. The compound of claim 59,

61. R ３Ａ is C １－４ Alkyl, C ３－６ Cycloalkyl, C １－４ Heteroalkyl, phenyl, 5- to 6-membered heteroaryl, -(CO)R １１Ａ or -C(O)NR １２Ａ R １３Ａ and said C １－４ Alkyl, C ３－６ Cycloalkyl, C １－４ Heteroalkyl, phenyl, or 5- to 6-membered heteroaryl each independently represent 1 to 3 R ９Ａ 61. The compound according to any one of claims 1 to 60, optionally substituted with a substituent.

62. R ９Ａ is C １－４ Alkyl, C ３－５ Cycloalkyl, -(CO)R １１Ａ , C １－４ Hydroxyalkyl, C １－４ Heteroalkyl, 4-6 membered heterocycloalkyl, C １－４ Alkoxy, or C ３－５ 62. The compound of claim 61, independently selected from the group consisting of cycloalkoxy.

63. R ９Ａ is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -(CO)R １１Ａ , C ２－３ Hydroxyalkyl, C ２－４ 63. The compound of claim 61 or claim 62, independently selected from the group consisting of heteroalkyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, imidazolyl, or piperidinyl.

64. R ３Ａ is -CH ３ , unsubstituted phenyl, (4-methoxy)-phenyl, isopropyl, cyclopropyl, 【Chemistry 41】 The compound according to any one of claims 1 to 63,

65. R ３Ａ is -CH ３ , unsubstituted phenyl, isopropyl, cyclopropyl, 【Chemistry 42】 65. The compound of claim 64, wherein:

66. R ４Ａ is phenyl or 5- to 10-membered heteroaryl, each of which independently represents 1 to 3 R １０Ａ Optionally substituted with a substituent, optionally with two independent R １０Ａ 66. The compound of any one of claims 1 to 65, wherein the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached.

67. R ４Ａ is 1 to 3 R １０Ａ phenyl optionally substituted with a substituent, optionally having two independent R １０Ａ 67. The compound of any one of claims 1 to 66, wherein the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached.

68. R ４Ａ is 1 to 3 R １０Ａ 5-6 membered heteroaryl optionally substituted with a substituent, optionally having two independent R １０Ａ 67. The compound of any one of claims 1 to 66, wherein the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached.

69. R １０Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, —OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ Haloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl.

70. R １０Ａ Ha, Haro, C １－４ Alkyl, C ３－５ Cycloalkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Heteroalkyl, 3- to 5-membered heterocycloalkyl, —OH, C １－４ Alkoxy, C ３－５ Cycloalkoxy, C １－４ Haloalkoxy, or -NR １２Ａ R １３Ａ 70. The compound of any one of claims 66 to 69, independently selected from the group consisting of:

71. R １０Ａ is halo, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, C １－３ Haloalkyl, C ２－３ Hydroxyalkyl, C ２－４ Heteroalkyl, -OH, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, C １－４ Haloalkoxy, or -NR １２Ａ R １３Ａ 71. The compound of any one of claims 66 to 70, independently selected from the group consisting of:

72. R １２Ａ and R １３Ａ is hydrogen, C １－４ Alkyl, C ３－５ Cycloalkyl, C １－４ Hydroxyalkyl, C １－４ Heteroalkyl, —OH, or C １－４ 72. The compound of any one of claims 69 to 71, each independently selected from the group consisting of alkoxy.

73. R １２Ａ and R １３Ａ are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, or ethoxy.

74. R １２Ａ and R １３Ａ are each independently selected from the group consisting of hydrogen or methyl.

75. R １２Ａ and R １３Ａ The compound according to any one of claims 69 to 74, wherein each is hydrogen.

76. R ４Ａ is hydrogen, unsubstituted phenyl, 【Chemistry 43】 The compound according to any one of claims 1 to 75,

77. R ４Ａ is hydrogen, unsubstituted phenyl, 【Chemistry 44】 77. The compound of claim 76,

78. Compound of formula IIa(1): 【Chemistry 45】 or a pharma- ceutically acceptable form thereof, R １Ａ is hydrogen; R ２Ａ is a 5- or 6-membered heteroaryl, said 5- or 6-membered heteroaryl being selected from 1 to 3 R ８Ａ Optionally substituted with a substituent, optionally with two independent R ８Ａ the substituents combine to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl containing the atom(s) to which each is attached; R ８Ａ , Haro, CN, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, 3- to 6-membered heterocycloalkyl, -NR １２Ａ R １３Ａ , -(CO)R １１Ａ , oxo, -OH, C １－６ Alkoxy, C ３－６ Cycloalkoxy, C １－６ selected from the group consisting of haloalkoxy, 5-6 membered heteroaryl, biotinamide, or biotinylation substituents; R １１Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, or C １－６ Heteroalkyl, wherein C １－６ Alkyl, C ３－６ Cycloalkyl, and C １－６ Heteroalkyl is each independently one to three R ８Ａ is optionally substituted with a substituent; R １２Ａ and R １３Ａ is hydrogen, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Heteroalkyl, —OH, or C １－６ alkoxy, or R １２Ａ and R １３Ａ combine to form a 5- or 6-membered heterocycloalkyl containing the nitrogen atom to which they are both attached; R １８Ａ is C １－３ Alkyl or C ３－６ cycloalkyl).

79. R １８Ａ is methyl, ethyl, isopropyl, or cyclopropyl.

80. R １８Ａ is methyl.

81. R １８Ａ is ethyl.

82. R １８Ａ is isopropyl.

83. R １８Ａ is cyclopropyl.

84. R ８Ａ is C １－６ Alkyl, C ３－６ Cycloalkyl, 3-6 membered heterocycloalkyl, C １－６ Alkoxy, or C ３－６ Cycloalkoxy, -NR １２Ａ R １３Ａ or 5-6 membered heteroaryl.

85. R ２Ａ is pyridyl, pyrimidyl, pyrazyl, or pyrazolyl, and said pyridyl, pyrimidyl, pyrazyl, or pyrazolyl is selected from 1 to 3 R ８Ａ Optionally substituted with a substituent, optionally with two independent R ８Ａ 85. The compound of any one of claims 78-84, wherein the substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl containing the atom(s) to which each is attached.

86. R ２Ａ is 1 to 2 R ８Ａ 86. The compound of claim 85 which is pyridyl optionally substituted with a substituent.

87. R ２Ａ teeth, 【Chemistry 46】 87. The compound of claim 86, wherein:

88. R ２Ａ is 1 to 2 R ８Ａ 86. The compound of claim 85 which is pyrimidyl optionally substituted with a substituent.

89. R ２Ａ teeth, 【Chemistry 47】 89. The compound of claim 88, wherein:

90. R ２Ａ is 1 to 2 R ８Ａ 86. The compound of claim 85 which is a pyrazyl optionally substituted with a substituent.

91. R ２Ａ is 1 to 2 R ８Ａ 86. The compound of claim 85 which is a pyrazolyl optionally substituted with a substituent.

92. R ２Ａ teeth, 【Chemistry 48】 92. The compound of claim 91, wherein:

93. Two independent R ８Ａ 93. The compound of any one of claims 85-92, wherein the substituents combine to form a 5-membered cycloalkyl or 5-membered heterocycloalkyl containing the atom(s) to which each is attached.

94. R １Ａ and R ２Ａ together with the nitrogen to which they are attached, 【Chemistry 49】 The compound according to any one of claims 78 to 93, having the structure:

95. R １Ａ and R ２Ａ together with the nitrogen to which they are attached, 【Chemistry 50】 The compound according to any one of claims 78 to 94, having the structure:

96. 96. The compound of any one of claims 78 to 95, wherein the compound is selected from the group consisting of compounds 6, 57, 58, 62, 63, 64, 68, 84, 91, 100, 102, 104, 107, 124, 126, 136, 137, 141, 142, 143, 144, 145, 157, 221, 222, 226, 235, 238, 252, 255, 260, 265, 267, and 268.

97. The compound according to any one of claims 78 to 96, wherein the compound is selected from the group consisting of compounds 6, 84, 100, 102, 104, 124, 221, 222, 235, 238, 252, 255, 260, and 267.

98. 98. The compound of any one of claims 1 to 97, wherein the compound has a MW of 1,000 g / mol or less.

99. 99. The compound of any one of claims 1 to 98, wherein the compound has a MW of 900 g / mol or less, 800 g / mol or less, 700 g / mol or less, 600 g / mol or less, or 500 g / mol or less.

100. 100. The compound of any one of claims 1 to 99, wherein the compound has a MW of 600 g / mol or less.

101. The compound according to any one of claims 1 to 100, wherein the compound has a MW of 500 g / mol or less.

102. The compound is compound 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, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 1 50, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 1 81, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 21 2, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243 , 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274,275, and 276, or a pharma- ceutically acceptable form thereof.

103. The compounds are compounds 6, 17, 22, 32, 34, 37, 42, 43, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 156, 157, 158, 1 65, 166, 167, 169, 170, 172, 173, 174, 175, 176, 177, 178, 179, 186, 187, 188, 196, 200, 202, 208, 211, 212, 213, 214, 215, 216, 217, 220, 221, 222, 223, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 2 38, 239, 240, 241, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 254, 255, 256, 257, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, and 276, or a pharma- ceutically acceptable form thereof.

104. The compounds are compounds 6, 17, 22, 37, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 1 02, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 149, 150, 151, 152, 153, 154, 156, 157, 158 , 165, 166, 169, 170, 173, 175, 176, 177, 178, 179, 186, 187, 188, 196, 202, 208, 211, 212, 213, 214, 215, 216, 217, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 104. The compound of any one of claims 1 to 103, selected from the group consisting of: 241, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 254, 255, 256, 257, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, and 276, or a pharma- ceutically acceptable form thereof.

105. 105. The compound of any one of claims 1 to 104, wherein the compound is selected from the group consisting of compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 36, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharma- ceutically acceptable form thereof.

106. 106. The compound of any one of claims 1 to 105, wherein the compound is selected from the group consisting of compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharma- ceutically acceptable form thereof.

107. The compounds are compounds 49, 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 130, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 183, 1 90, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharma- ceutically acceptable form thereof.

108. The compounds are compounds 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 183, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 198, 199, 199, 198, 199, 199, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 183, 190, 191, 192, 193 108. The compound of any one of claims 1 to 104 or 107, selected from the group consisting of: 1, 192, 193, 194, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharma- ceutically acceptable form thereof.

109. 109. The compound of any one of claims 1 to 108, wherein the compound is selected from the group consisting of compounds 17, 20, 23, 25, 29, 30, 31, 32, 33, 34, 42, 203, 209, 210, 219, 270, 271, 272, 273, and 274, or a pharma- ceutically acceptable form thereof.

110. The compounds are compounds 1, 2, 18, 19, 21, 47, 48, 49, 50, 51, 57, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 93, 94, 95, 96, 97, 98, 100 , 101, 102, 103, 104, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 122, 124, 125, 126, 127, 128, 129, 130, 135, 136, 137, 138, 143, 145, 149, 151, 156, 157, 158, 165, 166, 169 , 170, 173, 174, 175, 176, 178, 179, 187, 190, 191, 192, 193, 194, 195, 196, 204, 205, 207, 208, 213, 217, 218, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 237, 238, 240, 24 109. The compound of any one of claims 1 to 108, selected from the group consisting of: 1, 242, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 254, 255, 256, 257, 259, 260, 263, 264, 265, 266, 267, 268, 275, and 276, or a pharma- ceutically acceptable form thereof.

111. 11. The compound of any one of claims 1 to 110, wherein the compound is selected from the group consisting of compounds 27, 29, 30, 31, 32, 33, 36, 43, 44, 47, 51, 52, 55, 59, 85, 96, 97, 98, 99, 116, 141, 144, 156, 203, 205, 207, 208, 209, 210, 211, 214, 219, 230, 269, 272, 273, and 274, or a pharma- ceutically acceptable form thereof.

112. 112. The compound of any one of claims 1 to 111, wherein the compound is selected from the group consisting of compounds 29, 30, 31, 32, 33, 36, 44, 47, 59, 85, 97, 98, 99, 116, 141, 144, 156, 203, 205, 207, 208, 209, 210, 211, 214, 219, 230, 269, 272, 273, and 274, or a pharma- ceutically acceptable form thereof.

113. 11. The compound of any one of claims 1 to 110, wherein the compound is selected from the group consisting of compounds 56, 63, 84, 88, 89, 90, 95, 100, 101, 103, 104, 106, 108, 109, 111, 112, 113, 114, 129, 166, 173, 179, 183, 186, 216, 241, 247, 248, 250, 255, 256, 257, and 266, or a pharma- ceutically acceptable form thereof.

114. The compound of any one of claims 1 to 113, wherein the compound is selected from the group consisting of compounds 29, 30, 32, 33, and 34, or a pharma- ceutically acceptable form thereof.

115. The compound of any one of claims 1 to 114, wherein the compound is selected from the group consisting of compounds 29, 32, 33, and 34, or a pharma- ceutically acceptable form thereof.

116. The compound according to any one of claims 1 to 115, wherein the compound is selected from the group consisting of compounds 29, 32, and 34, or a pharma- ceutically acceptable form thereof.

117. 114. The compound of any one of claims 1 to 113, wherein the compound is selected from the group consisting of compounds 1, 2, 3, 4, 6, 7, 8, 9, 11, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharma- ceutically acceptable form thereof.

118. 118. The compound of any one of claims 1-113 or 117, wherein the compound is selected from the group consisting of compounds 3, 4, 6, 7, 11, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharma- ceutically acceptable form thereof.

119. 119. The compound of any one of claims 1-113, 117, or 118, wherein the compound is selected from the group consisting of compounds 3, 6, 7, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharma- ceutically acceptable form thereof.

120. 120. The compound of any one of claims 1 to 119, wherein the compound is selected from the group consisting of compounds 29, 30, 32, 33, 34, 46, 47, 188, 196, 197, 203, 205, 207, 208, 209, 210, 212, 213, 214, 215, 217, and 220, or a pharma- ceutically acceptable form thereof.

121. The compound of any one of claims 1 to 120, wherein the compound is selected from the group consisting of compounds 29, 32, 33, 34, 46, 207, and 209, or a pharma- ceutically acceptable form thereof.

122. 120. The compound of any one of claims 1 to 119, wherein the compound is selected from the group consisting of compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, 93, and 218, or a pharma- ceutically acceptable form thereof.

123. 123. The compound of any one of claims 1-119 or 122, wherein the compound is selected from the group consisting of compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharma- ceutically acceptable form thereof.

124. 124. The compound of any one of claims 1-119, 122 or 123, wherein the compound is selected from the group consisting of compounds 1, 2, 3, 7, 8, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharma- ceutically acceptable form thereof.

125. The compounds are compounds 6, 13, 22, 26, 29, 30, 32, 33, 34, 42, 45, 46, 48, 49, 50, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 68, 72, 73, 74, 76, 78, 79, 81, 82, 83, 84, 86, 89, 91, 93, 94, 95, 96, 97, 98, 10 0, 101, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141, 142, 143, 14 4, 145, 146, 149, 156, 157, 158, 165, 169, 170, 173, 174, 175, 176, 196, 203, 209, 210, 213, 214, 217, 219, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 23 9, 240, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 255, 257, 263, 264, 265, 266, 267, 268, 269, 270, 271, 274, and 276, or a pharma- ceutically acceptable form thereof.

126. The compounds are compounds 6, 13, 22, 26, 29, 30, 32, 33, 34, 42, 48, 49, 50, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 68, 72, 73, 74, 76, 78, 79, 81, 82, 83, 84, 86, 89, 91, 93, 94, 95, 96, 97, 98, 100 , 101, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 122, 123, 124, 125, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145 , 146, 149, 156, 157, 158, 165, 169, 170, 173, 174, 175, 176, 196, 203, 209, 210, 213, 217, 219, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 24 126. The compound of any one of claims 1 to 125, selected from the group consisting of: 0, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 255, 257, 263, 264, 265, 266, 267, 268, 269, 270, 271, 274, and 276, or a pharma- ceutically acceptable form thereof.

127. The compounds are compounds 6, 13, 22, 32, 34, 48, 49, 50, 53, 54, 55, 56, 57, 58, 59, 62, 63, 64, 65, 68, 73, 74, 76, 78, 79, 81, 82, 83, 84, 86, 89, 91, 93, 94, 95, 96, 97, 98, 100, 10 1, 102, 104, 106, 107, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 122, 123, 124, 125, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144 127. The compound of claim 1, wherein the compound is selected from the group consisting of:

128. The compounds are compounds 6, 48, 49, 50, 53, 54, 55, 57, 58, 62, 63, 64, 65, 68, 73, 76, 79, 82, 84, 89, 91, 94, 95, 97, 98, 100, 102, 104, 106, 107, 110, 112, 113, 114, 115, 117, 118, 120, 122, 123, 124, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145 128. The compound of claim 1, wherein the compound is selected from the group consisting of:

129. The compounds are compounds 1, 4, 6, 13, 19, 20, 22, 23, 27, 29, 30, 31, 32, 33, 34, 40, 42, 45, 46, 67, 81, 82, 85, 86, 89, 93, 99, 104, 105, 111, 113, 143, 149, 160, 161, 163, 164, 166, 173, 175, 176, 177, 192, 193, 194, 196, 1 99, 201, 203, 204, 206, 207, 208, 209, 210, 217, 219, 238, 247, 248, 249, 250, 257, 260, 263, 264, 265, 268, 269, 270, 271, 272, 273, and 274, or a pharma- ceutically acceptable form thereof.

130. The compound of any one of claims 1 to 129, wherein the compound is selected from the group consisting of compounds 4, 23, 29, 30, 31, 32, 33, 42, 45, 46, 93, 99, 149, 166, 196, 203, 207, 209, 210, 219, 269, 270, 271, 272, 273, and 274, or a pharma- ceutically acceptable form thereof.

131. 131. The compound of any one of claims 1 to 130, wherein the compound is selected from the group consisting of compounds 53, 55, 57, 58, 84, 91, 100, 102, 116, 118, 124, 137, 141, 142, 145, 158, 221, 222, 255, and 267, or a pharma- ceutically acceptable form thereof.

132. The compound according to any one of claims 1 to 131, wherein the compound is selected from the group consisting of compounds 91, 102, 118, and 255, or a pharma- ceutically acceptable form thereof.

133. 133. The compound of any one of claims 1 to 132, wherein the compound is selected from the group consisting of compounds 6, 102, 104, 124, 126, 128, 129, 137, 141, 142, 144, 145, 156, 157, 224, 226, 227, 235, 238, 248, 255, 265, and 267, or a pharma- ceutically acceptable form thereof.

134. 134. The compound of any one of claims 1 to 133, wherein the compound is selected from the group consisting of compounds 6, 58, 84, 100, 102, 104, 124, 221, 222, 235, 238, 252, 255, and 267, or a pharma- ceutically acceptable form thereof.

135. 135. The compound of any one of claims 1 to 134, wherein the pharma- ceutically acceptable form of the compound is an isomer, an isotopic variant, a pharma- ceutically acceptable salt, a polymorph, or a solvate of the compound.

136. The compound of any one of claims 1 to 134, wherein the pharma- ceutically acceptable form of the compound excludes a salt form.

137. The compound of any one of claims 1 to 136, wherein the isomer of the compound is a diastereomer or an enantiomer of the compound.

138. The compound according to any one of claims 1 to 137, wherein the compound is a tautomer of the compound.

139. The compound according to any one of claims 1 to 138, wherein the compound is a racemate or a mixture of diastereomers.

140. The compound of any one of claims 1 to 138, wherein the compound is a single enantiomer or a single diastereomer.

141. 141. The compound of claim 140, wherein the compound is the (R)-enantiomer.

142. 142. The compound of claim 140 or claim 141, wherein the compound has an enantiomeric excess of greater than 10% of the (R)-enantiomer.

143. 143. The compound of any one of claims 140-142, wherein the compound has an enantiomeric excess of the (R)-enantiomer 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.

144. 144. The compound of any one of claims 140-143, 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.

145. 141. The compound of claim 140, wherein the compound is the (S)-enantiomer.

146. The compound of claim 140 or claim 145, wherein the compound has an enantiomeric excess of greater than 10% of the (S)-enantiomer.

147. 147. The compound of any one of claims 140, 145, or 146, wherein the compound has an enantiomeric excess of the (S)-enantiomer 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.

148. 148. The compound of any one of claims 140 or 145-147, 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.

149. The compound of any one of claims 1 to 148, wherein the compound, or a pharma- ceutically acceptable form thereof, is a modulator of Ras superfamily activity according to a Ras superfamily activity assay.

150. The compound of claim 149, wherein the compound or a pharma- ceutically acceptable form thereof modulates the Ras superfamily activity of one or more GTPases 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.

151. The compound of any one of claims 1 to 150, wherein the compound or a pharma- ceutically acceptable form thereof inhibits phosphorylation of Erk1 / 2 according to an Erk1 / 2 phosphorylation assay.

152. The compound of claim 151, wherein the compound or a pharma- ceutically 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 an Erk1 / 2 phosphorylation assay.

153. The compound according to any one of claims 1 to 150, wherein the compound or a pharma- ceutically acceptable form thereof activates phosphorylation of Erk1 / 2 according to an Erk1 / 2 phosphorylation assay.

154. The compound of claim 153, wherein the compound or a pharma- ceutically 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 100% or more at 10 μM according to an Erk1 / 2 phosphorylation assay.

155. The compound of any one of claims 1 to 154, wherein the compound or a pharma- ceutically acceptable form thereof inhibits phosphorylation of Akt according to an Akt phosphorylation assay.

156. The compound of claim 155, wherein the compound or a pharma- ceutically 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 an Akt phosphorylation assay.

157. The compound of any one of claims 1 to 154, wherein the compound or a pharma- ceutically acceptable form thereof activates phosphorylation of Akt according to an Akt phosphorylation assay.

158. The compound of claim 157, wherein the compound or a pharma- ceutically 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 100% or more at 10 μM according to an Akt phosphorylation assay.

159. The compound of any one of claims 1 to 158, wherein the compound or a pharma- ceutically acceptable form thereof inhibits phosphorylation of Smad2 / 3 according to a Phospho-Smad2 / 3 inhibition assay.

160. 160. The compound of claim 159, wherein the compound or a pharma- ceutically 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 a Phospho-Smad2 / 3 inhibition assay.

161. The compound according to any one of claims 1 to 158, wherein the compound or a pharma- ceutically acceptable form thereof activates phosphorylation of Smad2 / 3 according to a Phospho-Smad2 / 3 inhibition assay.

162. 162. The compound of claim 161, wherein the compound or a pharma- ceutically 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 100% or more at 10 μM according to a Phospho-Smad2 / 3 inhibition assay.

163. The compound of any one of claims 1 to 162, wherein the compound or a pharma- ceutically acceptable form thereof inhibits JNK according to a JNK activation assay.

164. The compound of claim 163, wherein the compound or a pharma- ceutically acceptable form thereof inhibits JNK by 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, or 95% or more at 10 μM according to a JNK activation assay.

165. The compound of any one of claims 1 to 162, wherein the compound or a pharma- ceutically acceptable form thereof activates JNK according to a JNK activation assay.

166. The compound of claim 165, wherein the compound or a pharma- ceutically acceptable form thereof activates JNK by 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, or 100% or more at 10 μM according to a JNK activation assay.

167. The compound of any one of claims 1 to 166, wherein the compound or a pharma- ceutically acceptable form thereof inhibits MAPK p38 according to a MAPK p38 activation assay.

168. The compound of claim 167, wherein the compound or a pharma- ceutically acceptable form thereof inhibits MAPK p38 by 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, or 95% or more at 10 μM according to a MAPK p38 activation assay.

169. The compound of any one of claims 1 to 166, wherein the compound, or a pharma- ceutically acceptable form thereof, activates MAPK p38 according to a MAPK p38 activation assay.

170. The compound of claim 169, wherein the compound or a pharma- ceutically acceptable form thereof activates MAPK p38 by 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, or 100% or more at 10 μM according to a MAPK p38 activation assay.

171. The compound of any one of claims 1 to 170, wherein the compound or a pharma- ceutically acceptable form thereof inhibits proliferation of MiaPaca2 according to a proliferation assay.

172. The compound, or a pharma- ceutically acceptable form thereof, inhibits MiaPaca2 proliferation according to a proliferation assay with an IC ５０ The compound described in claim 171, which inhibits at a value.

173. The compound of any one of claims 1 to 172, wherein the compound or a pharma- ceutically acceptable form thereof inhibits IL-6 according to an IL-6 quantification assay.

174. 174. The compound of claim 173, wherein the compound or a pharma- ceutically 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 an IL-6 quantification assay.

175. The compound of any one of claims 1 to 174, wherein the compound or a pharma- ceutically acceptable form thereof inhibits TNF-alpha according to a TNF-alpha quantification assay.

176. The compound of claim 175, wherein the compound or a pharma- ceutically 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 a TNF-alpha quantification assay.

177. 177. The compound of any one of claims 1 to 176, wherein the compound or a pharma- ceutically acceptable form thereof has a half-life in mouse liver microsomes of 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, or 50 minutes or more according to a mouse liver microsomal metabolic stability assay.

178. 178. The compound of any one of claims 1-177, wherein the compound or a pharma- ceutically 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 containing 2% DMSO according to a kinetic solubility assay.

179. The compound of any one of claims 1 to 178, wherein the compound or a pharma- ceutically acceptable form thereof inhibits proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 according to a proliferation assay.

180. The compound, or a pharma- ceutically acceptable form thereof, has an IC50 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 a proliferation assay for NCI-H358, A375, GP2d, BT549, or MM.R1. ５０ The compound described in claim 179, which inhibits at a value.

181. The compound, or a pharma- ceutically acceptable form thereof, inhibits proliferation of MM.R1 according to a proliferation assay with an IC ５０ The compound described in claim 180, which inhibits at a value.

182. 182. A pharmaceutical composition comprising a compound according to any one of claims 1 to 181, or a pharma- ceutically acceptable form thereof, and a pharma- ceutically acceptable carrier, excipient or diluent.

183. 182. A method of modulating a Ras superfamily protein, comprising contacting said Ras superfamily protein with an effective amount of a compound according to any one of claims 1 to 181, or a pharma- ceutically acceptable form thereof.

184. 183. A method for modulating a Ras superfamily protein, comprising contacting the Ras superfamily protein with an effective amount of the pharmaceutical composition of claim 182.

185. The method of claim 183 or claim 184, wherein the Ras superfamily protein is present in a cell.

186. The method of any one of claims 183 to 185, wherein the method inhibits a Ras superfamily protein.

187. The method according to any one of claims 183 to 186, wherein the Ras superfamily protein is a Ras protein, or a mutant thereof.

188. The method of claim 187, 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.

189. The method of claim 187 or claim 188, wherein the Ras protein is HRAS; KRAS; or NRAS, or a mutant thereof.

190. The method of any one of claims 187 to 189, wherein the Ras protein is a KRAS mutant.

191. 191. The method of claim 190, wherein the KRAS mutant is a KRas G12D mutant, a KRas G12C mutant, or a KRas Q61H mutant.

192. The method of any one of claims 187 to 189, wherein the Ras protein is HRAS or a mutant thereof.

193. The method of any one of claims 187 to 189, wherein the Ras protein is NRAS or a mutant thereof.

194. The method according to any one of claims 183 to 186, wherein the Ras superfamily protein is a Rac protein or a mutant thereof.

195. 195. The method of claim 194, wherein the Rac protein is RAC1; RAC2; RAC3; RHOG, or a mutant thereof.

196. The method of claim 194 or claim 195, wherein the Rac protein is wild-type RAC1.

197. The method according to any one of claims 183 to 186, wherein the Ras superfamily protein is a Rho protein or a mutant thereof.

198. The method of claim 197, 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.

199. The method of claim 197 or claim 198, wherein the Rho protein is wild-type RHOA.

200. The method of any one of claims 183 to 186, wherein the Ras superfamily protein is a Cdc42 protein, or a mutant thereof.

201. The method of any one of claims 183 to 186, wherein the Ras superfamily protein is a Rheb protein, or a mutant thereof.

202. The method of any one of claims 183 to 201, wherein the contacting of the Ras superfamily protein is performed in a cell.

203. The method of claim 202, wherein the cell is in a subject.

204. The method of claim 202 or claim 203, wherein the cell is a mammalian cell.

205. The method of any one of claims 202 to 204, wherein the cell is a human cell.

206. The method of any one of claims 203 to 205, wherein the subject is suffering from cancer.

207. The method of any one of claims 183 to 206, wherein the modulation is performed in a subject suffering from cancer.

208. The method of claim 206 or claim 207, wherein the cancer is a solid tumor or a blood-borne tumor (or blood cancer).

209. The method of any one of claims 206 to 208, wherein the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrial cancer, skin cancer (melanoma), cervical cancer, urinary tract cancer, glioblastoma, or multiple myeloma.

210. 210. The method of claim 209, wherein the cancer is pancreatic cancer.

211. 210. The method of claim 209, wherein the cancer is colon cancer.

212. 210. The method of claim 209, wherein the cancer is triple negative breast cancer.

213. 210. The method of claim 209, wherein the cancer is multiple myeloma.

214. The method according to any one of claims 206 to 213, wherein the cancer is a cancer dependent on a Ras superfamily protein.

215. The method of any one of claims 202 to 214, wherein the subject is a human.

216. 182. A method of modulating caspase activity comprising contacting said caspase with an effective amount of a compound according to any one of claims 1-181, or a pharma- ceutically acceptable form thereof.

217. A method for modulating caspase activity, comprising contacting the caspase with an effective amount of the pharmaceutical composition of claim 182.

218. The method of claim 216 or claim 217, wherein the method activates the caspase.

219. The method of any one of claims 216 to 218, wherein the caspase is caspase 3, caspase 6, or caspase 9.

220. The method of any one of claims 216 to 219, wherein the contacting of the caspase is performed in a cell.

221. The method of claim 220, wherein the regulated caspase activity induces apoptosis of the cell.

222. The method of claim 220 or 221, wherein the cell is in a subject.

223. The method of any one of claims 220 to 222, wherein the cell is a mammalian cell.

224. The method of any one of claims 220 to 223, wherein the cell is a human cell.

225. The method of any one of claims 220 to 224, wherein the subject is suffering from cancer.

226. The method of any one of claims 216 to 225, wherein the modulation is performed in a subject suffering from cancer.

227. The method of claim 225 or claim 226, wherein the cancer is a solid tumor or is a blood-borne tumor (or blood cancer).

228. The method of any one of claims 225 to 227, wherein the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrial cancer, skin cancer (melanoma), cervical cancer, urinary tract cancer, glioblastoma, or multiple myeloma.

229. 229. The method of claim 228, wherein the cancer is pancreatic cancer.

230. 229. The method of claim 228, wherein the cancer is colon cancer.

231. 229. The method of claim 228, wherein the cancer is triple negative breast cancer.

232. The method of claim 228, wherein the cancer is multiple myeloma.

233. The method of any one of claims 222 to 232, wherein the subject is a human.

234. 20. A method of treating cancer in a subject, comprising administering to the subject having cancer a therapeutically effective amount of a compound according to any one of claims 1-181, or a pharma- ceutically acceptable form thereof.

235. 183. A method of treating cancer in a subject, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 182 to the subject having cancer.

236. The method of claim 234 or claim 235, wherein the cancer is a solid tumor or is a blood-borne tumor (or blood cancer).

237. The method of any one of claims 234 to 236, wherein the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrial cancer, skin cancer (melanoma), cervical cancer, urinary tract cancer, glioblastoma, or multiple myeloma.

238. 238. The method of claim 237, wherein the cancer is pancreatic cancer.

239. 238. The method of claim 237, wherein the cancer is colon cancer.

240. 238. The method of claim 237, wherein the cancer is triple negative breast cancer.

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

242. The method of any one of claims 234 to 241, wherein the cancer is a cancer dependent on a Ras superfamily protein.

243. 243. The method of claim 242, wherein the Ras superfamily protein is a Ras protein, or a mutant thereof.

244. The method of claim 243, 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.

245. 245. The method of claim 244, wherein the Ras protein is HRAS; KRAS; or NRAS, or a mutant thereof.

246. 246. The method of claim 245, wherein the Ras protein is a KRAS mutant.

247. 247. The method of claim 246, wherein the KRAS mutant is a KRas G12D mutant, a KRas G12C mutant, or a KRas Q61H mutant.

248. 246. The method of claim 245, wherein the Ras protein is HRAS or a mutant thereof.

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

250. 243. The method of claim 242, wherein the Ras superfamily protein is a Rac protein, or a mutant thereof.

251. The method of claim 250, wherein the Rac protein is RAC1; RAC2; RAC3; RHOG, or a mutant thereof.

252. The method of claim 251, wherein the Rac protein is wild-type RAC1.

253. 243. The method of claim 242, wherein the Ras superfamily protein is a Rho protein, or a mutant thereof.

254. The method of claim 253, 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.

255. 255. The method of claim 254, wherein the Rho protein is wild-type RHOA.

256. 243. The method of claim 242, wherein the Ras superfamily protein is a Cdc42 protein, or a mutant thereof.

257. 243. The method of claim 242, wherein the Ras superfamily protein is a Rheb protein, or a mutant thereof.

258. The method of any one of claims 234 to 240, wherein said administering activates caspase activity in cancer cells of the subject.

259. The method of claim 258, wherein the activation induces apoptosis of the cancer cell.

260. The method of any one of claims 234 to 259, wherein the subject is a human.

261. 182. A method of modulating Erk1 / 2 activity, comprising contacting Erk1 / 2 protein with an effective amount of a compound according to any one of claims 1-181, or a pharma- ceutically acceptable form thereof.

262. 183. A method for modulating Erk1 / 2 activity, comprising contacting Erk1 / 2 protein with an effective amount of the pharmaceutical composition of claim 182.

263. The method of claim 261 or claim 262, wherein the method inhibits phosphorylation of the Erk1 / 2 protein.

264. The method of claim 261 or claim 262, wherein the method activates phosphorylation of the Erk1 / 2 protein.

265. 182. A method of modulating Akt activity, comprising contacting an Akt protein with an effective amount of a compound according to any one of claims 1-181, or a pharma- ceutically acceptable form thereof.

266. A method for modulating Akt activity, comprising contacting an Akt protein with an effective amount of the pharmaceutical composition of claim 182.

267. The method of claim 265 or claim 266, wherein the method inhibits phosphorylation of the Akt protein.

268. The method of claim 265 or claim 266, wherein the method activates phosphorylation of the Akt protein.

269. 182. A method of modulating Smad2 / 3 activity, comprising contacting a Smad2 / 3 protein with an effective amount of a compound of any one of claims 1-181, or a pharma- ceutically acceptable form thereof.

270. 183. A method for modulating Smad2 / 3 activity, comprising contacting a Smad2 / 3 protein with an effective amount of the pharmaceutical composition of claim 182.

271. The method of claim 269 or claim 270, wherein the method inhibits phosphorylation of the Smad2 / 3 protein.

272. The method of claim 269 or claim 270, wherein the method activates phosphorylation of the Smad2 / 3 protein.

273. 182. A method of modulating JNK activity, comprising contacting a JNK protein with an effective amount of a compound according to any one of claims 1-181, or a pharma- ceutically acceptable form thereof.

274. 183. A method of modulating JNK activity comprising contacting a JNK protein with an effective amount of the pharmaceutical composition of claim 182.

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

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

277. 182. A method of modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of a compound according to any one of claims 1-181, or a pharma- ceutically acceptable form thereof.

278. 183. A method of modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of the pharmaceutical composition of claim 182.

279. The method of claim 277 or claim 278, wherein the method inhibits phosphorylation of the MAPK p38 protein.

280. The method of claim 277 or claim 278, wherein the method activates phosphorylation of the MAPK p38 protein.

281. 182. A method of modulating IL-6 activity, comprising contacting an IL-6 protein with an effective amount of a compound according to any one of claims 1 to 181, or a pharma- ceutically acceptable form thereof.

282. 183. A method for modulating IL-6 activity, comprising contacting an IL-6 protein with an effective amount of the pharmaceutical composition of claim 182.

283. The method of claim 281 or claim 282, wherein the method inhibits IL-6 activity.

284. 182. A method of modulating TNF-alpha activity, comprising contacting a TNF-alpha protein with an effective amount of a compound according to any one of claims 1 to 181, or a pharma- ceutically acceptable form thereof.

285. 183. A method of modulating TNF-alpha activity comprising contacting a TNF-alpha protein with an effective amount of the pharmaceutical composition of claim 182.

286. The method of claim 284 or claim 285, wherein the method inhibits TNF-alpha activity.

287. 20. A method of treating a fibrotic disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 181, or a pharma- ceutically acceptable form thereof.

288. 183. A method of treating a fibrotic disease in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 182.

289. 20. A method of treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 181, or a pharma- ceutically acceptable form thereof.

290. 183. A method for treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 182.

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