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

Abstract

Provided herein are compounds of Formula I, or pharmaceutically acceptable forms thereof, and pharmaceutical compositions comprising them. 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 pharmaceutically acceptable form thereof. Further provided herein are methods of treating cancer, fibrotic diseases, and inflammatory diseases by administering a compound, or a pharmaceutically acceptable form thereof, to a subject. # imgabs0 #

Description

[0001] Cross-references

[0002] This application claims priority to 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. The entire contents of each of the foregoing related applications are incorporated herein by reference. 1. Technical Field

[0003] This document provides compounds of Formula I or their pharmaceutically acceptable forms, and pharmaceutical compositions comprising them. This document also provides methods for modulating the activity of cellular targets by administering a compound of Formula I or its pharmaceutically acceptable form to a subject. This document further provides methods for treating cancer, fibrotic diseases, and inflammatory diseases by administering a compound of Formula I or its pharmaceutically acceptable form to a subject. 2. Summary of the Invention

[0004] This article provides a compound of formula I:

[0005]

[0006] Or in its pharmaceutically acceptable form, wherein:

[0007] X is -NR 1A R 2A OR 2A ;

[0008] Y is an imidazolyl, pyridinyl, or an 8-10 membered fused heteroaryl group; wherein

[0009] The imidazole group is optionally surrounded by one R 6A Substituents are substituted and optionally replaced by 1-2 R groups. 7A Substituent substitution; and

[0010] The pyridyl group or the 8-10 fused heteroaryl group is optionally surrounded by 1-4 R groups. 7A Substituent substitution;

[0011] R 1A is hydrogen or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups are optionally surrounded by 1-4 Rs 8A Substituent substitution;

[0012] R 2A It is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, C 3-7 Heterocyclic alkyl, C 5-10 Yuanfangji, -S(O)2R15A -p(O)R 16A R 17A Or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-10-membered heteroaryl groups are each independently and optionally bound by 1-4 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A Substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group comprising one or more atoms attached to it; or R 1A and R 2A Combining to form 3-6 membered heterocyclic alkyl groups, each of which is attached to a nitrogen atom, wherein R 1A and R 2A The 3-6 membered heterocyclic alkyl group formed is fused with a 5-6 membered heteroaryl group;

[0013] R 3A It 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 Wherein C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, aryl, and 5-10-membered heteroaryl groups are each independently and optionally bounded by 1-3 R groups. 9A Substituent substitution;

[0014] R 4A It is hydrogen, aryl, or 5-10 heteroaryl, wherein the aryl and 5-10 heteroaryl groups are each optionally independently bound by 1-4 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0015] R 5A is hydrogen or C 1-6 alkyl;

[0016] R 6A and R 7A Each is independently C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, aryl, C 5-10 heteroaryl, C 3-7 Heterocyclic alkyl, C 1-6 Heteroalkyl, halogen, -NR12A 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, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, aryl, C 5-10 heteroaryl, C 3-7 Heterocyclic alkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0017] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -NR 12A R 13A -(CO)R 11A -C(O)OR 14A -C(O)NR 12A R 13A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, 5-6 membered heteroaryl, biotinamide or biotinylated substituent;

[0018] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6Heteroalkyl, 3-6 membered heterocyclic alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Halogenated alkoxy groups or 5-6 heteroaryl groups are each optionally and independently bound by 1-3 R groups. 8A Substituent substitution;

[0019] R 11A It is -OH, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0020] R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Heterocyclic alkyl, aryl, or 5-10-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Heterocyclic alkyl groups, aryl groups, and 5-10-membered heteroaryl groups are optionally surrounded by 1-3 R groups. 8A Substituent substitution, or R 12A and R 13A They combine to form 3-7 membered heterocyclic alkyl groups, each of which has a nitrogen atom attached to it.

[0021] R 14A It is hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0022] R 15A It is C1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0023] R 16A and R 17A Each was independently selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution, or R 16A and R 17A The combination forms 3-7 membered heterocyclic alkyl groups, each of which is attached to a phosphorus atom; and

[0024] Where X is OH or Y is an N-methylimidazolium group, and R 5A When it is H, R 3A and R 4A At least one of them is not an unsubstituted phenyl group.

[0025] This article also provides a compound of formula II:

[0026]

[0027] Or in its pharmaceutically acceptable form, wherein:

[0028] X is -NR 1A R 2A OR 2A ;

[0029] R 1A is hydrogen or C 1-6 alkyl;

[0030] R 2A It is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, -S(O)2R 15A -P(O)R 16A R 17A Or 5-6 heteroaryl, wherein C 1-6 Alkyl, C3-6 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A Substituents combine to form 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl groups, each with one or more atoms attached; or R 1A and R 2A Combining to form 3-6 membered heterocyclic alkyl groups comprising nitrogen atoms to which they are all attached, optionally wherein R 1A and R 2A The 3-6 membered heterocyclic alkyl group formed is fused with a 5-6 membered heteroaryl group;

[0031] R 3A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl, 5-10 heteroaryl, -(CO)R 11A or -C(O)NR 12A R 13A Wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0032] R 4A It is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0033] R 5A It is hydrogen;

[0034] R 6A and R 7A Each is independently C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0035] R 8A and R9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -NR 12A R 13A -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, 5-6 membered heteroaryl, biotinamide or biotinylated substituent;

[0036] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Halogenated alkoxy groups or 5-6 heteroaryl groups are each optionally and independently bound by 1-3 R groups. 8A Substituent substitution;

[0037] R 11A It is C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0038] R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, or R 12A and R 13A They combine to form 3-6 membered heterocyclic alkyl groups, each of which has a nitrogen atom attached to it.

[0039] R 15A It is C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0040] R 16A and R 17A Each was independently selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution, or R 16A and R 17A The combination forms 3-7 membered heterocyclic alkyl groups, each of which is attached to a phosphorus atom;

[0041] m is 0, 1, or 2; and

[0042] Where X is OH or Y is an N-methylimidazolium group, and R 5A When it is H, R 3A and R 4A At least one of them is not an unsubstituted phenyl group.

[0043] This article also provides a compound of formula IIa:

[0044]

[0045] Or in its pharmaceutically acceptable form, wherein:

[0046] R 1A It is hydrogen;

[0047] R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C1-6 Heteroalkyl, -S(O)2R 15A Or 5-6 heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0048] R 3A It is C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl, 5-membered, 6-membered or 9-membered heteroaryl, -(CO)R 11A or -C(O)NR 12A R 13A Wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl, and 5-, 6-, or 9-membered heteroaryl groups are each independently and optionally bounded by 1-3 R groups. 9A Substituent substitution;

[0049] R 4A It is hydrogen, phenyl, or a 5-, 6-, or 9-membered heteroaryl group, wherein the phenyl and the 5-, 6-, or 9-membered heteroaryl group are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0050] R 5A It is hydrogen;

[0051] R 6A It is C 1-3 Alkyl or C 1-3 Heteroalkyl, wherein the C 1-3 Alkyl or C 1-3 The heteroalkyl group may optionally be replaced by biotinamide;

[0052] R 7A It is methyl;

[0053] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -NR 12A R 13A -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, 5-6 membered heteroaryl, biotinamide or biotinylated substituent;

[0054] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 11A R 12A Or 5-6 heteroaryl, wherein C 1-6 Alkyl or C 1-6 The heteroalkyl group may optionally be replaced by biotinamide;

[0055] R 11A It is C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0056] R 12A and R 13A are each independently selected from 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 Combining to form 5- or 6-membered heterocyclic alkyl groups, each of which is attached to a nitrogen atom;

[0057] R 15A It is C 1-3 Alkyl, C 3-6 cycloalkyl or C 1-4 Heteroalkyl;

[0058] R 16A and R17A Each was independently selected from C 1-3 Alkyl or C 1-3 alkoxy, or R 16A and R 17A The combination forms a 5-membered heterocyclic alkyl group, in which phosphorus atoms are all attached; and

[0059] m is 0 or 1.

[0060] This article also provides a compound of formula IIa(1):

[0061]

[0062] Or in its pharmaceutically acceptable form, wherein:

[0063] R 1A It is hydrogen;

[0064] R 2A It is a 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered heteroaryl group is optionally surrounded by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0065] R 8A Selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -NR 12A R 13A -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, 5-6 membered heteroaryl, biotinamide or biotinylated substituent;

[0066] R 11A It is C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0067] R 12A and R 13A are each independently selected from hydrogen, C1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy, or R i2A and R 13A The combination forms 5- or 6-membered heterocyclic alkyl groups, each of which is attached to a nitrogen atom; and

[0068] R 18A It is C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0069] This article also provides a compound of formula IIb:

[0070]

[0071] Or in its pharmaceutically acceptable form, wherein:

[0072] R 1A and R 2A Combining to form 4-6 membered heterocyclic alkyl groups comprising nitrogen atoms to which they are all attached, optionally wherein R 1A and R 2A The 4-6 membered heterocyclic alkyl group formed is fused with a 6 membered heteroaryl group;

[0073] R 3A It is C 1-3 alkyl or phenyl, wherein the C 1-3 Alkyl and phenyl groups are each independently and optionally marked with 1-3 R groups. 9A Substituent substitution;

[0074] R 4A It is a phenyl or a 5-membered heteroaryl group, wherein the phenyl and the 5-membered heteroaryl group are each optionally independently bound by 1-3 R groups. i0A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0075] R 5A It is hydrogen;

[0076] R 6A It is methyl;

[0077] R 7A It is methyl;

[0078] R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0079] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0080] R 11A It is C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0081] R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 Alkoxy;

[0082] m is 0 or 1; and

[0083] Where R 1A and R 2A Combination R 6A It is a methyl group, m is 0, and R SA When it is H, R 3A and R 4A At least one of them is not an unsubstituted phenyl group.

[0084] This article also provides a compound of formula IIc:

[0085]

[0086]

[0087] Or in its pharmaceutically acceptable form, wherein:

[0088] R 2A It is hydrogen, C 1-6 Heteroalkyl or 6-membered heteroaryl, wherein the C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each optionally surrounded by 1-3 R groups. 8A Substituent substitution;

[0089] R 3A It is C 1-3 alkyl or phenyl, wherein the C 1-3 Alkyl or phenyl groups are each optionally independently bound by 1-3 R groups. 9A Substituent substitution;

[0090] R 4A It is hydrogen, phenyl, or a 5- or 6-membered heteroaryl group, wherein the phenyl and the 5- or 6-membered heteroaryl group are each optionally independently bound by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0091] R 5A It is hydrogen;

[0092] R 6A It is methyl;

[0093] R 7A It is methyl;

[0094] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0095] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0096] R 11A It is C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0097] R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 Alkoxy;

[0098] m is 0 or 1; and

[0099] Where R 2A It's H, R 6A It is a methyl group, m is 0, and R SA When it is H, R 3A and R 4A At least one of them is not an unsubstituted phenyl group.

[0100] This article also provides a compound of formula III:

[0101]

[0102] Or in its pharmaceutically acceptable form, wherein:

[0103] X is NR 1A R 2A OR 2A ;

[0104] R 1A is hydrogen or C 1-6 alkyl;

[0105] R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 5-6-membered heteroaryl, wherein the C1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A Substituents combine to form 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl groups, each with one or more atoms attached; or R 1A and R 2A They combine to form 3-6 membered heterocyclic alkyl groups, each of which has a nitrogen atom attached to it.

[0106] R 3A It is C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0107] R 4A It is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0108] R 5A is hydrogen or C 1-6 alkyl;

[0109] R 6A and R 7A Each is independently C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0110] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0111] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0112] R 11A It is C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0113] R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy groups; and

[0114] m can be 0, 1, or 2.

[0115] This article also provides a compound of formula IIIa:

[0116]

[0117]

[0118] Or in its pharmaceutically acceptable form, wherein:

[0119] R 1A It is hydrogen;

[0120] R 2A It is hydrogen, C 1-6 Alkyl, C3-6 Cycloalkyl, C 1-6 Heteroalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0121] R 3A It is C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0122] R 4A It is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0123] R 5A is hydrogen or C 1-6 alkyl;

[0124] R 6A and R 7A Each is independently C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0125] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0126] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0127] R 11A It is C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0128] R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy groups; and

[0129] m can be 0, 1, or 2.

[0130] This article also provides a compound of formula IIIb:

[0131]

[0132] Or in its pharmaceutically acceptable form, wherein:

[0133] R 1A and R 2A They combine to form 4-6 membered heterocyclic alkyl groups, each of which has a nitrogen atom attached to it.

[0134] R 3A It is C 1-6 Alkyl, C1-6 Heteroalkyl, phenyl, or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0135] R 4A It is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0136] R 5A is hydrogen or C 1-6 alkyl;

[0137] R 6A and R 7A Each is independently C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0138] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0139] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0140] R 11A It is C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0141] R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy groups; and

[0142] m can be 0, 1, or 2.

[0143] This article also provides a compound of formula IIIc:

[0144]

[0145] Or in its pharmaceutically acceptable form, wherein:

[0146] R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution;

[0147] R 3A It is C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0148] R 4AIt is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0149] R SA is hydrogen or C 1-6 alkyl;

[0150] R 6A and R 7A Each is independently C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0151] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0152] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0153] R 11A It is C 1-6 Alkyl, C3-6 cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0154] R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy groups; and

[0155] m can be 0, 1, or 2.

[0156] This article also provides a compound of formula IV:

[0157]

[0158] Or in its pharmaceutically acceptable form, wherein:

[0159] X is -NR 1A R 2A OR 2A ;

[0160] R 1A is hydrogen or C 1-6 alkyl;

[0161] R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A Substituents combine to form 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl groups, each with one or more atoms attached; or R 1A and R 2A They combine to form 3-6 membered heterocyclic alkyl groups, each of which has a nitrogen atom attached to it.

[0162] R 3A It is C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0163] R 4A It is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0164] R 5A is hydrogen or C 1-6 alkyl;

[0165] R 7A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, aryl, C 5-10 heteroaryl, C 3-7 Heterocyclic alkyl, C 1-6 Heteroalkyl, halogen, -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, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, aryl, C s-10 heteroaryl, C 3-7 Heterocyclic alkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0166] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0167] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0168] R 11A It is C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0169] R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy groups; and

[0170] m can be 0, 1, 2, 3, or 4.

[0171] This article also provides a compound of formula IVa:

[0172]

[0173] Or in its pharmaceutically acceptable form, wherein:

[0174] R 1A It is hydrogen;

[0175] R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 The heteroalkyl and 6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups.8A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0176] R 3A It is C 1-6 alkyl or phenyl, wherein the C 1-6 Alkyl and phenyl groups are each independently and optionally marked with 1-3 R groups. 9A Substituent substitution;

[0177] R 4A It is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0178] R 5A It is hydrogen;

[0179] R 7A It is methyl;

[0180] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0181] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0182] R 11A It is C 1-6 Alkyl, C 3-6 cycloalkyl or C 1-6Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0183] R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy groups; and

[0184] m can be 0, 1, 2, 3, or 4.

[0185] This article also provides a compound of formula IVb:

[0186]

[0187] Or in its pharmaceutically acceptable form, wherein:

[0188] R 1A and R 2A They combine to form 4-6 membered heterocyclic alkyl groups, each of which has a nitrogen atom attached to it.

[0189] R 3A It is C 1-6 alkyl or phenyl, wherein the C 1-6 Alkyl and phenyl groups are each independently and optionally marked with 1-3 R groups. 9A Substituent substitution;

[0190] R 4A It is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0191] R 5A It is hydrogen;

[0192] R 7A It is methyl;

[0193] R SA and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0194] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0195] R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0196] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy; and

[0197] m can be 0, 1, 2, 3, or 4.

[0198] This article also provides a compound of formula IVc:

[0199]

[0200] Or in a pharmaceutically acceptable form, wherein:

[0201] R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution;

[0202] R 3A It is C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0203] R 4A It is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0204] R 5A It is hydrogen;

[0205] R 7A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0206] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0207] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0208] R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0209] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy; and

[0210] m can be 0, 1, 2, 3, or 4.

[0211] This document also provides compounds of formulas I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, selected from 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, 5 9, 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, 1 63, 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, 19 4, 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, 256257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275 and 276, or their pharmaceutically acceptable forms.

[0212] This document also provides compounds of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or their pharmaceutically acceptable forms, wherein, according to a Ras superfamily activity assay, the compound is a modulator of Ras superfamily activity. In one embodiment, according to a Ras superfamily activity assay, the compound or its pharmaceutically acceptable form 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. In one embodiment, the compound or its pharmaceutically acceptable form 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.

[0213] This document also provides 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, wherein the compound inhibits the phosphorylation of Erk1 / 2 according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form inhibits the 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, according to an Erk1 / 2 phosphorylation assay. In one embodiment, based on an Erk1 / 2 phosphorylation assay, the compound or its pharmaceutically acceptable form inhibits the 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.

[0214] This document also provides compounds of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or their pharmaceutically acceptable forms, wherein the compound activates the phosphorylation of Erk1 / 2 according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal to or greater than 100% at 10 μM according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the 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, based on an Erk1 / 2 phosphorylation assay.

[0215] This document also provides compounds of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or their pharmaceutically acceptable forms, wherein, according to an Akt phosphorylation assay, the compound inhibits the phosphorylation of Akt. In one embodiment, according to an Akt phosphorylation assay, the compound or its pharmaceutically acceptable form inhibits the 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. In one embodiment, according to an Akt phosphorylation assay, the compound or its pharmaceutically acceptable form inhibits the 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% of the phosphorylation of Akt.

[0216] This document also provides compounds of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or their pharmaceutically acceptable forms, wherein the compound activates the phosphorylation of Akt according to an Akt phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal to or greater than 100% at 10 μM, according to an Akt phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 μM, according to an Akt phosphorylation assay.

[0217] This document also provides 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, wherein the compounds inhibit the phosphorylation of Smad2 / 3 according to a phosphate-Smad2 / 3 inhibition assay. In one embodiment, the compound or its pharmaceutically acceptable form inhibits the 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 phosphate-Smad2 / 3 inhibition assay. In one embodiment, based on a phosphoric acid-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form inhibits the 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.

[0218] This document also provides compounds of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or their pharmaceutically acceptable forms, which, according to a phosphate-Smad2 / 3 inhibition assay, activate the phosphorylation of Smad2 / 3. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal to or greater than 100% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form activates the 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 phosphorylated Smad2 / 3 inhibition assay.

[0219] This document also provides 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, wherein the compounds inhibit JNK according to a JNK activation assay. In one embodiment, the compound or its pharmaceutically acceptable form 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, according to a JNK activation assay. In one embodiment, the compound or its pharmaceutically acceptable form 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.

[0220] This document also provides compounds of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or their pharmaceutically acceptable forms, wherein the compound activates JNK according to a JNK activation assay. In one embodiment, the compound or its pharmaceutically acceptable form 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 equal to or greater than 100%. In one embodiment, the compound or its pharmaceutically acceptable form activates JNK by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 μM, according to a JNK activation assay.

[0221] This document also provides compounds of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or their pharmaceutically acceptable forms, wherein the compounds inhibit MAPK p38 according to a MAPK p38 activation assay. In one embodiment, the compound or its pharmaceutically acceptable form inhibits 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, or 95% or more, according to a MAPK p38 activation assay. In one embodiment, based on a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form 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.

[0222] This document also provides compounds of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or their pharmaceutically acceptable forms, wherein the compound activates MAPK p38 according to a MAPK p38 activation assay. In one embodiment, the compound or its pharmaceutically acceptable form 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 equal to or greater than 100%. In one embodiment, the compound or its pharmaceutically acceptable form 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.

[0223] This document also provides compounds of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or their pharmaceutically acceptable forms, wherein, according to a proliferation assay, the compound inhibits the proliferation of MiaPaca2. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of 1 μM or less, 0.9 μM or less, 0.8 μM or less, 0.75 μM or less, 0.7 μM or less, 0.6 μM or less, 0.5 μM or less, 0.4 μM or less, 0.3 μM or less, 0.25 μM or less, 0.2 μM or less, 0.15 μM or less, or 0.1 μM or less.

[0224] This document also provides compounds of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or their pharmaceutically acceptable forms, wherein the compound inhibits IL-6 as determined by IL-6 quantification. In one embodiment, the compound or its pharmaceutically acceptable form 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, as determined by IL-6 quantification. In another embodiment, the compound or its pharmaceutically acceptable form 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, as determined by IL-6 quantification.

[0225] This document also provides compounds of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or their pharmaceutically acceptable forms, wherein the compounds inhibit TNF-α according to a TNF-α quantification. In one embodiment, the compound or its pharmaceutically acceptable form inhibits TNF-α 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-α quantification. In one embodiment, the compound or its pharmaceutically acceptable form inhibits TNF-α 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%, according to a TNF-α quantification.

[0226] This article also provides 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, according to mouse liver microsomal metabolic stability assays, have a half-life in mouse liver microsomes of 10 minutes or longer, 20 minutes or longer, 30 minutes or longer, 40 minutes or longer, or 50 minutes or longer.

[0227] This document also provides 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, according to kinetic solubility determination, have kinetic solubility in a pH 7.4 buffer containing 2% DMSO 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.

[0228] This document also provides 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, wherein, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 with IC50 values ​​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, based on a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MM.R1 with an IC50 value of 1 nM or less, 0.1 nM or less, or 0.01 nM or less.

[0229] This article also provides a method for regulating Ras superfamily proteins, which includes 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.

[0230] This article also provides a method for modulating Ras superfamily proteins, comprising contacting the Ras superfamily protein with an effective amount of a compound comprising 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.

[0231] This article also provides a method for regulating caspase activity, comprising contacting the 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.

[0232] This article also provides a method for regulating caspase activity, comprising contacting the caspase with an effective amount of a compound comprising 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.

[0233] This article also provides a method for modulating the activity of Erk1 / 2, which includes contacting the 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.

[0234] This article also provides a method for modulating the activity of Erk1 / 2, which includes contacting the Erk1 / 2 protein with an effective amount of a compound comprising 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.

[0235] This article also provides a method for modulating Akt activity, which includes contacting 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.

[0236] This article also provides a method for modulating Akt activity, which includes contacting the AKT protein with an effective amount of a compound comprising 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.

[0237] This article also provides a method for modulating Smad2 / 3 activity, which includes contacting the 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.

[0238] This article also provides a method for modulating Smad2 / 3 activity, which includes contacting the Smad2 / 3 protein with an effective amount of a compound comprising 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.

[0239] This article also provides a method for modulating JNK activity, which includes contacting the 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.

[0240] This article also provides a method for modulating JNK activity, which includes contacting the JNK protein with an effective amount of a compound comprising 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.

[0241] This article also provides a method for modulating the activity of MAPK p38, which includes contacting the 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.

[0242] This article also provides a method for modulating the activity of MAPK p38, which includes contacting the MAPK p38 protein with an effective amount of a compound comprising 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.

[0243] This article also provides a method for modulating IL-6 activity, which includes contacting the 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.

[0244] This article also provides a method for modulating IL-6 activity, which includes contacting the IL-6 protein with an effective amount of a compound comprising 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.

[0245] This article also provides a method for modulating TNF-α activity, which includes contacting TNF-α 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.

[0246] This article also provides a method for modulating TNF-α activity, which includes contacting TNF-α protein with an effective amount of a compound comprising 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.

[0247] This article also provides a method for treating a subject with cancer, which includes administering to a subject with cancer 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. In some embodiments, the compound is selected from 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, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 1 33, 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, 242243, 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 their pharmaceutically acceptable forms.

[0248] This article also provides a method for treating a subject with cancer, which includes administering to a subject with cancer a therapeutically effective amount of a compound comprising formula I, Ia, Ib, Ic, II, IIa, IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or a pharmaceutically acceptable form thereof.

[0249] This article also provides a method for treating a subject with fibrotic disease, 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.

[0250] This article also provides a method for treating a subject with fibrotic disease, comprising administering to the subject a therapeutically effective amount of a compound comprising 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.

[0251] This article also provides a method for 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.

[0252] This article also provides a method for treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound comprising 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.

[0253] This document also provides pharmaceutical compositions provided herein that comprise therapeutically effective amounts of one or more compounds provided herein (e.g., compounds of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc) and pharmaceutically acceptable carriers, diluents, or excipients. 3. Detailed Implementation

[0254] 3.1. Definition

[0255] To facilitate understanding of the public information presented in this article, several terms are defined below.

[0256] 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 herein by reference in their entirety. Where terms herein have multiple definitions, those defined in this section shall prevail unless otherwise stated.

[0257] Unless the context clearly indicates otherwise, the singular forms “a,” “a,” and “the” include plural indicators.

[0258] As used in this article, “subject” refers to an animal, such as a mammal, including humans, such as a patient.

[0259] As used herein, bioactivity refers to the in vivo activity of a compound or the physiological response that occurs when the compound, composition, or other mixture is administered in vivo. Therefore, bioactivity encompasses the therapeutic effects and pharmacokinetic behavior of such compounds, compositions, and mixtures. Bioactivity can be observed in in vitro systems designed to test such activities.

[0260] As used herein, pharmaceutically acceptable derivatives of compounds include, but are not limited to, their salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, clathrates, solvates, or hydrates. Such derivatives can be readily 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 toxicity and are pharmaceutically active or prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as, but not limited to, N,N,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucosamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-1′-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, etc. Examples of salts include, but are not limited to, lithium, potassium, and sodium salts; alkaline earth metal salts, such as, but not limited to, barium, calcium, and magnesium salts; transition metal salts, such as, but not limited to, zinc salts; and inorganic salts, such as, but not limited to, sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of inorganic acids, such as, but not limited to, hydrochlorides and sulfates; and salts of organic acids, such as, but not limited to, acetates, lactates, malates, tartrates, citrates, ascorbic acid salts, succinates, butyrates, valerates, methanesulfonates, and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters with acidic groups, said acidic groups including, but not limited to, carboxyl, phosphate, phosphonate, sulfonate, sulfinate, and borate. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of the formula C=C(OR), wherein 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 compounds with one or more solvent molecules or water molecules, or 1 to about 100, 1 to about 10, or 1 to about 2, 3, or 4 solvent molecules or water molecules.

[0261] As used herein, treatment means any manner in which one or more symptoms of a disease or condition are improved or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions described herein, such as for the treatment of fibrotic diseases, such as DMD.

[0262] As used herein, improvement of symptoms of a particular condition by application of a particular compound or pharmaceutical composition means any relief attributable to or related to the application of the composition, whether permanent or temporary, continuous or transient.

[0263] As used herein, and unless otherwise specified, the term “management” encompasses the prevention of relapse of a specified disease or condition in a subject who already has that disease or condition, and / or the prolongation of the time a subject with that disease or condition remains in remission. The term also encompasses modulating the thresholds, progression, and / or duration of the disease or condition, or altering the manner in which a subject responds to the disease or condition.

[0264] As used herein, the terms “fibrosis” or “fibrotic disease” are used interchangeably and refer to any pathological wound healing process in which connective tissue replaces normal parenchymal tissue, resulting in substantial tissue remodeling and permanent scar tissue formation. For example, in some embodiments, the fibrotic disease can be renal fibrosis, such as progressive nephropathy. In some embodiments, the fibrotic disease can be cardiovascular fibrosis, such as atherosclerosis or restenosis. In some embodiments, the fibrotic disease can be pulmonary fibrosis. In some embodiments, the fibrotic disease can be cystic fibrosis. In some embodiments, the fibrotic disease can be idiopathic fibrosis, such as idiopathic pulmonary fibrosis. In some embodiments, the fibrotic disease can be pulmonary fibrosis, such as progressive massive fibrosis or radiation-induced lung injury. In some embodiments, the fibrotic disease can be bridging fibrosis. In some embodiments, the fibrotic disease can be hepatic fibrosis, such as cirrhosis. In some embodiments, the fibrotic disease can be intestinal fibrosis, such as Crohn's disease. In some embodiments, the fibrotic disease can be fibrosis of the muscular system, such as Duchenne muscular dystrophy (DMD). In some embodiments, the fibrotic disease can be fibrosis of the brain, such as glial scars. In some embodiments, the fibrotic disease can be joint fibrosis, such as arterial stiffness, knee fibrosis, or shoulder fibrosis. In some embodiments, the fibrotic disease can be fibrosis of the skin, such as keloids. In some embodiments, the fibrotic disease can be fibrosis of the bone marrow, such as myelofibrosis. In some embodiments, the fibrotic disease can be fibrosis of the heart, such as myocardial fibrosis. In some embodiments, the fibrotic disease can be fibrosis of soft tissues. 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 formation.

[0265] As used herein, “Duchenne muscular dystrophy” (“DMD”) refers to muscular dystrophy and all forms of Duchenne muscular dystrophy (DMD). For example, in some implementations, DMD can be Becker muscular dystrophy (BMD), an intermediate clinical presentation between DMD and BMD, or dilated cardiomyopathy (cardiac disease) associated with DMD with little or no clinical skeletal or voluntary muscle disease.

[0266] As used in this article, IC 50 This refers to the amount, concentration, or dose of a specific test compound that achieves 50% inhibition of the maximum reaction in a assay measuring this type of reaction.

[0267] As used in this article, K d It refers to the equilibrium dissociation constant measured between a compound (or ligand) and a protein (or the binding domain of a protein).

[0268] As used in this article, “Smad 2 / 3” together refers to members of the receptor-regulated transcription factor Smad (R-Smad) family, namely Smad2 and Smad3.

[0269] As used in this article, "MAPK" refers to mitogen-activated protein kinase, which includes stress-activated MAPK proteins, MAPKp38, or simply p38.

[0270] As used in this article, "JNK" refers to the stress-activated MAPK protein c-Jun NH2-terminal kinase.

[0271] As used in this article, the "Ras superfamily" refers to the protein superfamily of guanosine triphosphatases (GTPases), which consists of five main families: Ras, Rho, Rab, Ran, and Arf, or their mutants. It also includes subfamilies of the five main families, such as the Rac subfamily of the Rho main family.

[0272] Unbound by theory, the Ras superfamily of proteins consists of small GTPases with substantial amino acid sequence homology, acting as signal transducers between cell surface receptors and several intracellular signal transduction cascades. These proteins participate in the regulation of essential cellular functions such as cell survival, proliferation, motility, and cytoskeleton organization (see Karnoub et al., Nat. Rev. Mol. Cell Biol., 9: 517-531 (2008)). These proteins play important roles in regulating many biological processes, including but not limited to cell growth, cell differentiation, cell migration, lipid vesicle transport, fibrosis, inflammation, and apoptosis.

[0273] Studies have primarily defined many subfamilies of the Ras superfamily based on amino acid sequence homology. These subfamilies are often referred to by abbreviations based on the most frequently studied category members.

[0274] The GTP binding domain of a subfamily of the Ras superfamily that has substantial sequence homology is usually referred to as the Ras family or Ras.

[0275] There are four isoforms of the Ras protein, expressed by three different genes: H-Ras (Harvey's sarcoma virus oncogene), N-Ras (neuroblastoma oncogene), and splice variants K-Ras4A and K-Ras4B (Koston's sarcoma virus oncogene) (see Karnoub et al., ibid.).

[0276] The GTP-binding domain of another subfamily of the Ras superfamily, which has substantial sequence homology, is commonly referred to as the Rho family, and includes proteins and proteomes called Rho, Rac, and Cdc42.

[0277] Unbound by theory, all Ras isoforms share sequence identity in all regions responsible for 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 way, distinct from other Ras proteins, both in normal physiological processes and in pathogenesis (Quinlan et al., Future Oncol., 5:105-116 (2009)).

[0278] Unbound by theory, several cell surface receptors activate Ras, such as receptor tyrosine kinases (RTKs), growth factor receptors, cytokine receptors, and integrins.

[0279] Unbound by theory, the Ras protein cycles 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 the son of sevenless (Sos) (Bar-Sagi D, Trends Endocrin. Metab. 5, 165-169 (1994)). These GEFs promote the activation of the Ras protein by stimulating the exchange of GDP for GTP and by accelerating the GTPase activator protein (GAP) of Ras-mediated GTP hydrolysis to GDP.

[0280] Unbound by theory, the Sos region on Ras that has nucleotide exchange function spans about 500 residues and contains conserved sequence blocks in Sos and other Ras-specific GEFs such as Cdc25, Sdc25 and Ras guanine nucleotide release factor (GRF) (Boguske et al., Nature 366, 643-654 (1993)).

[0281] Unbound by theory, once activated, Ras initiates signaling along the “MAPK pathway” (also known as the Ras-RAF-MEK-MAPK / ERK1 / 2 pathway) that influences cell growth, differentiation, proliferation, apoptosis, and migration. The MAPK pathway works through a series of interactions between kinases. MAPK kinases (MAPK3), such as Raf, MLK, or TAK, activated by Ras in an “on” GTP-binding state, phosphorylate and activate MAPK kinases (such as MEK), which then phosphorylate one or more MAPKs (such as ERK1 / 2) and increase their activity.

[0282] Unbound by theory, Ras activation also initiates signaling in the "Akt pathway," which influences cell survival, proliferation, migration, anti-apoptosis, and cell cycle regulation. Ras in its "on" GTP-binding state activates phosphatidylinositol 3-kinase (PI3K), which in turn induces the production of phosphatidylinositol (3,4,5) triphosphates (PIP3). These lipids serve as plasma membrane docking sites for proteins with Plek substrate-protein homology (PH) domains, including Akt (also known as protein kinase B or PKB) and its upstream activator PDK1. Three highly correlated Akt isoforms (Akt1, Akt2, and Akt3) exist, which phosphorylate common substrates, but isoform-specific Akt substrates have also been identified. On the membrane, Akt is phosphorylated and activated by PDK1, PDK2, and mTORC2. The Akt pathway can also be activated by receptor tyrosine kinases, integrins, B and T cell receptors, cytokine receptors, and G protein-coupled receptors that directly interact with and activate PI3K.

[0283] Unbound by theory, Ras activation is also associated with signal transduction via other molecular pathways besides phosphoinositol 3-kinase (PI3K), such as Rac1 GEF and Ral-guanine nucleotide dissociation stimulant (GDS). PI3K, as part of the PI3K / AKT / mTOR pathway regulating intracellular signal transduction, is important for several cellular functions such as survival, anti-apoptosis, and cell cycle regulation.

[0284] Unbound by theoretical frameworks, Ras and its downstream pathways, including ERK1 / 2 and Akt, have been extensively studied. They have causal relationships with a range of diseases, including certain cancers, inflammatory conditions, Ras-associated autoimmune leukoproliferative disorders, type II diabetes, and certain Ras diseases.

[0285] Unbound by theory, activation of MAPK, particularly ERK1 / 2, is an integral part of the inflammatory response. Therefore, the compounds presented herein (which are ERK1 / 2 inhibitors via inhibition of Ras and / or members of the Ras superfamily) may be used to treat inflammatory diseases.

[0286] Unbound by theory, Akt activation is an integral part of the inflammatory response. Therefore, the compounds presented in this paper (which are Akt inhibitors via inhibition of Ras and / or members of the Ras superfamily) may be used to treat inflammatory diseases.

[0287] Unbound by theory, there exist more than one different aberrant Ras activation pathway, including mutational activation of Ras itself, overactivation of wild-type proteins via upstream signaling, and loss of GAP function required to terminate protein activity.

[0288] The literature reports that one million deaths each year are attributed solely to mutations in K-Ras. (Frank McCormick. "K-Ras protein as a drug target." Journal of Molecular Medicine (Berhn) 2016: 94: 253-258)

[0289] Unbound by theory, Ras has a causal relationship with inflammatory diseases, including: rheumatoid arthritis (Abreu JR, de Launay D, Sanders ME, Grabiec AM, Sande van de MG, Tak PP, ReedquistmA: 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 among adults (Hootman JM, Braault MW, Helmick CG, Theis KA, Armour BS. Prevalence and most common causes of disability among adults - United States 2005, MMWR, 2009, 58(16): 421-6); atherosclerosis (Fonarow G (2003), Cleve. Clin. J. Med. 70: 431-434); inflammatory bowel disease (IBD), such as Crohn's disease (Ignacio CS, Sandvik AK, Bruland T, Andreu-Ballester JC, J. Crohns Colitis, 2017 Mar 16. doi: 10); ulcerative colitis; spondyloarthritis; idiopathic pulmonary fibrosis; juvenile arthritis; psoriasis; psoriatic arthritis, etc.

[0290] Unbound by theory, Ras is causally related to Ras-associated autoimmune leukoproliferative disorders (a non-malignant clinical syndrome initially 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, April 30, 2015; 125(18): 2753-2758)

[0291] Unbound by theory, Ras signaling is causally linked in Ras diseases. Therefore, the compounds presented in this paper that inhibit the function of one or more members of the Ras superfamily may be used to treat Ras diseases, including neurofibromatosis type 1, Noonan's syndrome, and Costello syndrome.

[0292] As used in this article, “Ras” or “Ras family” or “Ras subfamily” or “Ras group” refers to 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 their mutants.

[0293] As used in this article, “Rho” or “Rho family” or “Rho subfamily” or “Rho group” refers to RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; RAC1; RAC2; RAC3; CDC42, or their mutants.

[0294] As used in this article, “Rac” or “Rac family” or “Rac subfamily” or “Rac group” means RAC1; RAC2; RAC3; RHOG, or their mutants.

[0295] Unbound by theory, the Rho subfamily of the Ras superfamily currently includes approximately 22 proteins. Scientists typically classify most proteins into subgroups, including those called Cdc42, Rac, and Rho. (Boureux A, Vignal E, Faure S, Fort P (2007). "Evolution of the Rho family of ras-like GTPases ineukaryotes". Mol Biol Evol 24(1): 203-16).

[0296] Unbound by theory, the three most frequently studied members of the Rho subfamily are Cdc42, Rac 1, and RhoA.

[0297] Unbound by theory, the Cdc42 group includes Cdc42, TC10, TCL, Chip, and Wrch-1.

[0298] Unbound by theory, the Rac group includes Rac1, Rac2, Rac3, and RhoG.

[0299] Unbound by theory, the RhoA group includes RhoA, RhoB, and RhoC.

[0300] Unbound by theory, other Rho subfamily GTPases not included in the Cdc42, Rac, or Rho groups include RhoE / Rnd3, RhoH / TTF, Rif, RhoBTB1, RhoBTB2, Miro-1, Miro-2, RhoD, Rnd1, and Rnd2.

[0301] Unbound 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 regulated by guanine nucleotide exchange factor (GEF) and GTPase activator protein (GAP). GEF promotes the activation of Rho subfamily proteins by stimulating GDP release and GTP binding, while GAP accelerates the Rho subfamily members' mediated GTP hydrolysis to GDP. Guanine nucleotide dissociation inhibitor (GDI) proteins form large complexes with Rho proteins, helping to prevent intramembrane diffusion and entry into the cytosol, thus acting as anchors and allowing for tight spatial control of Rho activation.

[0302] Unbound by theory, members of the Rho subfamily are intracellular proteins that influence a wide range of downstream pathways, broadly involving cytoskeleton organization, cell polarity, migration, transcription, and proliferation, and more specifically membrane and vesicle transport, cell cycle, microtubule stability, actin membrane junctions, actin polymerization, myosin phosphorylation, API-dependent gene expression, cell adhesion, cell contractility, cell adhesion, and MTOC orientation. (Martin Schwartz. “Rho Signalling at a Glance.” Journal of Cell Science. 2004: (117: pp. 5457-5458) and (Bustelo XR, Sauzeau V, Berenjeno IM (2007). "GTP-binding proteins of the Rho / Rac family: regulation, effectors and functions in vivo" BioEssays. 29(4): 356-370).

[0303] Unbound by theory, Rho subfamily-associated kinases (ROCK 1 and ROCK 2) are suggested as mediators of multiple profibrotic processes, including those associated with idiopathic pulmonary fibrosis. (Knipe RS, Tager EM, and Liao JK. "The Rhokinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis." Pharmacol Rev. 2015 67(1): 103-17.)

[0304] Unbound by theory, members of the Rho subfamily have been identified as potential therapeutic molecular targets given their role in the disease process.

[0305] Unbound by theory, members of the Rho subfamily have been identified as potential therapeutic molecular targets in cancer.

[0306] Unbound by theory, members of the Rho subfamily have been identified as potential therapeutic molecular targets for fibrotic diseases.

[0307] As used herein, "GTP binding site" or "GTP binding domain" means a region of a protein that binds GTP, and a surrounding region of the protein to which another compound may bind, wherein such binding blocks the ability of GTP to bind to the protein.

[0308] As used herein, "GDP binding site" or "GDP binding domain" refers to a region of a protein that binds GDP, as well as a surrounding region of the protein to which another compound may bind, wherein such binding blocks the ability of GDP to bind to the protein.

[0309] As used in this article, "guanosine-binding region" refers to a region of a protein that is part of a GDP-binding domain or a GTP-binding domain, which mediates interaction with the guanosine moiety of GDP or GTP.

[0310] As used in this article, "metal region" refers to a region of a protein that is part of a GDP-binding domain or a GTP-binding domain and is close to a magnesium (Mg2O2) binding site.

[0311] As used in this article, “alternative Tyr32 conformation” refers to the conformation of the GTP or GDP binding domain in the Tyr 32 region of the KRas crystal structure PDB code: 3gft, compared to the KRas crystal structure PDB code: 4epr.

[0312] Unbound by theory, as used in this article, "apoptosis" refers to a programmed cell death process that plays a crucial role in physiology and pathology. It is activated during and after embryonic development to eliminate unwanted or damaged cells. Apoptosis also plays a vital role in cancer prevention. Loss of apoptosis control allows tumor cells to survive longer and provides them with time to accumulate mutations that can increase invasiveness during cancer progression, stimulate angiogenesis, deregulate cell proliferation, and interfere with differentiation.

[0313] Unbound by theoretical constraints, several members of the Ras superfamily of small GTPases have been shown to possess both pro- and anti-apoptotic functions regarding apoptosis. Members of the Rho family of GTPases, such as Rho, Rac, and cdc42, can activate apoptosis via the JNK or p38 pathway. On the other hand, members of the Ras and Rab families of GTPases possess anti-apoptotic activity mediated by activation of the PI3K / Akt / mTOR survival pathway, preventing apoptosis and leading to increased cell proliferation. Furthermore, GTPase activating proteins (GAPs) have been shown to promote tumor cell apoptosis by regulating apoptosis-related proteins and pathways. It should be noted that some GAPs also exert apoptosis-inhibiting effect and thus promote tumor progression.

[0314] Unbound by theory, the c-Jun N-terminal kinase (JNK) pathway is one of the major signaling cascades in the mitogen-activated protein kinase (MAPK) signaling pathway. It plays a role in the control of many cellular processes, including proliferation, embryonic development, and apoptosis. The JNK pathway is activated by environmental stresses (ionizing radiation, heat, oxidative stresses such as reactive oxygen species (ROS) and DNA damage), inflammatory cytokines, and growth factors. JNK activation often involves the Rho family of GTPases, such as Rho, Cdc42, and Rac.

[0315] Unbound by theoretical constraints, JNK activates apoptosis signaling through transactivation upregulation of pro-apoptotic genes via c-Jun / AP1-dependent or p53 / 73 protein-dependent mechanisms. Within these pathways targeting mitochondrial apoptosis proteins, activated JNK directly regulates the activity of mitochondrial pro-apoptotic proteins through various phosphorylation events.

[0316] Unbound by theory, another member of the MAPK signaling pathway is p38MAPK (also referred to as MAPKp38 in this paper), which allows cells to interpret a wide range of external signals and respond by activating downstream pathways that mediate several biological effects. This pathway also plays a role in the control of apoptosis and cytokine release in macrophages and neutrophils.

[0317] Unbound by theory, apoptosis can be activated through both extrinsic (death ligand) and intrinsic (mitochondrial) pathways. Members of the Bcl-2 protein family, such as Bax and Bak, regulate and mediate the intrinsic apoptotic process that promotes cell death in mitochondria. Upon apoptotic stimulation, these proteins are activated and oligomerize at the outer mitochondrial membrane to mediate its permeation. Permeation allows cytochrome c to be released from the mitochondria, inducing a series of biochemical reactions that lead to caspase activation and subsequent cell death.

[0318] Unbound by theory, apoptosis induction, such as in mammalian cells, can be mediated through several mechanisms, including inhibition of the ubiquitin-proteasome system (UPS). The UPS system is a major proteolytic pathway for the removal of cytoplasmic, nuclear, and membrane-associated proteins and plays a vital role in homeostasis, including preventing misfolding or the accumulation of harmful proteins. Proteins targeted for degradation are selected by covalently tagging a tetraubiquitin chain linked to lysine 48 with ubiquitin, followed by proteolysis within the 26S proteasome. The 26S proteasome holoenzyme consists of a 19S regulatory particle (RP) responsible for recognizing ubiquitin signals and unfolding target proteins, and a 20S core particle (CP) that hydrolyzes the unfolded polypeptide into short peptides of varying lengths. Therefore, UPS impairment has been associated with several pathological conditions, including cancer. Tumor cells are characterized by the loss of cell cycle checkpoint control and often experience elevated levels of stress due to overactivation of oncogenic signaling and / or adverse microenvironmental conditions. Thus, transformed cells largely depend on the proper functioning of the UPS for survival and proliferation. Inhibition of UPS, such as with proteasome inhibitors, is known to induce cell death and apoptosis. To date, three proteasome inhibitors have been approved by the FDA for the treatment of patients with multiple myeloma. These three proteasome inhibitors, Velcade (bortezomib), Kyprolis (carfilzomib), and Ninlaro (ixazomib), have reportedly targeted proteolytic sites within the 20S CP.

[0319] Unbound by theory, as used herein, "cystasparase" refers to one or more members of the cysteine ​​protease family that cleave proteins after an aspartic acid residue. All cystasparases are synthesized in the cell as non-catalytically active zymogens and must undergo a cleavage activation process to yield large and small subunits, which dimerize to produce the active enzyme. Cysteines exist in a hierarchical structure comprising so-called upstream cystasparases 2, 8, 9, and 10 and downstream cystasparases 3, 6, and 7. Active cystasparase-9 initiates cystasparase cleavage, which activates downstream executors cystasparases 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 apoptosis induction, as determined by an annexin V apoptosis assay kit.

[0320] It should be understood that the compounds provided herein may contain a chiral center. Such a chiral center may be in (R) configuration or (S) configuration, or a mixture thereof. Therefore, the compounds provided herein may be enantiomerically pure, or a mixture of stereoisomers or diastereomers. Thus, those skilled in the art will recognize that, for compounds that undergo epimerization in vivo, administration of the (R) form is equivalent to administration of the (S) form.

[0321] As used herein, substantially pure means sufficiently homogeneous to exhibit the absence of readily detectable impurities, as determined by standard analytical methods (such as thin-layer chromatography (TLC), gel electrophoresis, high-performance liquid chromatography (HPLC), and mass spectrometry (MS)) used by those skilled in the art to assess such purity, or means sufficiently pure that further purification does not detectably alter the enzymatic and biological activities of the substance. Methods for purifying compounds to produce substantially chemically pure compounds are known to those skilled in the art. However, substantially chemically pure compounds can be mixtures of stereoisomers. In such cases, further purification may increase the specific activity of the compound. This disclosure is intended 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 reversed-phase HPLC. When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, and unless otherwise specified, it is desirable for the compounds to include both E and Z geometric isomers. Similarly, all tautomer forms are intended to be included. For example, Formula A includes, but is not limited to, the following three tautomer structures.

[0322]

[0323] Unless otherwise stated, as used herein, abbreviations for any protecting groups, amino acids, and other compounds are the accepted abbreviations according to their common usage, IUPAC-IUB Committee on Biochemical Nomenclature (see, (1972) Biochem. 11: 942-944), or IUPAC Organic Nomenclature (see, Favre HA and Powell WH, Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013, Cambridge, UK: The Royal Society of Chemistry, 2013: Print ISBN 978-0-85404-182-4, PDF eISBN 978-1-84973-306-9, DOI 10.1039 / 9781849733069; Organic Nomenclature, Chapters A, B, C, D, E, F and H, Pergamon) Press, Oxford, 1979. Copyright 1979 IUPAC; and IUPAC Guide to the Nomenclature of Organic Compounds (Recommended 1993), 1993, Blackwell Scientific publications, copyright 1993 IUPAC).

[0324] As used herein, alkyl, alkenyl, and alkynyl carbon chains, if not specified, contain 1 to 20 carbons or 1 to 16 carbons and are straight-chain or branched. In some embodiments, alkenyl carbon chains of 2 to 20 carbons contain 1 to 8 double bonds, and in some embodiments, alkenyl carbon chains of 2 to 16 carbons contain 1 to 5 double bonds. In some embodiments, alkynyl carbon chains of 2 to 20 carbons contain 1 to 8 triple bonds, and in some embodiments, alkynyl carbon chains of 2 to 16 carbons 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, vinyl, propenyl, butenyl, pentenyl, ethynyl, and hexynyl. As used herein, lower alkyl, lower alkenyl, and lower alkynyl refer to carbon chains having about one or about two carbons to about six carbons. As used herein, "alkane(alken(alkynyl)" refers to an alkyl group containing at least one double bond and at least one triple bond.

[0325] As used herein, “heteroalkyl” refers to a hydrocarbon chain containing one or more oxygen, sulfur (including S(=O) and 6(=O)2 groups) or substituted or unsubstituted nitrogen atoms (including -NR- and -N) inserted into it. + The RR-group, in one embodiment having 1 to about 20 atoms in the chain, and in another embodiment having 1 to 12 atoms, is a straight-chain or branched aliphatic hydrocarbon group, wherein the nitrogen substituent is alkyl, aryl, aralkyl, heteroaryl, heteroaryl, S(=O)2R′ or COR′, wherein R′ is alkyl, aryl, aralkyl, heteroaryl, heteroaryl, -OY or -NYY′, wherein Y and Y′ are each independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic.

[0326] As used herein, “cycloalkyl” refers to a saturated monocyclic or polycyclic ring system having 3 to 10 carbon atoms in some embodiments and 3 to 6 carbon atoms in other embodiments; cycloalkenyl and cycloynyl refer to monocyclic or polycyclic ring systems containing at least one double bond and at least one triple bond, respectively. In some embodiments, the cycloalkenyl and cycloynyl groups may contain 3 to 10 carbon atoms, in further embodiments the cycloalkenyl group contains 4 to 7 carbon atoms, and in further embodiments the cycloynyl group contains 8 to 10 carbon atoms. Cycloalkyl, cycloalkenyl, and cycloynyl ring systems may consist of one, two, or more rings connected together in a fused, bridged, or helical manner. “Cycloalkyl(alkenyl(ynyl))” 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.

[0327] As used herein, "carbon ring" refers to a monocyclic or polycyclic ring system in which all the atoms constituting the ring are carbon atoms, such as benzene or cyclopropane. In some embodiments, the carbon ring is unsaturated or partially saturated.

[0328] 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 substituted with one or more substituents, and in some embodiments with one to three or four substituents, wherein such substituents are as defined herein.

[0329] 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.

[0330] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system of about 5 to about 15 members in some embodiments, wherein one or more (1 to 3 in one embodiment) atoms in the ring system are heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, or sulfur. The heteroaryl group may optionally be fused to a benzene ring. Heteroaryl groups include, but are not limited to, furanyl, imidazolyl, pyrimidinyl, tetrazolyl, thiophene, pyridinyl, pyrroleyl, N-methylpyrroleyl, quinolinyl, and isoquinolinyl. In some embodiments, the heteroaryl group may optionally be fused to a heterocyclic alkyl ring. In some embodiments, the heteroaryl group may be a partially saturated heteroaryl group, such as a benzene ring fused to a heterocyclic alkyl ring, for example, a benzene ring fused to a tetrahydrofuranyl ring.

[0331] As used herein, “heterocyclic alkyl,” “heterocyclic group,” or “heterocycle” refers to a monocyclic or polycyclic non-aromatic ring system that is 3 to 10 members in one embodiment, 4 to 7 members in another embodiment, and 5 to 6 members in yet another embodiment, wherein one or more (1 to 3 in some embodiments) atoms in the ring system are heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, or sulfur. In embodiments where the heteroatom is nitrogen, the nitrogen is optionally substituted with hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyl, heterocyclic group, cycloalkylalkyl, heterocyclic alkyl, acyl, guanidinyl, amidine, or sulfonyl, or the nitrogen may be quaternized to form an ammonium group, wherein the substituents are selected as above. In some embodiments, the heterocyclic ring is saturated. In some embodiments, the heterocyclic ring is unsaturated or partially saturated.

[0332] As used herein, “substituted aryl,” “substituted heteroaryl,” and “substituted heterocyclic” refer to an aryl, heteroaryl, or heterocyclic group that is substituted by one or more substituents, or in some embodiments by one to three or four substituents, as defined herein.

[0333] As used herein, "aralkyl" or "arylalkyl" refers to an alkyl group in which one hydrogen atom of an alkyl group is replaced by an aryl group.

[0334] As used herein, “heteroaryl” refers to an alkyl group in which one hydrogen atom of the alkyl group is replaced by a heteroaryl group.

[0335] As used in this article, "halogen," "halogen," or "halogen" refers to F, Cl, Br, or I.

[0336] As used herein, “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl, and 1-chloro-2-fluoroethyl.

[0337] As used in this article, “haloalkoxy” refers to RO in which R is a haloalkyl group.

[0338] As used in this article, "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group (-OH).

[0339] As used in this article, "cycloalkoxy" refers to the -OR group in which R is a cycloalkyl group.

[0340] As used in this article, "carboxyl group" refers to the divalent group -C(O)O-.

[0341] As used in this article, "aminocarbonyl" refers to -C(O)NH2.

[0342] As used herein, “alkylaminocarbonyl” means -C(O)NHR, where R is an alkyl group, including lower alkyl groups. As used herein, “dialkylaminocarbonyl” means -C(O)NR′R, where R′ and R are independently alkyl groups, including lower alkyl groups; “formamide” means a group of the formula -NR′COR, where R′ and R are independently alkyl groups, including lower alkyl groups.

[0343] As used herein, “arylalkylaminocarbonyl” means -C(O)NRR′, where one of R and R′ is an aryl group, including lower aryl groups such as phenyl, and the other of R and R′ is an alkyl group, including lower alkyl groups.

[0344] As used herein, “arylaminocarbonyl” refers to -C(O)NHR, where R is an aryl group, including lower aryl groups such as phenyl.

[0345] As used in this article, "hydroxycarbonyl" refers to -COOH.

[0346] As used herein, “alkoxycarbonyl” refers to -C(O)OR, where R is an alkyl group, including lower alkyl groups.

[0347] As used in this article, "aryloxycarbonyl" refers to -C(O)OR, where R is an aryl group, including lower aryl groups such as phenyl.

[0348] As used herein, “alkoxy” and “alkathio” refer to RO- and RS-, where R is an alkyl group, including lower alkyl groups.

[0349] As used herein, “aryloxy” and “arylthio” refer to RO- and RS-, where R is an aryl group, including lower aryl groups such as phenyl.

[0350] Without specifying any given number of substituents (e.g., "haloalkyl"), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens.

[0351] As used herein, "cyclic structure" can be a cycloalkyl, carbocyclic, heterocyclic, aryl, or heteroaryl group.

[0352] Unless otherwise stated, as used herein, abbreviations for any protecting groups, amino acids, and other compounds are the accepted abbreviations according to their common usage, IUPAC-IUB Committee on Biochemical Nomenclature (see, (1972) Biochem. 11: 942-944), or IUPAC Organic Nomenclature (see, Favre HA and Powell WH, Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013, Cambridge, UK: The Royal Society of Chemistry, 2013: Print ISBN 978-0-85404-182-4, PDF eISBN 978-1-84973-306-9, DOI 10.1039 / 9781849733069; Organic Nomenclature, Chapters A, B, C, D, E, F and H, Pergamon) Press, Oxford, 1979. Copyright 1979 IUPAC; and IUPAC Guide to the Nomenclature of Organic Compounds (Recommended 1993), 1993, Blackwell Scientific publications, copyright 1993 IUPAC).

[0353] The term "subject" refers to an animal, including but not limited to primates (e.g., humans), cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein, for example, referring to a mammalian subject, such as a human subject, which in one embodiment refers to a person.

[0354] The term “treatment” is intended to include the relief or elimination of a symptom, disease, or condition, or one or more symptoms associated with such a symptom, disease, or condition; or the relief or eradication of the cause of the symptom, disease, or condition itself.

[0355] The term “prevention” is intended to include delaying and / or eliminating the onset of a condition, disease or symptom and / or its accompanying symptoms; preventing a subject from acquiring a condition, disease or symptom; or methods to reduce the risk of a subject acquiring a condition, disease or symptom.

[0356] The term "therapeuticly effective amount" is intended to include an amount of compound, when administered, sufficient to prevent the development of one or more symptoms of the treated condition, disease, or symptom, or to alleviate to some extent one or more symptoms of the treated condition, disease, or symptom. The term "therapeuticly effective amount" also refers to an amount of compound sufficient to elicit a biological or medical response in a biomolecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human as sought by a researcher, veterinarian, physician, or clinician. The compounds provided herein in a therapeutically effective amount may be administered in a single dose (i.e., a single dose) or administered intermittently over time (i.e., continuous or multiple subdose administrations). Single-dose administration, continuous administration, or multiple subdose administrations may be repeated, for example, to maintain the level of the compound in a biomolecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human.

[0357] The terms “pharmaceutically acceptable carrier,” “pharmaceuticalally acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refer to pharmaceutically acceptable materials, compositions, or media, such as liquid or solid fillers, diluents, solvents, or encapsulating materials. In one embodiment, each component is “pharmaceutically acceptable” in the sense of compatibility with other components of the pharmaceutical formulation and is suitable for use in contact with human or animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, in proportion to a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 22nd edition; edited by Loyd et al.; The Pharmaceutical Press, 2012; Handbook of Pharmaceutical Excipients, 7th edition; edited by Rowe et al.; The Pharmaceutical Press, 2012; Handbook of Pharmaceutical Additives, 3rd edition; edited by Ash and Ash; Synapse Information Resources, Inc., 2007; Pharmaceutical Preformulation and Formulation, 2nd edition; edited by Gibson; CRC Press LLC, 2009.

[0358] As used herein, a “pharmaceutically acceptable form” of the compounds disclosed herein includes, but is not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopes (i.e., isotopically labeled derivatives) of the compounds disclosed herein. In one embodiment, a “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, solvates, isomers, and isotopes (i.e., isotopically labeled derivatives) of compounds of formulas I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc disclosed herein.

[0359] The terms "about" or "approximately" mean an acceptable error for a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined. In some embodiments, the terms "about" or "approximately" mean within 1, 2, 3, or 4 standard deviations. In some embodiments, the terms "about" or "approximately" mean 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.

[0360] The term "weight percentage" or "weight %" refers to the percentage of the weight of a specified component (e.g., an active compound or excipient) in a composition (e.g., a pharmaceutical composition) out of the total weight of the composition. Therefore, the sum of the weight percentages of all components in the composition is 100%.

[0361] The terms “active ingredient” and “active substance” refer to a compound, alone or in combination with one or more pharmaceutically acceptable excipients, administered to a subject to treat, prevent, or improve one or more symptoms of a disease, condition, or illness. As used herein, “active ingredient” and “active substance” can be optically active isomers or isotopic variants of the compounds described herein.

[0362] The terms “drug,” “therapeutic agent,” and “chemotherapy agent” refer to a compound or pharmaceutical composition thereof administered to a subject to treat, prevent, or improve one or more symptoms of a disease, condition, or illness.

[0363] In some embodiments, "optical activity" and "enantiomeric activity" refer to a molecular aggregate having an enantiomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In some embodiments, based on the total weight of the racemates under discussion, the compound comprises about 95% or more of one enantiomer and about 5% or less of another enantiomer.

[0364] In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the molecule with respect to its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, that is, the direction in which the optically active compound rotates the plane of polarization. The prefix (-) indicates that the compound is levorotatory, meaning it rotates the plane of polarization to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, meaning it rotates the plane of polarization to the right or clockwise. However, the signs (+) and (-) for optical rotation are independent of the absolute configuration R and S of the molecule.

[0365] The term "racemate" should be understood as an equimolar mixture of a pair of enantiomers. It does not exhibit optical activity. The chemical name or formula of the racemate is distinguished from that of the enantiomer 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.

[0366] Racemic compounds containing two asymmetric centers with known relative configurations, as disclosed herein, are named using the configuration descriptor R,S or R,R, preceded by the prefix rac-. For example, the following racemic compound A 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.

[0367]

[0368] According to the Cahn-Ingold-Prelog rule, lowercase r / s stereo descriptors are used to describe pseudo-asymmetric centers (see RS Cahn, CK Ingold and V. Prelog, Angew. Chem. Intemat. Ed. Eng. 5, 385-415, 511 (1966); and V. Prelog and G. Helmchen, Angew. Chem. Intemat. Ed. Eng. 21, 567-583 (1982)). For example, the following compound B is named (1s,4s)-1-bromo-4-chlorocyclohexane.

[0369]

[0370] The compound names included in this article are used Versions 20.0.0.38, 20.1.0.112, and 22.2.0.3348 are derived from their respective chemical structures. If there is a discrepancy between the chemical structure and the name disclosed herein, the structure shall prevail.

[0371] The term "isotope variant" refers to a compound that contains an isotope in a non-natural proportion at one or more atoms constituting such a compound. In some embodiments, the "isotope variant" of the compound contains one or more isotopes in a non-natural proportion, including but not limited to hydrogen (…). 1 H), deuterium ( 2 H), tritium (3 H), 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 ( i5 N), oxygen-14 ( 14 O), oxygen-15 ( i5 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 ( 33 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl) and chlorine-37 ( 37 Cl). In some embodiments, the "isotopic variant" of the compound is a stable form, i.e., non-radioactive. It should be understood that in the compounds provided herein, any hydrogen may be, for example... 2 H, or any carbon, can be, for example 13 C, or any nitrogen, can be, for example... 15 N, and any oxygen can be 18 O, wherein it is feasible according to the judgment of a person skilled in the art. In some embodiments, the "isotopic variant" of the compound contains a non-natural proportion of deuterium. In some embodiments, a pharmaceutically acceptable derivative of the compound is an isotopic variant.

[0372] The term "solvent" refers to a complex or aggregate formed of one or more solute molecules (e.g., the compounds provided herein) and one or more solvent molecules, the solvent molecules being 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 some 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, hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, and pentahydrates.

[0373] The phrase “its isotopic variant; 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 mentioned herein; or a pharmaceutically acceptable salt of the compound mentioned herein; or a pharmaceutically acceptable salt of an isotopic variant of the compound mentioned herein; or a pharmaceutically acceptable solvate of the compound mentioned herein; or a pharmaceutically acceptable solvate of an isotopic variant of the compound mentioned herein; or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of the compound mentioned herein; or a pharmaceutically acceptable solvate of an isotopic variant of the compound mentioned herein or a pharmaceutically acceptable salt of the compound mentioned herein.”

[0374] 3.2. Compounds

[0375] This article provides a compound of formula I:

[0376]

[0377] Or in a pharmaceutically acceptable form, wherein:

[0378] X is -NR 1A R 2A OR 2A ;

[0379] Y is an imidazolyl, pyridinyl, or an 8-10 membered fused heteroaryl group; wherein

[0380] The imidazole group is optionally surrounded by one R 6A Substituents are substituted and optionally replaced by 1-2 R groups. 7A Substituent substitution; and

[0381] The pyridyl group or the 8-10 fused heteroaryl group is optionally surrounded by 1-4 R groups. 7A Substituent substitution;

[0382] R 1A Is it hydrogen or C? 1-6 Alkyl, wherein the C 1-6 Alkyl groups are optionally surrounded by 1-4 Rs 8A Substituent substitution;

[0383] R 2A It is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, C 3-7 Heterocyclic alkyl, C5- 10 Yuanfangji, -S(O)2R 15A -P(O)R 16A R 17A Or 5-10 heteroaryl, wherein C 1-6 Alkyl, C3-7 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-10-membered heteroaryl groups are each independently and optionally bound by 1-4 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A Substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group comprising one or more atoms attached to it; or R 1A and R 2A Combining to form 3-6 membered heterocyclic alkyl groups, each of which is attached to a nitrogen atom, wherein R μA and R 2A The 3-6 membered heterocyclic alkyl group formed is fused with a 5-6 membered heteroaryl group;

[0384] R 3A It 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 Wherein C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, aryl, and 5-10-membered heteroaryl groups are each independently and optionally bounded by 1-3 R groups. 9A Substituent substitution;

[0385] R 4A It is hydrogen, aryl, or 5-10 heteroaryl, wherein the aryl and 5-10 heteroaryl groups are each optionally independently bound by 1-4 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0386] R 5A Is it hydrogen or C? 1-6 alkyl;

[0387] R 6A and R 7A Each is C independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, aryl, C 5-10 heteroaryl, C 3-7 Heterocycloalkyl, C 1-6 Heteroalkyl, halogen, -NR 12A R 13A 、C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)NR 12A R13A -(CO)R 11A 、-C(O)OR 14A Or CN, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, aryl, C 5-10 heteroaryl, C 3-7 Heterocyclic alkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0388] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -NR 12A R 13A -(CO)R 11A 、-C(O)OR 14A 、-C(O)NR 12A R 13A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, 5-6 membered heteroaryl, biotinamide or biotinylated substituent;

[0389] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Halogenated alkoxy groups or 5-6 heteroaryl groups are each optionally and independently bound by 1-3 R groups.8A Substituent substitution;

[0390] R 11A It is -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0391] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Heterocyclic alkyl, aryl, or 5-10-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Heterocyclic alkyl groups, aryl groups, and 5-10-membered heteroaryl groups are optionally surrounded by 1-3 R groups. 8A Substituent substitution, or R 12A and R 13A They combine to form 3-7 membered heterocyclic alkyl groups, each of which has a nitrogen atom attached to it.

[0392] R 14A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0393] R 15A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C3-6 Cycloalkyl, C 1-6 Alkoxy and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0394] R 16A and R 17A Each is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution, or R 16A and R 17A The combination forms 3-7 membered heterocyclic alkyl groups, each of which is attached to a phosphorus atom; and

[0395] Where X is OH or Y is an N-methylimidazolium group, and R 5A When it is H, R 3A and R 4A At least one of them is not an unsubstituted phenyl group.

[0396] In some embodiments, the compound of formula I is such that Y is optionally coupled with one R. 6A Substituents are substituted and optionally replaced by 1-2 R groups. 7A Substituent-substituted imidazole group. In some embodiments, the compound of formula I is such that Y is a C-linked imidazole group, which is replaced by an R group at the nitrogen of the imidazole ring. 6A Substituents are substituted and optionally 1-2 R groups are formed at the carbon of the imidazole ring. 7A Substituent substitution. In some embodiments, the compound of formula I is the same as the compound of formula Ia:

[0397]

[0398] Or in a pharmaceutically acceptable form. In some embodiments, the compound of formula I is a compound of formula Ib:

[0399]

[0400] Or in a pharmaceutically acceptable form. In some embodiments, the compound of formula I is such that Y is optionally surrounded by 1-4 R... 7A The pyridyl group is substituted with a substituent. In some embodiments, the compound of formula I is a compound of formula Ib:

[0401]

[0402] Or in a pharmaceutically acceptable form.

[0403] In some embodiments, the compounds of formula I, Ia, Ib, or Ic are such that: R 4A and R 5A No more than one of them is hydrogen. In some embodiments, the compound is as follows: R 5A It is hydrogen, methyl, ethyl, or isopropyl. In some embodiments, the compound is as follows: R 5A It is hydrogen.

[0404] In some embodiments, the compounds of formula I, Ia, Ib, or Ic are such that: R 6A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, 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 , of which C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, aryl, C 5-10 heteroaryl, C 3-7 Heterocyclic alkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution. In some embodiments, the compound is as follows: R 6A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution. In some embodiments, the compound is as follows: R 6A It is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl groups are each optionally independently bounded by 1-3 R groups. 8A Replace, where R 8A It is -OH, C 1-3 Alkoxy or C 1-3Halogenated alkoxy group. In some embodiments, the compound is as follows: R 6A It is methyl, ethyl, or isopropyl. In some embodiments, the compound is as follows: R 6A It is a methyl group.

[0405] In some embodiments, the compounds of formula I, Ia, Ib, or Ic are such that: R 7A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution. In some embodiments, the compound is as follows: R 7A It is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl groups are each optionally independently bounded by 1-3 R groups. 8A Replace, where R 8A It is -OH, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy group. In some embodiments, the compound is as follows: R 7A It is methyl, ethyl, or isopropyl. In some embodiments, the compound is as follows: R 7A It 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.

[0406] In some embodiments, the compounds of formula I, Ia, Ib, or Ic are such that X is -OR 2A In some embodiments, the compounds of formula I, Ia, Ib, or Ic are 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 The compounds combine to form 3-6 membered heterocyclic alkyl groups, each containing a nitrogen atom to which it is attached. In some embodiments, the compound is as follows: R 1A Is it hydrogen or C? 1-3 Alkyl group. In some embodiments, the compound is as follows: R 1AIt is methyl, ethyl, or isopropyl. In some embodiments, the compound is as follows: R 1A It is hydrogen. In some embodiments, the compound is as follows: R 2A It is C 1-4 Alkyl, C 4-5 Cycloalkyl, C 1-4 Heteroalkyl or 5-6-membered heteroaryl, wherein the C 1-4 Alkyl, C 4-5 Cycloalkyl, C 1-4 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution. In some embodiments, the compound is as follows: R 2A It is a 5-6 aryl group, each of which is independently and optionally bounded by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group comprising one or more atoms, each attached to a substituent. In some embodiments, the compound is as follows: R 2A It is selected from the following 5-6 membered heteroaryl groups: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, or thiadiazolyl, each optionally independently bounded by 1-3 R groups. 8A Substituent substitution. In some embodiments, the 5-6 membered heteroaryl group is replaced by two independent R groups. 8A Substituents are used to form a 5-6 membered cycloalkyl group fused with a 5-6 membered heteroaryl group, comprising one or more atoms each attached. In some embodiments, the 5-6 membered heteroaryl group is replaced by two independent R groups. 8A Substituent substitution, whereby these substituents combine to form a 5-6 membered heterocyclic alkyl group fused with a 5-6 membered heteroaryl group, comprising one or more atoms each attached. In some embodiments, the two R groups... 8A The substituents combine to form a pyrazolo[5,1-b]oxazolyl ring. In some embodiments, the two R groups... 8A The substituents combine to form a 2,3-dihydropyrazolo[5,1-b]oxazolyl ring. In some embodiments, the 5-6 membered heteroaryl group is a pyrazolyl group. In some embodiments, the compound is as follows: R 8A Independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -NR 12A R 13A -(CO)R 11A Oxygen, C 1-6 Hydroxyalkyl, C 1-6Heteroalkyl, 3-6 membered heterocyclic alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkoxy. In some embodiments, the compound is as follows: R 8A Independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-5 Cycloalkyl, -NR 12A R 13A -(CO)R 11A Oxygen, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, 3-5 membered heterocyclic alkyl, C 1-4 Alkoxy or C 3-5 Cycloalkoxy. In some embodiments, the compound is as follows: R 8A Independently selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -NR 12A R 13A -(CO)R 11A Oxygen, C 2-3 Hydroxyalkyl, C 2-4 Heteroalkyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, or cyclobutoxy.

[0407] In some embodiments, the compound of formula I, Ia, Ib or Ic is such that X is: -OH, -NH2,

[0408]

[0409]

[0410] In some embodiments, the compound of formula I, Ia, Ib or Ic is such that X is: -OH, -NH2,

[0411]

[0412]

[0413] In some embodiments, the compounds of formula I, Ia, Ib, or Ic are such that: R 3A It is 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 R13A , of which C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Heteroalkyl, phenyl and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution. In some embodiments, the compound is as follows: R 9A Independently selected from C 1-4 Alkyl, C 3-5 cycloalkyl, -(CO)R 11A 、C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, 4-6 membered heterocyclic alkyl, C 1-4 Alkoxy or C 3-5 Cycloalkoxy. In some embodiments, the compound is as follows: R 9A Independently selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -(CO)R 11A 、C 2-3 Hydroxyalkyl, C 2-4 Heteroalkyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, imidazolyl, or piperidinyl. In some embodiments, the compound is as follows: R 3A Yes: -CH3, unsubstituted phenyl, (4-methoxy)-phenyl, isopropyl, cyclopropyl, In some embodiments, the compound is as follows: R 3A Yes: -CH3, unsubstituted phenyl, isopropyl, cyclopropyl,

[0414] In some embodiments, the compounds of formula I, Ia, Ib, or Ic are such that: R 4A It is a phenyl or a 5-10-membered heteroaryl group, wherein each of the phenyl or 5-10-membered heteroaryl groups is independently and optionally surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group comprising one or more atoms, each attached to a substituent. In some embodiments, the compound is as follows: R 4A is optionally replaced by 1-3 R 10A A phenyl group substituted with a substituent. In some embodiments, the compound is as follows: R 4A is optionally replaced by 1-3 R 10A A 5-6 membered heteroaryl group substituted with a substituent. In some embodiments, the compound is as follows: R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or a 5-6 membered heteroaryl group. In some embodiments, the compound is as follows: R 10A Independently selected from halogen groups, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, 3-5 membered heterocyclic alkyl, -OH, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, C 1-4 Halogenated alkoxy or -NR 12A R 13A In some embodiments, the compound is as follows: R 10A Independently selected from halogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, C 1-3 Halogenated alkyl, C 2-3 Hydroxyalkyl, C 2-4 Heteroalkyl, -OH, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, C 1-4 Halogenated alkoxy or -NR 12A R 13A In some embodiments, the compound is as follows: R 12A and R 13A Each is independently selected from hydrogen and C. 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Hydroxyalkyl, C 1-4 heteroalkyl, -OH or C 1-4 Alkyl group. In some embodiments, the compound is as follows: R 12A and R 13A Each compound is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, or ethoxy. In some embodiments, the compound is as follows: R 12A and R 13A Each is independently selected from hydrogen or methyl. In some embodiments, the compound is as follows: R 12A and R 13A Each is hydrogen.

[0415] In some embodiments, the compound is as follows: R 4A Yes: hydrogen, unsubstituted phenyl, In some embodiments, the compound is as follows: R 4A Yes: hydrogen, unsubstituted phenyl,

[0416] In some embodiments, the compound of formula I is the compound of formula II:

[0417]

[0418] Or in a pharmaceutically acceptable form, wherein:

[0419] X is -NR 1A R 2A OR 2A ;

[0420] R 1A Is it hydrogen or C? 1-6 alkyl;

[0421] R 2A It is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, -S(O)2R 15A -P(O)R 16A R 17A Or 5-6 heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A Substituents combine to form 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl groups, each with one or more atoms attached; or R 1A and R 2A Combining to form 3-6 membered heterocyclic alkyl groups comprising nitrogen atoms to which they are all attached, optionally wherein R 1A and R 2A The 3-6 membered heterocyclic alkyl group formed is fused with a 5-6 membered heteroaryl group;

[0422] R 3A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl, 5-10 heteroaryl, -(CO)R 11A or -C(O)NR 12A R 13A Wherein C1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0423] R 4A It is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0424] R 5A It is hydrogen;

[0425] R 6A and R 7A Each is C independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0426] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -NR 12A R 13A -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, 5-6 membered heteroaryl, biotinamide or biotinylated substituent;

[0427] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Halogenated alkoxy groups or 5-6 heteroaryl groups are each optionally and independently bound by 1-3 R groups. 8A Substituent substitution;

[0428] R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0429] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, or R 12A and R 13A They combine to form 3-6 membered heterocyclic alkyl groups, each of which has a nitrogen atom attached to it.

[0430] R 15A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0431] R 16A and R 17A Each is independently selected from C 1-6 Alkyl, C 1-6Alkoxy or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution, or R 16A and R 17A The combination forms 3-7 membered heterocyclic alkyl groups, each of which is attached to a phosphorus atom;

[0432] m is 0, 1, or 2; and

[0433] Where X is OH or Y is an N-methylimidazolium group, and R 5A When it is H, R 3A and R 4A At least one of them is not an unsubstituted phenyl group.

[0434] In some embodiments, the compound of formula I is the same as the compound of formula IIa:

[0435]

[0436] Or in a pharmaceutically acceptable form, wherein:

[0437] R 1A It is hydrogen;

[0438] R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, -S(O)2R 15A Or 5-6 heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0439] R 3A It is C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl, 5-membered, 6-membered or 9-membered heteroaryl, -(CO)R 11A or -C(O)NR 12A R 13A Wherein C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-6Heteroalkyl, phenyl, and 5-, 6-, or 9-membered heteroaryl groups are each independently and optionally bounded by 1-3 R groups. 9A Substituent substitution;

[0440] R 4A It is hydrogen, phenyl, or a 5-, 6-, or 9-membered heteroaryl group, wherein the phenyl and the 5-, 6-, or 9-membered heteroaryl group are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0441] R 5A It is hydrogen;

[0442] R 6A It is C 1-3 Alkyl or C 1-3 Heteroalkyl, wherein the C 1-3 Alkyl or C 1-3 The heteroalkyl group may optionally be replaced by biotinamide;

[0443] R 7A It is methyl;

[0444] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -NR 12A R 13A -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, 5-6 membered heteroaryl, biotinamide or biotinylated substituent;

[0445] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 11A R 12A Or 5-6 heteroaryl, wherein C1-6 Alkyl or C 1-6 The heteroalkyl group may optionally be replaced by biotinamide;

[0446] R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0447] R 12A and R 13A Each is independently selected from hydrogen and 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 Combining to form 5- or 6-membered heterocyclic alkyl groups, each of which is attached to a nitrogen atom;

[0448] R 15A It is C 1-3 Alkyl, C 3-6 Cycloalkyl or C 1-4 Heteroalkyl;

[0449] R 16A and R 17A Each is independently selected from C 1-3 Alkyl or C 1-3 alkoxy, or R 16A and R 17A The combination forms a 5-membered heterocyclic alkyl group, in which phosphorus atoms are all attached; and

[0450] m is 0 or 1.

[0451] In some embodiments, the compound of formula IIa is as follows:

[0452] R 1A and R 2A Together with the nitrogen atoms attached to them, they have the following structure: -NH2,

[0453]

[0454]

[0455] R 3AIt is -CH3, unsubstituted phenyl, isopropyl, cyclopropyl,

[0456] R 4A It is hydrogen, unsubstituted phenyl,

[0457]

[0458] R SA It is hydrogen;

[0459] R 6A It is methyl, -CH2CH2NH2 or

[0460] R 7A It is methyl; and

[0461] m is 0 or 1.

[0462] In some embodiments, the compound of formula IIa is as follows:

[0463] R 1A and R 2A Together with the nitrogen atoms attached to them, they have the following structure: -NH2,

[0464]

[0465]

[0466]

[0467] R 3A It is -CH3, unsubstituted phenyl, isopropyl, cyclopropyl,

[0468] R 4A It is hydrogen, unsubstituted phenyl,

[0469] R 5A It is hydrogen;

[0470] R 6A It is methyl, -CH2CH2NH2 or and

[0471] m is 0.

[0472] In some embodiments, the compound of formula I is a compound of formula IIa(1):

[0473]

[0474] Or in a pharmaceutically acceptable form, wherein:

[0475] R 1A It is hydrogen;

[0476] R 2A It is a 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered heteroaryl group is optionally surrounded by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0477] R 8A Selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -NR 12A R 13A -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, 5-6 membered heteroaryl, biotinamide or biotinylated substituent;

[0478] R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0479] R 12A and R 13A Each is independently selected from hydrogen and 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 The combination forms 5- or 6-membered heterocyclic alkyl groups, each of which is attached to a nitrogen atom; and

[0480] R 18A It is C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0481] In some embodiments, the compound of formula IIa(1) is as follows: R 18A It is methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, the compound of formula IIa(1) is as follows: R 18A It is methyl. In some embodiments, the compound of formula IIa(1) is as follows: R 18A It is an ethyl group. In some embodiments, the compound of formula IIa(1) is as follows: R 18A It is isopropyl. In some embodiments, the compound of formula IIa(1) is as follows: R 18A It is cyclopropyl.

[0482] In some embodiments, the compound of formula IIa(1) is as follows: R 8A Selected from 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 heteroaryl compounds.

[0483] In some embodiments, the compound of formula IIa(1) is as follows: R 2A It is pyridyl, pyrimidinyl, pyrazolyl, or pyrazolyl, wherein the pyridyl, pyrimidinyl, pyrazolyl, or pyrazolyl is optionally surrounded by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group comprising one or more atoms each attached. In some embodiments, the compound of formula IIa(1) is such that R 2A is optionally replaced by 1-2 R 8A Substituent-substituted pyridinyl group. In some embodiments, the compound of formula IIa(1) is such that R 2A yes In some embodiments, the compound of formula IIa(1) is such that R 2A is optionally replaced by 1-2 R 8A Substituent-substituted pyrimidinyl group. In some embodiments, the compound of formula IIa(1) is as follows: R 2A yes In some embodiments, the compound of formula IIa(1) is such that R 2A is optionally replaced by 1-2 R8A The substituent is a pyrazyl group. In some embodiments, the compound of formula IIa(1) is such that R 2A is optionally replaced by 1-2 R 8A The substituent is a pyrazolyl group. In some embodiments, the compound of formula IIa(1) is such that R 2A yes In some embodiments, the compound of formula IIa(1) is such that two independent R 8A Substituents combine to form a 5-membered cycloalkyl or 5-membered heterocycloalkyl group, each of which is attached to one or more atoms.

[0484] In some embodiments, the compound of formula IIa(1) is such that R 1A and R 2A Together with the nitrogen atoms attached to them, they have the following structure: In some embodiments, the compound of formula IIa(1) is such that R 1A and R 2A Together with the nitrogen atoms attached to them, they have the following structure:

[0485] In some embodiments, the compounds of formula IIa(1) are selected from 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 compounds of formula IIa(1) are selected from compounds 6, 84, 100, 102, 104, 124, 221, 222, 235, 238, 252, 255, 260, and 267.

[0486] In some embodiments, the compound of formula I is a compound of formula IIb:

[0487]

[0488]

[0489] Or in a pharmaceutically acceptable form, wherein:

[0490] R 1A and R 2A Combining to form 4-6 membered heterocyclic alkyl groups comprising nitrogen atoms to which they are all attached, optionally wherein R 1A and R2A The 4-6 membered heterocyclic alkyl group formed is fused with a 6 membered heteroaryl group;

[0491] R 3A It is C 1-3 alkyl or phenyl, wherein the C 1-3 Alkyl and phenyl groups are each independently and optionally marked with 1-3 R groups. 9A Substituent substitution;

[0492] R 4A It is a phenyl or a 5-membered heteroaryl group, wherein the phenyl and the 5-membered heteroaryl group are each optionally independently bound by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0493] R 5A It is hydrogen;

[0494] R 6A It is methyl;

[0495] R 7A It is methyl;

[0496] R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0497] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0498] R 11A It is C 1-6 Alkyl, C 3-6Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0499] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 Alkoxy;

[0500] m is 0 or 1; and

[0501] Where R 1A and R 2A Combination R 6A It is a methyl group, m is 0, and R SA When it is H, R 3A and R 4A At least one of them is not an unsubstituted phenyl group.

[0502] In some embodiments, the compound of formula IIb is as follows:

[0503] R 1A and R 2A Combination

[0504] R 3A It is -CH3, unsubstituted phenyl, (4-methoxy)-phenyl, or isopropyl;

[0505] R 4A yes

[0506] R 5A It is hydrogen;

[0507] R 6A It is methyl; and

[0508] m is 0.

[0509] In some embodiments, the compound of formula IIb is as follows:

[0510] R 1A and R 2A Combination

[0511] R3A It is -CH3 or an unsubstituted phenyl group;

[0512] R 4A yes

[0513] R 5A It is hydrogen;

[0514] R 6A It is methyl; and

[0515] m is 0.

[0516] In some embodiments, the compound of formula I is the compound of formula IIc:

[0517]

[0518] Or in a pharmaceutically acceptable form, wherein:

[0519] R 2A It is hydrogen, C 1-6 Heteroalkyl or 6-membered heteroaryl, wherein the C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each optionally surrounded by 1-3 R groups. 8A Substituent substitution;

[0520] R 3A It is C 1-3 alkyl or phenyl, wherein the C 1-3 Alkyl or phenyl groups are each optionally independently bound by 1-3 R groups. 9A Substituent substitution;

[0521] R 4A It is hydrogen, phenyl, or a 5- or 6-membered heteroaryl group, wherein the phenyl and the 5- or 6-membered heteroaryl group are each optionally independently bound by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0522] R 5A It is hydrogen;

[0523] R 6A It is methyl;

[0524] R 7A It is methyl;

[0525] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0526] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0527] R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0528] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 Alkoxy;

[0529] m is 0 or 1; and

[0530] Where R 2A It is H, R 6A It is a methyl group, m is 0, and R SA When it is H, R 3A and R 4A At least one of them is not an unsubstituted phenyl group.

[0531] In some embodiments, the compound of formula IIc is as follows:

[0532] R 2A Together with the attached oxygen, it has the following structure: -OH,

[0533] R 3A It is -CH3 or an unsubstituted phenyl group;

[0534] R 4A It is hydrogen, unsubstituted phenyl,

[0535] R 5A It is hydrogen;

[0536] R 6A It is methyl; and

[0537] m is 0.

[0538] In some embodiments, the compound of formula I is the compound of formula III:

[0539]

[0540] Or in a pharmaceutically acceptable form, wherein:

[0541] X is NR 1A R 2A OR 2A ;

[0542] R 1A Is it hydrogen or C? 1-6 alkyl;

[0543] R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A Substituents combine to form 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl groups, each with one or more atoms attached; or R 1A and R 2A They combine to form 3-6 membered heterocyclic alkyl groups, each of which has a nitrogen atom attached to it.

[0544] R 3A It is C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0545] R 4A It is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0546] R 5A Is it hydrogen or C? 1-6 alkyl;

[0547] R 6A and R 7A Each is C independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0548] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0549] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0550] R11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0551] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy; and

[0552] m can be 0, 1, or 2.

[0553] In some embodiments, the compound of formula I is a compound of formula IIia:

[0554]

[0555] Or in a pharmaceutically acceptable form, wherein:

[0556] R 1A It is hydrogen;

[0557] R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0558] R 3A It is C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0559] R 4AIt is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. i0A Substituent substitution, optionally involving two independent R groups. i0A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0560] R 5A Is it hydrogen or C? 1-6 alkyl;

[0561] R 6A and R 7A Each is C independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0562] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0563] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0564] R 11A It is C 1-6 Alkyl, C3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0565] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy; and

[0566] m can be 0, 1, or 2.

[0567] In some embodiments, the compound of formula I is a compound of formula IIIb:

[0568]

[0569] Or in a pharmaceutically acceptable form, wherein:

[0570] R 1A and R 2A They combine to form 4-6 membered heterocyclic alkyl groups, each of which has a nitrogen atom attached to it.

[0571] R 3A It is C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0572] R 4A It is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0573] R 5A Is it hydrogen or C? 1-6 alkyl;

[0574] R 6A and R 7A Each is C independently 1-6 Alkyl, C3-6 Cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0575] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0576] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0577] R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0578] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6alkoxy; and

[0579] m can be 0, 1, or 2.

[0580] In some embodiments, the compound of formula I is a compound of formula IIIc:

[0581]

[0582]

[0583] Or in a pharmaceutically acceptable form, wherein:

[0584] R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution;

[0585] R 3A It is C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0586] R 4A It is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0587] R 5A Is it hydrogen or C? 1-6 alkyl;

[0588] R 6A and R 7A Each is C independently 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl groups and C1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0589] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0590] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0591] R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0592] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy; and

[0593] m can be 0, 1, or 2.

[0594] In some embodiments, the compound of formula I is the compound of formula IV:

[0595]

[0596] Or in a pharmaceutically acceptable form, wherein:

[0597] X is -NR 1A R 2A OR 2A ;

[0598] R iA Is it hydrogen or C? 1-6 alkyl;

[0599] R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A Substituents combine to form 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl groups, each with one or more atoms attached; or R iA and R 2A They combine to form 3-6 membered heterocyclic alkyl groups, each of which has a nitrogen atom attached to it.

[0600] R 3A It is C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0601] R 4A It is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0602] R 5A Is it hydrogen or C? 1-6 alkyl;

[0603] R 7A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C1-6 Halogenated alkyl, aryl, C 5-10 heteroaryl, C 3-7 Heterocycloalkyl, C 1-6 Heteroalkyl, halogen, -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, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, aryl, C 5-10 heteroaryl, C 3-7 Heterocyclic alkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0604] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0605] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0606] R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0607] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy; and

[0608] m can be 0, 1, 2, 3, or 4.

[0609] In some embodiments, the compound of formula I is a compound of formula IVa:

[0610]

[0611]

[0612] Or in a pharmaceutically acceptable form, wherein:

[0613] R 1A It is hydrogen;

[0614] R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 The heteroalkyl and 6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution, optionally involving two independent R groups. 8A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0615] R 3A It is C 1-6 alkyl or phenyl, wherein the C 1-6 Alkyl and phenyl groups are each independently and optionally marked with 1-3 R groups. 9A Substituent substitution;

[0616] R 4A It is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0617] R 5A It is hydrogen;

[0618] R 7A It is methyl;

[0619] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0620] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0621] R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0622] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy; and

[0623] m can be 0, 1, 2, 3, or 4.

[0624] In some implementations, the compound of formula IVa is as follows:

[0625] R 1A and R 2A Together with the nitrogen atoms attached to them, they have the following structure:

[0626] R 3A It is -CH3 or phenyl;

[0627] R 4A yes

[0628] R SA It is hydrogen;

[0629] R 7A It is methyl; and

[0630] m is 0.

[0631] In some embodiments, the compound of formula I is a compound of formula IVb:

[0632]

[0633] Or in a pharmaceutically acceptable form, wherein:

[0634] R 1A and R 2A They combine to form 4-6 membered heterocyclic alkyl groups, each of which has a nitrogen atom attached to it.

[0635] R 3A It is C 1-6 alkyl or phenyl, wherein the C 1-6 Alkyl and phenyl groups are each independently and optionally marked with 1-3 R groups. 9A Substituent substitution;

[0636] R 4A It is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally surrounded by 1-3 R groups. 10A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0637] R 5A It is hydrogen;

[0638] R 7A It is methyl;

[0639] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0640] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0641] R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0642] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy; and

[0643] m can be 0, 1, 2, 3, or 4.

[0644] In some implementations, the compound of formula IVb is as follows:

[0645] R 1A and R 2A Combination

[0646] R 3A It is -CH3 or phenyl;

[0647] R 4A yes

[0648] R 5A It is hydrogen;

[0649] R 7A It is methyl; and

[0650] m is 0.

[0651] In some embodiments, the compound of formula I is a compound of formula IVc:

[0652]

[0653] Or in a pharmaceutically acceptable form, wherein:

[0654] R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 5-6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl groups and 5-6-membered heteroaryl groups are each independently and optionally bound by 1-3 R groups. 8A Substituent substitution;

[0655] R 3A It is C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl, or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 heteroaryl groups are each independently and optionally bound by 1-3 R groups. 9A Substituent substitution;

[0656] R 4A It is hydrogen, phenyl, or 5-10 heteroaryl, wherein the phenyl and 5-10 heteroaryl groups are each optionally independently surrounded by 1-3 R groups. i0A Substituent substitution, optionally involving two independent R groups. 10A The substituents combine to form a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, each of which is attached to one or more atoms;

[0657] R 5A It is hydrogen;

[0658] R 7A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0659] R 8A and R 9A Each is independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -(CO)R 11A , Oxygen, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy or 5-6 membered heteroaryl;

[0660] R 10A Independently selected from halogen groups, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclic alkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A Or 5-6 heteroaryl groups;

[0661] R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 cycloalkyl and C 1-6 Each heteroalkyl group is independently and optionally bound by 1-3 R 8A Substituent substitution;

[0662] R 12A and R 13A Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, -OH or C 1-6 alkoxy; and

[0663] m can be 0, 1, 2, 3, or 4.

[0664] In some implementations, the compound of formula IVc is as follows:

[0665] R2A It is hydrogen;

[0666] R 3A It is -CH3;

[0667] R 4A yes

[0668] R SA It is hydrogen;

[0669] R 7A It is methyl;

[0670] m is 0.

[0671] In one embodiment, the compound of formula I, Ia, II or IIb is such that Y, X, R 1A 、R 2A 、R 3A 、R 4A and R SA The combination of substituents does not form:

[0672] In one embodiment, the compound of formula I, Ia, II, or IIb is not

[0673] 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 not more than 1000 g / mol. In one embodiment, the compound has a MW of not more than 900 g / mol, not more than 800 g / mol, not more than 700 g / mol, not more than 600 g / mol, or not more than 500 g / mol. In one embodiment, the compound has a MW of not more than 900 g / mol. In one embodiment, the compound has a MW of not more than 800 g / mol. In one embodiment, the compound has a MW of not more than 700 g / mol. In one embodiment, the compound has a MW of not more than 600 g / mol. In one embodiment, the compound has a MW of not more than 500 g / mol. In one embodiment, the compound has a MW of not more than 450 g / mol.

[0674] In one embodiment, the compounds of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc are selected from 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, 10 0, 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, 1 94, 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, 22 5, 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, 256257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275 and 276, or their pharmaceutically acceptable forms.

[0675] 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 the 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 its pharmaceutically acceptable form, according to a Ras superfamily activity assay, 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. In one embodiment, the compound or its pharmaceutically acceptable form, according to a Ras superfamily activity assay, modulates the Ras superfamily activity of one or more GTPases by 45% or more at 20 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to a Ras superfamily activity assay, modulates the Ras superfamily activity of one or more GTPases by 50% or more at 20 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to a Ras superfamily activity assay, modulates the Ras superfamily activity of one or more GTPases by 75% or more at 20 μM. In one embodiment, according to a Ras superfamily activity assay, the compound or its pharmaceutically acceptable form modulates the Ras superfamily activity of one or more GTPases by 90% or more at 20 μM. In one embodiment, according to a Ras superfamily activity assay, the compound or its pharmaceutically acceptable form modulates the Ras superfamily activity of one or more GTPases by 95% or more at 20 μM. In one embodiment, according to a Ras superfamily activity assay, the compound or its pharmaceutically acceptable form modulates the Ras superfamily activity of one or more GTPases by about 50% to about 60% at 20 μM. In one embodiment, according to a Ras superfamily activity assay, the compound or its pharmaceutically acceptable form modulates the Ras superfamily activity of one or more GTPases by about 60% to about 70% at 20 μM. In one embodiment, according to a Ras superfamily activity assay, the compound or its pharmaceutically acceptable form modulates the Ras superfamily activity of one or more GTPases by about 70% to about 80% at 20 μM.In one embodiment, the compound or its pharmaceutically acceptable form 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 another embodiment, the compound or its pharmaceutically acceptable form modulates the 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 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, 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, 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 their pharmaceutically acceptable forms.In one embodiment, the compound is selected from 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, 9 7, 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, 1 51, 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, 23 2, 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 their pharmaceutically acceptable forms.

[0676] 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 phosphorylation of Erk1 / 2, as determined by an Erk1 / 2 phosphorylation assay. In one embodiment, the compound, or a pharmaceutically acceptable form thereof, inhibits the 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, as determined by an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by an Erk1 / 2 phosphorylation assay, inhibits the 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. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by an Erk1 / 2 phosphorylation assay, inhibits the phosphorylation of Erk1 / 2 by 50% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by an Erk1 / 2 phosphorylation assay, inhibits the phosphorylation of Erk1 / 2 by 75% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by an Erk1 / 2 phosphorylation assay, inhibits the phosphorylation of Erk1 / 2 by 80% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by an Erk1 / 2 phosphorylation assay, inhibits the phosphorylation of Erk1 / 2 by 85% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by an Erk1 / 2 phosphorylation assay, inhibits the phosphorylation of Erk1 / 2 by 90% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by an Erk1 / 2 phosphorylation assay, inhibits the phosphorylation of Erk1 / 2 by 95% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by an Erk1 / 2 phosphorylation assay, inhibits the phosphorylation of Erk1 / 2 by about 50% to about 60% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by an Erk1 / 2 phosphorylation assay, inhibits the phosphorylation of Erk1 / 2 by about 60% to about 70% at 10 μM. In one embodiment, based on Erk1 / 2 phosphorylation assays, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Erk1 / 2 by about 70% to about 80% at 10 μM.In one embodiment, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Erk1 / 2 by about 80% to about 90% at 10 μM, based on an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Erk1 / 2 by about 90% to about 100% at 10 μM, based on an Erk1 / 2 phosphorylation assay. In one embodiment, the compound is selected from 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 their pharmaceutically acceptable forms. In one embodiment, the compound is selected from 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 their pharmaceutically acceptable forms.

[0677] In one embodiment, according to an Erk1 / 2 phosphorylation assay, 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 the phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal to or greater than 100% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form activates the 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 its pharmaceutically acceptable form activates the phosphorylation of Erk1 / 2 by 50% or more at 10 μM, according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Erk1 / 2 by 75% or more at 10 μM, according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Erk1 / 2 by 85% or more at 10 μM, according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Erk1 / 2 by 90% or more at 10 μM, according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Erk1 / 2 by 95% or more at 10 μM, according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Erk1 / 2 by 100% or more at 10 μM, according to an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the 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 its pharmaceutically acceptable form activates the phosphorylation of Erk1 / 2 by about 60% to about 70% at 10 μM, according to an Erk1 / 2 phosphorylation assay. In one embodiment, based on Erk1 / 2 phosphorylation assays, the compound or its pharmaceutically acceptable form activates the phosphorylation of Erk1 / 2 by about 70% to about 80% at 10 μM.In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Erk1 / 2 by about 80% to about 90% at 10 μM, based on an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Erk1 / 2 by about 90% to about 100% at 10 μM, based on an Erk1 / 2 phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Erk1 / 2 by about 100% or more at 10 μM, based on an Erk1 / 2 phosphorylation assay. In one embodiment, the compound is selected from 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, 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 their pharmaceutically acceptable forms. In one embodiment, the compound is selected from 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, 1 75, 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 their pharmaceutically acceptable forms.

[0678] In one embodiment, according to an Akt phosphorylation assay, 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 phosphorylation of Akt. In one embodiment, according to an Akt phosphorylation assay, the compound or a pharmaceutically acceptable form thereof inhibits the 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. In one embodiment, according to an Akt phosphorylation assay, the compound or a pharmaceutically acceptable form thereof inhibits the 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% of the phosphorylation of Akt. In one embodiment, the compound or its pharmaceutically acceptable form, according to an Akt phosphorylation assay, inhibits Akt phosphorylation by 50% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to an Akt phosphorylation assay, inhibits Akt phosphorylation by 75% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to an Akt phosphorylation assay, inhibits Akt phosphorylation by 85% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to an Akt phosphorylation assay, inhibits Akt phosphorylation by 90% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to an Akt phosphorylation assay, inhibits Akt phosphorylation by 95% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to an Akt phosphorylation assay, inhibits Akt phosphorylation by about 50% to about 60% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by an Akt phosphorylation assay, inhibits Akt phosphorylation by about 60% to about 70% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by an Akt phosphorylation assay, inhibits Akt phosphorylation by about 70% to about 80% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by an Akt phosphorylation assay, inhibits Akt phosphorylation by about 80% to about 90% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by an Akt phosphorylation assay, inhibits Akt phosphorylation by about 90% to about 100% at 10 μM.In one embodiment, the compound is selected from compounds 17, 20, 23, 25, 29, 30, 31, 32, 33, 34, 42, 203, 209, 210, 219, 270, 271, 272, 273, and 274, or in a pharmaceutically acceptable form thereof. In one embodiment, the compound...

[0679] In one embodiment, according to an Akt phosphorylation assay, 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 Akt phosphorylation by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal to or greater than 100% at 10 μM. In one embodiment, according to an Akt phosphorylation assay, the compound or its pharmaceutically acceptable form activates the 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. In one embodiment, according to an Akt phosphorylation assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by 50% or more at 10 μM. In one embodiment, according to an Akt phosphorylation assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by 75% or more at 10 μM. In one embodiment, according to an Akt phosphorylation assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by 85% or more at 10 μM. In one embodiment, according to an Akt phosphorylation assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by 90% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by 95% or more at 10 μM, according to an Akt phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by equal to or greater than 100% at 10 μM, according to an Akt phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by about 50% to about 60% at 10 μM, according to an Akt phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by about 60% to about 70% at 10 μM, according to an Akt phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by about 70% to about 80% at 10 μM, according to an Akt phosphorylation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by about 80% to about 90% at 10 μM, according to an Akt phosphorylation assay.In one embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by about 90% to about 100% at 10 μM, according to an Akt phosphorylation assay. In another embodiment, the compound or its pharmaceutically acceptable form activates the phosphorylation of Akt by about 100% or more at 10 μM, according to an Akt phosphorylation assay. In one embodiment, the compound is selected from 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, 9 4, 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, 13 / , 138, 143, 145, 149, 1 51, 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 their pharmaceutically acceptable forms.

[0680] In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, 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 phosphorylation of Smad2 / 3. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or a pharmaceutically acceptable form thereof inhibits the 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. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form inhibits the 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. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Smad2 / 3 by 50% or more at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Smad2 / 3 by 75% or more at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Smad2 / 3 by 80% or more at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Smad2 / 3 by 85% or more at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Smad2 / 3 by 90% or more at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Smad2 / 3 by 95% or more at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Smad2 / 3 by about 50% to about 60% at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Smad2 / 3 by about 60% to about 70% at 10 μM. In one embodiment, based on a phosphorylated Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Smad2 / 3 by about 70% to about 80% at 10 μM.In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Smad2 / 3 by about 80% to about 90% at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form inhibits the phosphorylation of Smad2 / 3 by about 90% to about 100% at 10 μM. In one embodiment, the compound is selected from 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 their pharmaceutically acceptable forms. In one embodiment, the compound is selected from 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 in a pharmaceutically acceptable form thereof.

[0681] In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, 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 the phosphorylation of Smad2 / 3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal to or greater than 100% at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the 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. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Smad2 / 3 by 50% or more at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Smad2 / 3 by 75% or more at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Smad2 / 3 by 85% or more at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Smad2 / 3 by 90% or more at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Smad2 / 3 by 95% or more at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Smad2 / 3 by 100% or more at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Smad2 / 3 by about 50% to about 60% at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Smad2 / 3 by about 60% to about 70% at 10 μM.In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Smad2 / 3 by about 70% to about 80% at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Smad2 / 3 by about 80% to about 90% at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Smad2 / 3 by about 90% to about 100% at 10 μM. In one embodiment, according to a phosphate-Smad2 / 3 inhibition assay, the compound or its pharmaceutically acceptable form activates the phosphorylation of Smad2 / 3 by about 100% or more at 10 μM. In one embodiment, the compound is selected from 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 in a pharmaceutically acceptable form thereof.

[0682] In one embodiment, according to a JNK activation assay, 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. In one embodiment, according to a JNK activation assay, 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. In one embodiment, according to a JNK activation assay, 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. In one embodiment, the compound or its pharmaceutically acceptable form, according to a JNK activation assay, inhibits JNK by 25% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to a JNK activation assay, inhibits JNK by 30% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to a JNK activation assay, inhibits JNK by 50% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to a JNK activation assay, inhibits JNK by 75% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to a JNK activation assay, inhibits JNK by 85% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to a JNK activation assay, inhibits JNK by 90% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to a JNK activation assay, inhibits JNK by 95% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to a JNK activation assay, inhibits JNK by about 50% to about 60% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to a JNK activation assay, inhibits JNK by about 60% to about 70% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to a JNK activation assay, inhibits JNK by about 70% to about 80% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, according to a JNK activation assay, inhibits JNK by about 80% to about 90% at 10 μM.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 compounds 29, 30, 32, 33, and 34, or pharmaceutically acceptable forms thereof. In one embodiment, the compound is selected from compounds 29, 32, and 34, or pharmaceutically acceptable forms thereof. In one embodiment, the compound is selected from compounds 29, 32, and 34, or pharmaceutically acceptable forms thereof.

[0683] In one embodiment, according to a JNK activation assay, 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 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 equal to or greater than 100%. In one embodiment, according to a JNK activation assay, the compound or its pharmaceutically acceptable form 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. In one embodiment, according to a JNK activation assay, the compound or its pharmaceutically acceptable form activates JNK by 25% or more at 10 μM. In one embodiment, according to a JNK activation assay, the compound or its pharmaceutically acceptable form activates JNK by 30% or more at 10 μM. In one embodiment, according to a JNK activation assay, the compound or its pharmaceutically acceptable form activates JNK by 50% or more at 10 μM. In one embodiment, according to a JNK activation assay, the compound or its pharmaceutically acceptable form activates JNK by 75% or more at 10 μM. In one embodiment, according to a JNK activation assay, the compound or its pharmaceutically acceptable form activates JNK by 85% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form activates JNK by 90% or more at 10 μM, according to a JNK activation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates JNK by 95% or more at 10 μM, according to a JNK activation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates JNK by 100% or more at 10 μM, according to a JNK activation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates JNK by about 50% to about 60% at 10 μM, according to a JNK activation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates JNK by about 60% to about 70% at 10 μM, according to a JNK activation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates JNK by about 70% to about 80% at 10 μM, according to a JNK activation assay.In one embodiment, the compound or its pharmaceutically acceptable form activates JNK by about 80% to about 90% at 10 μM, according to a JNK activation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates JNK by about 90% to about 100% at 10 μM, according to a JNK activation assay. In one embodiment, the compound or its pharmaceutically acceptable form activates JNK by about 100% or more at 10 μM, according to a JNK activation assay. In one embodiment, the compound is selected from 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 their pharmaceutically acceptable forms. In one embodiment, the compound is selected from 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 their pharmaceutically acceptable forms. In one embodiment, the compound is selected from 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 their pharmaceutically acceptable forms.

[0684] 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, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form 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. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form inhibits MAPK p38 by 25% or more at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form inhibits MAPK p38 by 30% or more at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form inhibits MAPK p38 by 50% or more at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form inhibits MAPK p38 by 75% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form inhibits MAPK p38 by 85% or more at 10 μM, according to a MAPK p38 activation assay. In one embodiment, the compound or its pharmaceutically acceptable form inhibits MAPK p38 by 90% or more at 10 μM, according to a MAPK p38 activation assay. In one embodiment, the compound or its pharmaceutically acceptable form 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 its pharmaceutically acceptable form 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 its pharmaceutically acceptable form 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 its pharmaceutically acceptable form, as determined by a MAPK p38 activation assay, inhibits MAPK p38 by about 80% to about 90% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by a MAPK p38 activation assay, inhibits MAPK p38 by about 90% to about 100% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by a MAPK p38 activation assay, inhibits MAPK p38 by 95% or more at 10 μM. In one embodiment, the compound is selected from 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 their pharmaceutically acceptable forms. In one embodiment, the compound is selected from compounds 29, 32, 33, 34, 46, 207 and 209 or their pharmaceutically acceptable forms.

[0685] 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 equal to or greater than 100%. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form 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. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by 25% or more at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by 30% or more at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by 50% or more at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by 75% or more at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by 85% or more at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by 90% or more at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by 95% or more at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by equal to or greater than 100% at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by about 50% to about 60% at 10 μM.In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by about 60% to about 70% at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by about 70% to about 80% at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by about 80% to about 90% at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by about 90% to about 1000% at 10 μM. In one embodiment, according to a MAPK p38 activation assay, the compound or its pharmaceutically acceptable form activates MAPK p38 by about 100% or more at 10 μM. In one embodiment, the compound is selected from 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 in a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from 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 their pharmaceutically acceptable forms. In one embodiment, the compound is selected from 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 their pharmaceutically acceptable forms.

[0686] In one embodiment, according to a proliferation assay, 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 MiaPaca2. In one embodiment, according to a proliferation assay, the compound or a pharmaceutically acceptable form thereof inhibits the proliferation of MiaPaca2 with an IC50 value of 1.25 μM or less, 1.1 μM or less, 1 μM or less, 0.9 μM or less, 0.8 μM or less, 0.75 μM or less, 0.7 μM or less, 0.6 μM or less, 0.5 μM or less, 0.4 μM or less, 0.3 μM or less, 0.25 μM or less, 0.2 μM or less, 0.15 μM or less, or 0.1 μM or less. In one embodiment, based on a proliferation assay, the compound or its pharmaceutically acceptable form is present in amounts from about 1.25 μM to about 1.1 μM, from about 1.1 μM to about 1 μM, from about 1.0 μM to about 0.9 μM, from about 0.9 μM to about 0.8 μM, from about 0.8 μM to about 0.75 μM, from about 0.75 μM to about 0.7 μM, from about 0.7 μM to about 0.6 μM, from about 0.6 μM to about 0.5 μM, from about 0.5 μM to about 0.4 μM. The compound inhibits the proliferation of MiaPaca2 with IC50 values ​​of 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, based on a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of 1.25 μM or less. In another embodiment, based on a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of 1 μM or less. In one embodiment, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of 0.6 μM or less, according to a proliferation assay. In one embodiment, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of 0.5 μM or less, according to a proliferation assay. In one embodiment, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of 0.4 μM or less, according to a proliferation assay. In one embodiment, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of 0.3 μM or less, according to a proliferation assay.In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of 0.25 μM or less. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of 0.20 μM or less. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of 0.15 μM or less. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of 0.10 μM or less. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 1.25 μM to about 1.1 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 1.1 μM to about 1 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 1.0 μM to about 0.9 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.9 μM to about 0.8 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.8 μM to about 0.75 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.75 M to about 0.7 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.7 μM to about 0.6 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.6 μM to about 0.5 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.5 μM to about 0.4 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.4 μM to about 0.3 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.3 μM to about 0.25 μM.In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.25 μM to about 0.2 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.2 μM to about 0.15 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.15 μM to about 0.1 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.1 μM to about 0.01 μM. In one embodiment, according to a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.01 μM to about 0.001 μM. In one embodiment, based on a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of about 0.001 μM to about 0.0001 μM. In another embodiment, based on a proliferation assay, the compound or its pharmaceutically acceptable form inhibits the proliferation of MiaPaca2 with an IC50 value of less than about 0.0001 μM.In one embodiment, the compound is selected from 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, 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, 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, 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 their pharmaceutically acceptable forms.In one embodiment, the compound is selected from 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, 9 4, 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, 1 39, 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 their pharmaceutically acceptable forms.In one embodiment, the compound is selected from 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, 13 8, 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 their pharmaceutically acceptable forms. In one embodiment, the compound is selected from 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, 1 39, 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 their pharmaceutically acceptable forms.

[0687] 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. 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. 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. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by IL-6 quantification, inhibits IL-6 by 50% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by IL-6 quantification, inhibits IL-6 by 75% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by IL-6 quantification, inhibits IL-6 by 85% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by IL-6 quantification, inhibits IL-6 by 90% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by IL-6 quantification, inhibits IL-6 by 95% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by IL-6 quantification, inhibits IL-6 by about 50% to about 60% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by IL-6 quantification, inhibits IL-6 by about 60% to about 70% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by IL-6 quantification, inhibits IL-6 by about 70% to about 80% at 10 μM. In another embodiment, the compound or its pharmaceutically acceptable form, as determined by IL-6 quantification, inhibits IL-6 by about 80% to about 90% at 10 μM. In yet another embodiment, the compound or its pharmaceutically acceptable form, as determined by IL-6 quantification, inhibits IL-6 by about 90% to about 100% at 10 μM.In one embodiment, the compound is selected from 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, and 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 their pharmaceutically acceptable forms.

[0688] 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-α according to a TNF-α quantification. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits TNF-α 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-α quantification. In one embodiment, the compound or a pharmaceutically acceptable form thereof inhibits TNF-α 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-α quantification. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by a TNF-α quantification, inhibits TNF-α by 50% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by a TNF-α quantification, inhibits TNF-α by 75% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by a TNF-α quantification, inhibits TNF-α by 85% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by a TNF-α quantification, inhibits TNF-α by 90% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by a TNF-α quantification, inhibits TNF-α by 95% or more at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by a TNF-α quantification, inhibits TNF-α by about 50% to about 60% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by a TNF-α quantification, inhibits TNF-α by about 60% to about 70% at 10 μM. In one embodiment, the compound or its pharmaceutically acceptable form, as determined by a TNF-α quantification, inhibits TNF-α by about 70% to about 80% at 10 μM. In another embodiment, the compound or its pharmaceutically acceptable form, as determined by a TNF-α quantification, inhibits TNF-α by about 80% to about 90% at 10 μM. In yet another embodiment, the compound or its pharmaceutically acceptable form, as determined by a TNF-α quantification, inhibits TNF-α by about 90% to about 100% at 10 μM.In one embodiment, the compound is selected from 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 their pharmaceutically acceptable forms.

[0689] 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 in a pH 7.4 buffer containing 2% DMSO 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, according to a kinetic solubility determination. In one embodiment, the compound has a kinetic solubility of 10 μM or greater in a pH 7.4 buffer containing 2% DMSO, according to a kinetic solubility determination. In one embodiment, the compound has a kinetic solubility of 20 μM or greater in a pH 7.4 buffer containing 2% DMSO, according to a kinetic solubility determination. In one embodiment, the compound has a kinetic solubility of 30 μM or greater in a pH 7.4 buffer containing 2% DMSO, as determined by kinetic solubility determination. In one embodiment, the compound has a kinetic solubility of 40 μM or greater in a pH 7.4 buffer containing 2% DMSO, as determined by kinetic solubility determination. In one embodiment, the compound has a kinetic solubility of 50 μM or greater in a pH 7.4 buffer containing 2% DMSO, as determined by kinetic solubility determination. In one embodiment, the compound has a kinetic solubility of 60 μM or greater in a pH 7.4 buffer containing 2% DMSO, as determined by kinetic solubility determination. In one embodiment, the compound has a kinetic solubility of 70 μM or greater in a pH 7.4 buffer containing 2% DMSO, as determined by kinetic solubility determination. In one embodiment, the compound has a kinetic solubility of 80 μM or greater in a pH 7.4 buffer containing 2% DMSO, as determined by kinetic solubility determination. In one embodiment, the compound has a kinetic solubility of 90 μM or greater in a pH 7.4 buffer containing 2% DMSO, as determined by 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, as determined by 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, as determined by kinetic solubility assay. In one embodiment, the compound has a kinetic solubility of 200 μM or greater in a pH 7.4 buffer containing 2% DMSO, as determined by kinetic solubility assay.In one embodiment, the compound is selected from compounds 53, 55, 57, 58, 84, 91, 100, 102, 116, 118, 124, 137, 141, 142, 145, 158, 221, 222, 255, and 267, or in a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from compounds 91, 102, 118, and 255, or in a pharmaceutically acceptable form thereof.

[0690] 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, or its pharmaceutically acceptable form, has a half-life in mouse liver microsomes of 10 minutes or longer, 20 minutes or longer, 30 minutes or longer, 40 minutes or longer, or 50 minutes or longer, according to a mouse liver microsomal metabolic stability assay. In one embodiment, the compound has a half-life in mouse liver microsomes of 10 minutes or longer, according to a mouse liver microsomal metabolic stability assay. In one embodiment, the compound has a half-life in mouse liver microsomes of 20 minutes or longer, according to a mouse liver microsomal metabolic stability assay. In one embodiment, the compound has a half-life in mouse liver microsomes of 30 minutes or longer, according to a mouse liver microsomal metabolic stability assay. In one embodiment, the compound has a half-life in mouse liver microsomes of 40 minutes or longer, according to a mouse liver microsomal metabolic stability assay. In one embodiment, the compound has a half-life of 50 minutes or longer in mouse liver microsomes, as determined by a mouse liver microsomal metabolic stability assay. In one embodiment, the compound is selected from 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 in a pharmaceutically acceptable form thereof.

[0691] In one embodiment, according to a proliferation assay, a compound of formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or in a pharmaceutically acceptable form thereof, inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1. In one embodiment, according to a proliferation assay, the compound inhibits the proliferation of NCI-H358. In one embodiment, according to a proliferation assay, the compound inhibits the proliferation of A375. In one embodiment, according to a proliferation assay, the compound inhibits the proliferation of GP2d. In one embodiment, according to a proliferation assay, the compound inhibits the proliferation of MM.R1. In one embodiment, according to a proliferation assay, the compound is present at an IC50 concentration 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 The compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1. In one embodiment, based on proliferation assays, the compound inhibits proliferation at 50 nM or less via an IC50 concentration. 50 The compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1. In one embodiment, based on proliferation assays, the compound inhibits proliferation at an IC50 concentration of 40 nM or less. 50 The compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1. In one embodiment, based on proliferation assays, the compound inhibits proliferation at 30 nM or less via an IC50 concentration. 50 The compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1. In one embodiment, based on proliferation assays, the compound inhibits proliferation at 20 nM or less via an IC50 concentration. 50 The compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1. In one embodiment, based on proliferation assays, the compound inhibits proliferation at 10 nM or less via an IC50 concentration. 50 The compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1. In one embodiment, based on proliferation assays, the compound inhibits proliferation at 1 nM or less via IC50. 50 The compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1. In one embodiment, based on proliferation assays, the compound inhibits proliferation at 0.1 nM or less via an IC50 concentration. 50 The compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1. In one embodiment, based on proliferation assays, the compound inhibits proliferation at 0.01 nM or less via an IC50 concentration.50 The value inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1. In one embodiment, based on proliferation assays, the compound inhibits the proliferation of NCI-H358, A375, GP2d, BT549, or MM.R1 at IC50 values ​​of 1 nM or less, 0.1 nM or less, or 0.01 nM or less. 50 The compound inhibits the proliferation of MM.R1. In one embodiment, based on proliferation assays, the compound inhibits the proliferation of MM.R1 at an IC50 concentration of 1 nM or less. 50 The compound inhibits the proliferation of MM.R1. In one embodiment, based on proliferation assays, the compound inhibits the proliferation of MM.R1 at an IC50 concentration of 0.1 nM or less. 50 The compound inhibits the proliferation of MM.R1. In one embodiment, based on proliferation assays, the compound inhibits the proliferation of MM.R1 at an IC50 concentration of 0.01 nM or less. 50 The compound inhibits the proliferation of MM.R1. In one embodiment, the compound is selected from compounds 6, 58, 84, 100, 102, 104, 124, 221, 222, 235, 238, 252, 255 and 267 or their pharmaceutically acceptable forms.

[0692] In one embodiment, the 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, the pharmaceutically acceptable form of the compound does not include the salt form. In one embodiment, the isomer of the compound is a diastereomer or enantiomer of the compound.

[0693] 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.

[0694] 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 mixture of racemic or diastereomers.

[0695] 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 single enantiomer or a single diastereomer.

[0696] 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 an (R) enantiomer. In one embodiment, the compound has an enantiomeric excess of more than 10% of the (R) enantiomer. In one embodiment, the compound has an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (R) enantiomer. In one embodiment, the compound has an enantiomeric excess of 15% or more of the (R) enantiomer. In one embodiment, the compound has 25% or more of an enantiomer in excess of (R) enantiomers. In one embodiment, the compound has 50% or more of an enantiomer in excess of (R) enantiomers. In one embodiment, the compound has 75% or more of an enantiomer in excess of (R) enantiomers. In one embodiment, the compound has 90% or more of an enantiomer in excess of (R) enantiomers. In one embodiment, the compound has 95% or more of an enantiomer in excess of (R) enantiomers. In one embodiment, the compound has 98% or more of an enantiomer in excess of (R) enantiomers. In one embodiment, the compound has 99% or more of an enantiomer in excess of (R) enantiomers. In one embodiment, the compound has an enantiomer excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% (R) enantiomer.

[0697] 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 an (S) enantiomer. In one embodiment, the compound has an enantiomer excess of more than 10% of the (S) enantiomer. In one embodiment, the compound has an enantiomer excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (S) enantiomer. In one embodiment, the compound has an enantiomer excess of 15% or more of the (S) enantiomer. In one embodiment, the compound has 25% or more of an enantiomer in excess of the (S) enantiomer. In one embodiment, the compound has 50% or more of an enantiomer in excess of the (S) enantiomer. In one embodiment, the compound has 75% or more of an enantiomer in excess of the (S) enantiomer. In one embodiment, the compound has 90% or more of an enantiomer in excess of the (S) enantiomer. In one embodiment, the compound has 95% or more of an enantiomer in excess of the (S) enantiomer. In one embodiment, the compound has 98% or more of an enantiomer in excess of the (S) enantiomer. In one embodiment, the compound has 99% or more of an enantiomer in excess of the (S) enantiomer. In one embodiment, the compound has an enantiomer 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.

[0698] 3.3. Methods for regulating cell target activity

[0699] This document provides a method for modulating Ras superfamily proteins, 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. This document also provides a method for modulating Ras superfamily proteins, comprising contacting the Ras superfamily protein with an effective amount of a pharmaceutical composition comprising 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, as disclosed below. In some embodiments, the compound is selected from 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, 5 9, 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, 207208, 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 their pharmaceutically acceptable forms.

[0700] In some embodiments of the methods provided herein, the Ras superfamily protein is present in the cell.

[0701] In some embodiments, the method includes contacting the 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 includes contacting the 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 selected from 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, 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, 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 their pharmaceutically acceptable forms.In some embodiments, the compound is selected from 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, 9 7, 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, 1 51, 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, 23 2, 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 their pharmaceutically acceptable forms.

[0702] In some implementations, the methods described herein inhibit Ras superfamily proteins.

[0703] 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; NKIRASI; NRAS; RALA; RALB; RAPIA; RAPIB; RAP2A; RAP2B; RAP2C; RASDI; RASD2; RASLIOA; RASLIOB; RASLI IA; RASLIIB; RASL 12; 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.

[0704] In some embodiments of the methods provided herein, the Ras superfamily protein is a Rac protein or a mutant thereof. In some embodiments, the Rac protein is RAC1; RAC2; RAC3; RHOG, or a mutant thereof. In some embodiments, the Rac protein is wild-type RAC1.

[0705] 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.

[0706] In some embodiments of the methods provided herein, the Ras superfamily protein is the Cdc42 protein or a mutant thereof.

[0707] In some embodiments of the methods provided herein, the Ras superfamily protein is a Rheb protein or a mutant thereof.

[0708] In some embodiments of the methods provided herein, contact with the Ras superfamily protein occurs within 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 has cancer. In some embodiments, the subject is a human.

[0709] In some embodiments of the methods provided herein, modulation occurs in subjects with cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematopoietic 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 bowel cancer, biliary tract cancer, endometrial cancer, skin cancer (melanoma), cervical cancer, urethral 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 Ras superfamily protein-dependent cancer.

[0710] This document provides a method for modulating caspase activity, comprising contacting the 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. This document also provides a method for modulating caspase activity, comprising contacting the caspase with an effective amount of a pharmaceutical composition comprising 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, as disclosed below. In some embodiments, the compound is selected from 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, 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, 1 63, 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, 19 / , 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209210, 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 their pharmaceutically acceptable forms.

[0711] In some embodiments, the method provided herein activates caspase. In some embodiments, the caspase is caspase 3, caspase 6, or caspase 9.

[0712] In some embodiments of the methods provided herein, caspase contact occurs within cells. In some embodiments, regulation of caspase activity induces apoptosis. In some embodiments, the cells are in a subject. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are human cells. In some embodiments, the subject has cancer. In some embodiments, regulation occurs in a subject with cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematopoietic 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 bowel cancer, biliary tract cancer, endometrial cancer, skin cancer (melanoma), cervical cancer, urethral 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 a human.

[0713] This document provides a method for modulating the activity of Erk1 / 2, comprising contacting the 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. This document also provides a method for modulating the activity of Erk1 / 2, comprising contacting the Erk1 / 2 protein with an effective amount of a pharmaceutical composition comprising 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, as disclosed below. In some embodiments, the compound is selected from 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, and 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, 1 16, 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, 16 2, 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, 2 44, 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 their pharmaceutically acceptable forms.

[0714] In some embodiments of the method for modulating Erk1 / 2 activity described herein, the method inhibits the phosphorylation of the Erk1 / 2 protein. In some embodiments, the method includes contacting the Erk1 / 2 protein with a compound or a pharmaceutically acceptable form thereof that inhibits the phosphorylation of the Erk1 / 2 protein by 80% or more at 10 μM, based on an Erk1 / 2 phosphorylation assay. In some embodiments, the method includes contacting the Erk1 / 2 protein with a compound or a pharmaceutically acceptable form thereof that inhibits the phosphorylation of the Erk1 / 2 protein by 85% or more at 10 μM, based on an Erk1 / 2 phosphorylation assay. In some embodiments, the compound is selected from 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 in a pharmaceutically acceptable form thereof.

[0715] In some embodiments of the method for modulating Erk1 / 2 activity described herein, the method activates the phosphorylation of the Erk1 / 2 protein. In some embodiments, the method includes contacting the Erk1 / 2 protein with a compound or a pharmaceutically acceptable form thereof that activates the phosphorylation of the Erk1 / 2 protein by 45% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In some embodiments, the method includes contacting the Erk1 / 2 protein with a compound or a pharmaceutically acceptable form thereof that activates the phosphorylation of the Erk1 / 2 protein by 50% or more at 10 μM according to an Erk1 / 2 phosphorylation assay. In some embodiments, the compound is selected from 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, 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 their pharmaceutically acceptable forms. In some embodiments, the compound is selected from 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, 1 75, 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 their pharmaceutically acceptable forms.

[0716] In some embodiments of the methods provided herein, contact with the Erk1 / 2 protein occurs within 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.

[0717] This document provides methods for modulating Akt activity, comprising contacting 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. This document also provides methods for modulating Akt activity, comprising contacting Akt protein with an effective amount of a pharmaceutical composition comprising 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, as disclosed below. In some embodiments, the compound is selected from 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, and 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, 1l0, 111, 112, 1l3, 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, 19 / , 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211212, 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 their pharmaceutically acceptable forms.

[0718] In some embodiments of the method for modulating Akt activity described herein, the method inhibits the phosphorylation of the Akt protein. In some embodiments, the method includes contacting the Akt protein with a compound, or a pharmaceutically acceptable form thereof, which, according to an Akt phosphorylation assay, inhibits the phosphorylation of the Akt protein by 85% or more at 10 μM. In some embodiments, the compound is selected from 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.

[0719] In some embodiments of the method for modulating Akt activity described herein, the method activates the phosphorylation of the Akt protein. In some embodiments, the method includes contacting the Akt protein with a compound, or a pharmaceutically acceptable form thereof, which, according to an Akt phosphorylation assay, activates the phosphorylation of the Akt protein by 50% or more at 10 μM. In some embodiments, the compound is selected from 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, 9 4, 95, 96, 97, 98, 100, 101, 102, 103, 104, 106, 107, 108, 109, 110, 111, 1l2, 113, 114, 115 ,116,118,119,122,124,125,126,127,128,129,130,135,136,137,138,143,145,149,1 51, 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 their pharmaceutically acceptable forms.

[0720] In some embodiments of the methods provided herein, contact with the Akt protein occurs within 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.

[0721] This document provides methods for modulating Smad2 / 3 activity, comprising contacting the 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. This document also provides methods for modulating Smad2 / 3 activity, comprising contacting the Smad2 / 3 protein with an effective amount of a pharmaceutical composition comprising 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, as disclosed below. In some embodiments, the compound is selected from 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, 5 9, 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, 207208, 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 their pharmaceutically acceptable forms.

[0722] In some embodiments of the method for modulating Smad2 / 3 activity described herein, the method inhibits the phosphorylation of the Smad2 / 3 protein. In some embodiments, the method includes contacting the Smad2 / 3 protein with a compound or a pharmaceutically acceptable form thereof that inhibits the phosphorylation of the Smad2 / 3 protein by 80% or more at 10 μM according to a phosphate-Smad2 / 3 inhibition assay. In some embodiments, the method includes contacting the Smad2 / 3 protein with a compound or a pharmaceutically acceptable form thereof that inhibits the phosphorylation of the Smad2 / 3 protein by 85% or more. In some embodiments, the compound is selected from 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 in a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from 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 in a pharmaceutically acceptable form thereof.

[0723] In some embodiments of the method for modulating Smad2 / 3 activity described herein, the method activates the phosphorylation of the Smad2 / 3 protein. In some embodiments, the method comprises contacting the Smad2 / 3 protein with a compound, or a pharmaceutically acceptable form thereof, which, according to a phosphorylation-Smad2 / 3 inhibition assay, activates the phosphorylation of the Smad2 / 3 protein by 50% or more at 10 μM. In some embodiments, the compound is selected from 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 thereof, or a pharmaceutically acceptable form thereof.

[0724] In some embodiments of the methods provided herein, contact with the Smad2 / 3 protein occurs within 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.

[0725] This document provides 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. This document also provides methods for modulating JNK activity, comprising contacting a JNK protein with an effective amount of a pharmaceutical composition comprising 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, as disclosed below. In some embodiments, the compound is selected from 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, and 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, 211212, 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 their pharmaceutically acceptable forms.

[0726] In some embodiments of the method for modulating JNK activity described herein, the method inhibits the phosphorylation of the JNK protein. In some embodiments, the method includes contacting the 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 includes contacting the 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 includes contacting the JNK protein with a compound, or a pharmaceutically acceptable form thereof, that inhibits phosphorylation of the JNK protein by about 100% or more according to a JNK activation assay. In some embodiments, the compound is selected from compounds 29, 30, 32, 33, and 34, or pharmaceutically acceptable forms thereof. In some embodiments, the compound is selected from compounds 29, 32, and 34, or pharmaceutically acceptable forms thereof.

[0727] In some embodiments of the method for modulating JNK activity described herein, the method activates the phosphorylation of the JNK protein. In some embodiments, the method includes contacting the JNK protein with a compound or a pharmaceutically acceptable form thereof that activates the phosphorylation of the JNK protein by 30% or more according to a JNK activation assay. In some embodiments, the method includes contacting the JNK protein with a compound or a pharmaceutically acceptable form thereof that activates the phosphorylation of the JNK protein by 75% or more according to a JNK activation assay. In some embodiments, the method includes contacting the JNK protein with a compound or a pharmaceutically acceptable form thereof that activates the phosphorylation of the JNK protein by about 100% or more according to a JNK activation assay. In some embodiments, the compound is selected from 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 their pharmaceutically acceptable forms. In some embodiments, the compound is selected from 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 their pharmaceutically acceptable forms. In some embodiments, the compound is selected from 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 their pharmaceutically acceptable forms.

[0728] In some embodiments of the methods provided herein, contact with the JNK protein occurs within 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.

[0729] This document provides a method for modulating the activity of MAPK p38, comprising contacting the 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. This document also provides a method for modulating the activity of MAPK p38, comprising contacting the MAPK p38 protein with an effective amount of a pharmaceutical composition comprising 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, as disclosed below. In some embodiments, the compound is selected from 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, 1 15, 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, 206207, 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, 2 43, 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 their pharmaceutically acceptable forms.

[0730] In some embodiments of the method for modulating MAPK p38 activity described herein, the method inhibits the phosphorylation of the MAPK p38 protein. In some embodiments, the method includes contacting the MAPK p38 protein with a compound, or a pharmaceutically acceptable form thereof, which, according to a MAPK p38 activation assay, inhibits the phosphorylation of the MAPK p38 by 30% or more at 10 μM. In some embodiments, the method includes contacting the MAPK p38 protein with a compound, or a pharmaceutically acceptable form thereof, which, according to a MAPK p38 activation assay, inhibits the phosphorylation of the MAPK p38 by about 100% at 10 μM. In some embodiments, the compound is selected from 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 compounds 29, 32, 33, 34, 46, 207 and 209 or their pharmaceutically acceptable forms.

[0731] In some embodiments of the method for modulating MAPK p38 activity described herein, the method activates the phosphorylation of the MAPK p38 protein. In some embodiments, the method includes contacting the MAPK p38 protein with a compound or a pharmaceutically acceptable form thereof that activates the phosphorylation of the MAPK p38 by 30% or more at 10 μM according to a MAPK p38 activation assay. In some embodiments, the method includes contacting the MAPK p38 protein with a compound or a pharmaceutically acceptable form thereof that activates the phosphorylation of the MAPK p38 by 75% or more at 10 μM according to a MAPK p38 activation assay. In some embodiments, the method includes contacting the MAPK p38 protein with a compound or a pharmaceutically acceptable form thereof that activates the phosphorylation of the 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 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 in a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from 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 their pharmaceutically acceptable forms. In some embodiments, the compound is selected from 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 their pharmaceutically acceptable forms.

[0732] In some embodiments of the methods provided herein, contact with the MAPK p38 protein occurs within 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.

[0733] This document provides 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. This document also provides methods for modulating IL-6 activity, comprising contacting an IL-6 protein with an effective amount of a pharmaceutical composition comprising 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, as disclosed below. In some embodiments, the compound is selected from 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, 6. 0, 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, 1 17, 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, 210211, 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, 2 45, 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 their pharmaceutically acceptable forms.

[0734] In some embodiments of the method for modulating IL-6 activity described herein, the method inhibits IL-6 activity. In some embodiments, the method includes contacting the 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 IL-6 quantification. In some embodiments, the compound is selected from 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, and 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 their pharmaceutically acceptable forms.

[0735] In some embodiments of the methods provided herein, contact with the IL-6 protein occurs within 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.

[0736] This document provides methods for modulating TNF-α activity, comprising contacting a TNF-α 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. This document also provides methods for modulating TNF-α activity, comprising contacting a TNF-α protein with an effective amount of a pharmaceutical composition comprising 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, as disclosed below. In some embodiments, the compound is selected from 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, 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, 1 63, 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, 209210, 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 their pharmaceutically acceptable forms.

[0737] In some embodiments of the method for modulating IL-6 activity described herein, the method inhibits TNF-α activity. In some embodiments, the method includes contacting the TNF-α protein with a compound, or a pharmaceutically acceptable form thereof, that inhibits TNF-α activity by 75% or more at 10 μM according to a TNF-α quantification. In some embodiments, the compound is selected from 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.

[0738] In some embodiments of the methods provided herein, contact with the TNF-α protein occurs within cells. In some embodiments, the cells are in a subject. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are human cells.

[0739] 3.4. Methods of treating cancer

[0740] Unbound by theory, cancer is characterized primarily by an increase in the number of abnormal cells originating from a given normal tissue. These abnormal cells invade adjacent tissues, or malignant cells spread lymphaticly or hematogenously to regional lymph nodes and distant sites. Clinical data and molecular biological studies indicate that cancer is a multi-step process that begins with minute pretumoral changes, which can progress to tumor formation under certain conditions. Tumor lesions can clonally evolve and develop increasing capabilities for invasion, growth, metastasis, and heterogeneity, especially under conditions where tumor cells evade host immune surveillance. (Roitt, I., Brostoff, J., and Kale, D., Immunology, 17.1–17.12 (3rd ed., Mosby, St. Louis, Mo., 1993))

[0741] Unbound by theory, the various stages of tumor development can generally be described as follows:

[0742] a) Tumor evolution begins when cells in a normal population maintain genetic mutations that increase their proliferative tendency.

[0743] (b) Cells with these genetic alterations and their offspring continue to behave normally, but they proliferate excessively, leading to a condition known as hyperplasia. Altered cells can also secrete signaling factors or other molecules that alter their local cellular and extracellular environments (including, but not limited to, the immune system's response to them). These environmental influences can, in turn, affect the viability, proliferation, and further mutations of the altered cells. After a period of time (months or years), a very small fraction of these altered cells may retain additional mutations, subsequently losing control over cell growth and any further potential influence over their environment.

[0744] c) The progeny of these cells not only proliferate excessively but also exhibit abnormalities in shape and orientation. This tissue is now considered to exhibit a condition known as developmental dysplasia. Over time, one or more additional mutations can further alter cell behavior and the cell's influence on its environment.

[0745] d) Affected and genetically altered cells become more abnormal in growth and appearance. If a tumor mass does not invade through any boundaries between tissues, it is called a tumor in situ. Such tumors can remain confined indefinitely; however, some cells may acquire more mutations.

[0746] e) If genetic changes allow a tumor mass to begin invading underlying tissues and releasing cells into the bloodstream or lymphatic system, a malignant or invasive tumor develops. Defective cells can then implant new tumor sites throughout the body (metastasis).

[0747] Unbound by theory, metastasis represents the final product of a multi-step cellular biological process known as the invasion-metastasis cascade, involving the spread of cancer cells to anatomically distant organ sites and their subsequent adaptation to the foreign tissue microenvironment. Each of these events is driven by the acquisition of genetic and / or epigenetic alterations within tumor cells and by the co-selection of non-tumor stromal cells, which together confer the traits required for macroscopic metastasis in early metastatic cells. (Volastyan, S. et al., Cell, 2011, Vol. 147, 275-292)

[0748] Unbound by conventional wisdom, various cancers affect different tissues throughout the body, as detailed in the medical literature. Over 85% of human cancers are solid tumors, including carcinomas, sarcomas, and lymphomas. Different types of solid tumors are named after the types of cells that form them. Examples include lung cancer, colon cancer, rectal cancer, pancreatic cancer, prostate cancer, breast cancer, brain cancer, and colorectal cancer. Other human tumors originate from cells involved in the formation of immune cells and other blood cells, including leukemia and myeloma.

[0749] Cancer incidence rates continue to rise as the general population ages, new cancers emerge, and the susceptible population grows. Therefore, there is a significant need for new methods and compositions that can be used to treat subjects with cancer.

[0750] Unbound by theory, current cancer therapies can involve surgery, chemotherapy, hormone therapy, biotherapy, targeted therapy, immunotherapy and / or radiation therapy to eradicate tumor cells in patients (see, for example, 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 Techno1. 2015; 12(1): 3-20).

[0751] Unbound by theory, such therapies can be used alone or in combination. The choice of therapy will depend on the history and nature of the cancer, the patient's condition, and the expected efficacy and adverse effects of the treatments and methods considered in the context.

[0752] Unbound by theory, there are numerous chemotherapeutic agents and methods for delivering various cancers that exist. Most first-generation chemotherapeutic agents are not tumor-specific, have broad systemic effects, are toxic, and can cause significant and often dangerous side effects, including severe nausea, bone marrow suppression, and immunosuppression.

[0753] Unbound by theory, even with combinations of chemotherapy agents, many tumor cells develop resistance or become resistant to those agents. In fact, cells resistant to a particular chemotherapy agent used in a treatment regimen often prove resistant to other drugs, even those that act through different mechanisms than those used in the specific treatment. This phenomenon is called multidrug resistance. Due to resistance, many cancers have proven refractory to standard chemotherapy regimens.

[0754] Therefore, there is a significant need for alternative compounds, compositions, and methods for the treatment, prevention, and management of cancer.

[0755] Unbound by theory, while surgical resection and adjuvant therapy can cure well-limited primary tumors, metastatic disease is largely incurable due to the resistance of its systemic and disseminated tumor cells to existing therapeutic agents. This explains why over 90% of cancer deaths are attributable to metastasis, rather than the primary tumor that produces these malignancies.

[0756] This document provides a method for treating a subject with cancer, comprising administering to a subject with cancer 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. This document also provides a method for treating a subject with cancer, comprising administering to a subject with cancer a therapeutically effective amount of a drug comprising 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, as disclosed below. In some embodiments, the compound is selected from 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, 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, 1 63, 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, 209210, 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 their pharmaceutically acceptable forms.

[0757] In some embodiments of the methods for 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, based on 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, based on 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, based on Ras superfamily activity.In some embodiments, the compound is selected from 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, 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, 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 their pharmaceutically acceptable forms.In some embodiments, the compound is selected from 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, 9 7, 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, 1 51, 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, 23 2, 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 their pharmaceutically acceptable forms.

[0758] In some embodiments of the methods for treating cancer provided herein, the method involves administering a compound that modulates Erk1 / 2 activity, or a pharmaceutically acceptable form thereof. In some embodiments, the compound, or a pharmaceutically acceptable form thereof, inhibits phosphorylation of the Erk1 / 2 protein. In some embodiments, based on an Erk1 / 2 phosphorylation assay, the compound, or a pharmaceutically acceptable form thereof, inhibits the 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. In some embodiments, based on an Erk1 / 2 phosphorylation assay, the compound, or a pharmaceutically acceptable form thereof, inhibits the phosphorylation of Erk1 / 2 protein by 80% or more at 10 μM. In some embodiments, based on an Erk1 / 2 phosphorylation assay, the compound, or a pharmaceutically acceptable form thereof, inhibits the phosphorylation of Erk1 / 2 protein by 85% or more at 10 μM. In some embodiments, the compound is selected from 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 their pharmaceutically acceptable forms. In some embodiments, the compound is selected from 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 their pharmaceutically acceptable forms. In some embodiments, the compound or its pharmaceutically acceptable form activates phosphorylation of the Erk1 / 2 protein. In some embodiments, the compound or its pharmaceutically acceptable form activates the phosphorylation of Erk1 / 2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal to or greater than 100% at 10 μM, according to an Erk1 / 2 phosphorylation assay. In some embodiments, the compound or its pharmaceutically acceptable form activates the 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 its pharmaceutically acceptable form activates the 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 selected from 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, 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 their pharmaceutically acceptable forms. In some embodiments, the compound is selected from 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, 1 75, 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 their pharmaceutically acceptable forms.

[0759] In some embodiments of the methods for treating cancer provided herein, the method involves administering a compound that modulates Akt activity, or a pharmaceutically acceptable form thereof. In some embodiments, the compound, or a pharmaceutically acceptable form thereof, inhibits the phospho...

Claims

1. A compound of formula I: or a pharmaceutically acceptable form thereof, wherein: X is -NR 1A R 2A OR 2A ; Y is imidazolyl, pyridyl or 8-10 membered fused heteroaryl; wherein The imidazole group is optionally substituted with 1 R 6A The substituent is optionally substituted with 1-2 R 7A Substituents are substituted; and The pyridyl or the 8-10 membered fused heteroaryl is optionally substituted by 1-4 R 7A Substituent substitution; R 1A is hydrogen or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 4 R 8A Substituent substitution; R 2A It is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, C 3-7 Heterocycloalkyl, C 5-10 Aryl, -S(O)2R 15A 、-P(O)R 16A R 17A or a 5-10 membered heteroaryl group, wherein said C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 The heteroalkyl and 5-10 membered heteroaryl groups are each independently optionally substituted by 1-4 R 8A Substituents are substituted, optionally wherein 2 independent R 8A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group including the one or more atoms to which each is attached; or R 1A and R 2A are combined to form a 3-6 membered heterocycloalkyl group including the nitrogen atom to which they are both attached, optionally wherein R 1A and R 2A The 3-6 membered heterocycloalkyl formed is fused with a 5-6 membered heteroaryl; R 3A It 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 , wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1-3 R 9A Substituent substitution; R 4A is hydrogen, aryl or 5-10 membered heteroaryl, wherein the aryl and 5-10 membered heteroaryl are each independently optionally substituted by 1-4 R 10A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 5A is hydrogen or C 1-6 alkyl; R 6A and R 7A Each independently is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, aryl, C 5-10 Heteroaryl, C 3-7 Heterocycloalkyl, C 1-6 Heteroalkyl, halide, –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, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, aryl, C 5-10 Heteroaryl, C 3-7 Heterocycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 8A and R 9A Each independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 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 A haloalkoxy group, a 5-6 membered heteroaryl group, a biotinamide group or a biotinylated substituent group; R 10A are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, –OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, –NR 12A R 13A or a 5-6 membered heteroaryl group, wherein said C 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 The haloalkoxy or 5-6 membered heteroaryl groups are each independently optionally substituted with 1-3 R 8A Substituent substitution; R 11A Yes -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from 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 Halogenated alkoxy, C 3-7 Heterocycloalkyl, aryl or 5-10 membered heteroaryl, wherein the 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 Halogenated alkoxy, C 3-7 Heterocycloalkyl, aryl and 5-10 membered heteroaryl are optionally substituted by 1-3 R 8A Substituent substitution, or R 12A and R 13A combine to form a 3-7 membered heterocycloalkyl group including the nitrogen atom to which they are both attached; R 14A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 15A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 16A and R 17A Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution, or R 16A and R 17A combine to form a 3-7 membered heterocycloalkyl group including the phosphorus atom to which they are both attached; and Where, when X is OH or Y is N-methylimidazolyl, and R 5A When H is 3A and R 4A At least one of them is not unsubstituted phenyl.

2. The compound of claim 1, wherein Y is optionally substituted with 1 R 6A The substituent is optionally substituted with 1-2 R 7A The substituent is an imidazolyl group substituted with the substituent.

3. The compound of claim 1 or claim 2, wherein Y is an imidazolyl group connected by C, which is replaced by one R at the nitrogen of the imidazolyl ring. 6A Substituents are optionally substituted at the carbon of the imidazolyl ring with 1-2 R 7A Substituent substitution.

4. The compound of any one of claims 1 to 3, wherein the compound is a compound of formula Ia: or a pharmaceutically acceptable form thereof.

5. The compound of any one of claims 1 to 3, wherein the compound is a compound of formula Ib: or a pharmaceutically acceptable form thereof.

6. The compound of claim 1, wherein Y is optionally substituted by 1-4 R 7A The substituent is substituted pyridinyl.

7. The compound of claim 1 or claim 6, wherein the compound is a compound of formula Ic: or a pharmaceutically acceptable form thereof.

8. The compound of claim 1, wherein Y is optionally substituted by 1-4 R 7A The substituent is a substituted 8-10 membered fused heteroaryl group.

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

10. A compound as described in any one of claims 1 to 8, wherein X is -NR 1A R 2A .

11. A compound of formula II: or a pharmaceutically acceptable form thereof, wherein: X is -NR 1A R 2A OR 2A ; R 1A is hydrogen or C 1-6 alkyl; R 2A It is hydrogen, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Heteroalkyl, -S(O)2R 15A 、-P(O)R 16A R 17A or a 5-6 membered heteroaryl group, wherein said C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 The heteroalkyl and 5-6 membered heteroaryl groups are each independently optionally substituted by 1-3 R 8A Substituents are substituted, optionally wherein 2 independent R 8A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group including the one or more atoms to which each is attached; or R 1A and R 2A are combined to form a 3-6 membered heterocycloalkyl group including the nitrogen atom to which they are both attached, optionally wherein R 1A and R 2A The formed 3-6 membered heterocycloalkyl is fused with a 5-6 membered heteroaryl; R 3A It 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 , wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R 9A Substituent substitution; R 4A is hydrogen, phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R 10A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 5A It is hydrogen; R 6A and R 7A Each independently is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 8A and R 9A Each independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, –NR 12A R 13A 、-(CO)R 11A , oxo, –OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 A haloalkoxy group, a 5-6 membered heteroaryl group, a biotinamide group or a biotinylated substituent group; R 10A are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, –OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, –NR 12A R 13A or a 5-6 membered heteroaryl group, wherein said C 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 The haloalkoxy or 5-6 membered heteroaryl groups are each independently optionally substituted with 1-3 R 8A Substituent substitution; R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from 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 3-6 membered heterocycloalkyl group including the nitrogen atom to which they are both attached; R 15A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 16A and R 17A Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution, or R 16A and R 17A combine to form a 3-7 membered heterocycloalkyl group including the phosphorus atom to which they are both attached; m is 0, 1, or 2; and Where, when X is OH or Y is N-methylimidazolyl, and R 5A When H is 3A and R 4A At least one of them is not unsubstituted phenyl.

12. A compound of formula IIa: or a pharmaceutically acceptable form thereof, wherein: R 1A It is hydrogen; R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, -S(O)2R 15A or a 5-6 membered heteroaryl group, wherein said C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 The heteroalkyl and 5-6 membered heteroaryl groups are each independently optionally substituted by 1-3 R 8A Substituents are substituted, optionally wherein 2 independent R 8A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 3A It is C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl, phenyl, 5-membered, 6-membered or 9-membered heteroaryl, –(CO)R 11A or –C(O)NR 12A R 13A , wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl, phenyl and 5-, 6- or 9-membered heteroaryl are each independently optionally substituted with 1-3 R 9A Substituent substitution; R 4A is hydrogen, phenyl or 5-, 6- or 9-membered heteroaryl, wherein the phenyl and 5-, 6- or 9-membered heteroaryl are each independently optionally substituted by 1-3 R 10A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 5A It is hydrogen; R 6A It is C 1-3 Alkyl or C 1-3 heteroalkyl, wherein the C 1-3 Alkyl or C 1-3 The heteroalkyl is optionally substituted with biotinamide; R 7A It is methyl; R 8A and R 9A Each independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, –NR 12A R 13A 、-(CO)R 11A , oxo, –OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 A haloalkoxy group, a 5-6 membered heteroaryl group, a biotinamide group or a biotinylated substituent group; R 10A are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, –OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, –NR 11A R 12A or a 5-6 membered heteroaryl group, wherein said C 1-6 Alkyl or C 1-6 The heteroalkyl is optionally substituted with biotinamide; R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from 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 are combined to form a 5- or 6-membered heterocycloalkyl group including the nitrogen atom to which they are both attached; R 15A It is C 1-3 Alkyl, C 3-6 Cycloalkyl or C 1-4 heteroalkyl; R 16A and R 17A Each independently selected from C 1-3 Alkyl or C 1-3 Alkoxy, or R 16A and R 17A combine to form a 5-membered heterocycloalkyl group including the phosphorus atom to which they are both attached; and m is 0 or 1.

13. The compound of claim 12, wherein: R 1A and R 2A Together with the nitrogen to which they are attached, they have the following structure: -NH2, R 3A is -CH3, unsubstituted phenyl, isopropyl, cyclopropyl, R 4A is hydrogen, unsubstituted phenyl, R SA It is hydrogen; R 6A is methyl, -CH2CH2NH2 or R 7A is methyl; and m is 0 or 1.

14. The compound of claim 12, wherein: R 1A and R 2A Together with the nitrogen to which they are attached, they have the following structure: -NH2, R 3A is -CH3, unsubstituted phenyl, isopropyl, cyclopropyl, R 4A is hydrogen, unsubstituted phenyl, R 5A It is hydrogen; R 6A is methyl, -CH2CH2NH2 or and m is 0.

15. A compound of formula IIb: or a pharmaceutically acceptable form thereof, wherein: R 1A and R 2A are combined to form a 4-6 membered heterocycloalkyl group including the nitrogen atom to which they are both attached, optionally wherein R 1A and R 2A The formed 4-6 membered heterocycloalkyl is fused with a 6 membered heteroaryl; R 3A It is C 1-3 Alkyl or phenyl, wherein the C 1-3 The alkyl group and the phenyl group are each independently optionally substituted with 1 to 3 R 9A Substituent substitution; R 4A is phenyl or 5-membered heteroaryl, wherein the phenyl and 5-membered heteroaryl are each independently optionally substituted by 1-3 R 10A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 5A It is hydrogen; R 6A It is methyl; R 7A It is methyl; R 9A Each independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, 3-6 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 are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or a 5-6 membered heteroaryl; R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH or C 1-6 Alkoxy; m is 0 or 1; and Among them, when R 1A and R 2A Combination Formation R 6A is methyl, m is 0, and R SA When H is 3A and R 4A At least one of them is not unsubstituted phenyl.

16. The compound of claim 15, wherein: R 1A and R 2A Combination Formation R 3A is -CH3, unsubstituted phenyl, (4-methoxy)-phenyl or isopropyl; R 4A yes R 5A It is hydrogen; R 6A is methyl; and m is 0.

17. The compound of claim 15, wherein: R 1A and R 2A Combination Formation R 3A is -CH3 or unsubstituted phenyl; R 4A yes R 5A It is hydrogen; R 6A is methyl; and m is 0.

18. A compound of formula IIc: or a pharmaceutically acceptable form thereof, wherein: R 2A It is hydrogen, C 1-6 heteroalkyl or 6-membered heteroaryl, wherein the C 1-6 The heteroalkyl and 5-6 membered heteroaryl groups are each optionally substituted by 1-3 R 8A Substituent substitution; R 3A It is C 1-3 Alkyl or phenyl, wherein the C 1-3 The alkyl group or the phenyl group is each independently optionally substituted with 1 to 3 R 9A Substituent substitution; R 4A is hydrogen, phenyl or 5- or 6-membered heteroaryl, wherein the phenyl and 5- or 6-membered heteroaryl are each independently optionally substituted by 1-3 R 10A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 5A It is hydrogen; R 6A It is methyl; R 7A It is methyl; R 8A and R 9A Each independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, 3-6 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 are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, –OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, –NR 12A R 13A or a 5-6 membered heteroaryl; R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, –OH or C 1-6 Alkoxy; m is 0 or 1; and Among them, when R 2A Yes H, R 6A is methyl, m is 0, and R 5A When H is 3A and R 4A At least one of them is not unsubstituted phenyl.

19. The compound of claim 18, wherein: R 2A Together with its attached oxygen has the following structure: -OH, R 3A is -CH3 or unsubstituted phenyl; R 4A is hydrogen, unsubstituted phenyl, R 5A It is hydrogen; R 6A is methyl; and m is 0.

20. A compound of formula III: or a pharmaceutically acceptable form thereof, wherein: X is NR 1A R 2A OR 2A ; R 1A is hydrogen or C 1-6 alkyl; R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl or 5-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 The heteroalkyl and 5-6 membered heteroaryl groups are each independently optionally substituted by 1-3 R 8A Substituents are substituted, optionally wherein 2 independent R 8A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group including the one or more atoms to which each is attached; or R 1A and R 2A combine to form a 3-6 membered heterocycloalkyl group including the nitrogen atom to which they are both attached; R 3A It is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R 9A Substituent substitution; R 4A is hydrogen, phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R 10A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 5A is hydrogen or C 1-6 alkyl; R 6A and R 7A Each independently is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 8A and R 9A Each independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, 3-6 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 are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, –OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, –NR 12A R 13A or a 5-6 membered heteroaryl; R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH or C 1-6 alkoxy; and m is 0, 1 or 2.

21. A compound of formula IIia: or a pharmaceutically acceptable form thereof, wherein: R 1A It is hydrogen; R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl or 5-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 The heteroalkyl and 5-6 membered heteroaryl groups are each independently optionally substituted by 1-3 R 8A Substituents are substituted, optionally wherein 2 independent R 8A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 3A It is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R 9A Substituent substitution; R 4A is hydrogen, phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R i0A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 5A is hydrogen or C 1-6 alkyl; R 6A and R 7A Each independently is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 8A and R 9A Each independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, 3-6 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 are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or a 5-6 membered heteroaryl; R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH or C 1-6 alkoxy; and m is 0, 1 or 2.

22. A compound of formula IIIb: or a pharmaceutically acceptable form thereof, wherein: R 1A and R 2A combine to form a 4-6 membered heterocycloalkyl group including the nitrogen atom to which they are both attached; R 3A It is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R 9A Substituent substitution; R 4A is hydrogen, phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R 10A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 5A is hydrogen or C 1-6 alkyl; R 6A and R 7A Each independently is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 8A and R 9A Each independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, 3-6 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 are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, –OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, –NR 12A R 13A or a 5-6 membered heteroaryl; R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, –OH or C 1-6 alkoxy; and m is 0, 1 or 2.

23. A compound of formula IIIc: or a pharmaceutically acceptable form thereof, wherein: R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl or 5-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 The heteroalkyl and 5-6 membered heteroaryl groups are each independently optionally substituted by 1-3 R 8A Substituent substitution; R 3A It is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R 9A Substituent substitution; R 4A is hydrogen, phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R i0A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 5A is hydrogen or C 1-6 alkyl; R 6A and R 7A Each independently is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 8A and R 9A Each independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, 3-6 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 are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or a 5-6 membered heteroaryl; R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH or C 1-6 alkoxy; and m is 0, 1 or 2.

24. A compound of formula IV: or a pharmaceutically acceptable form thereof, wherein: X is -NR 1A R 2A OR 2A ; R 1A is hydrogen or C 1-6 alkyl; R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl or 5-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 The heteroalkyl and 5-6 membered heteroaryl groups are each independently optionally substituted by 1-3 R 8A Substituents are substituted, optionally wherein 2 independent R 8A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group including the one or more atoms to which each is attached; or R 1A and R 2A combine to form a 3-6 membered heterocycloalkyl group including the nitrogen atom to which they are both attached; R 3A It is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R 9A Substituent substitution; R 4A is hydrogen, phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R 10A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 5A is hydrogen or C 1-6 alkyl; R 7A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, aryl, C 5-10 Heteroaryl, C 3-7 Heterocycloalkyl, C 1-6 Heteroalkyl, halide, –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, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, aryl, C 5-10 Heteroaryl, C 3-7 Heterocycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 8A and R 9A Each independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, 3-6 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 are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, –OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, –NR 12A R 13A or a 5-6 membered heteroaryl; R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, –OH or C 1-6 alkoxy; and m is 0, 1, 2, 3 or 4.

25. A compound of formula IVa: or a pharmaceutically acceptable form thereof, wherein: R 1A It is hydrogen; R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl or 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 The heteroalkyl and 6-membered heteroaryl groups are each independently optionally substituted by 1-3 R 8A Substituents are substituted, optionally wherein 2 independent R 8A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 3A It is C 1-6 Alkyl or phenyl, wherein the C 1-6 The alkyl group and the phenyl group are each independently optionally substituted with 1 to 3 R 9A Substituent substitution; R 4A is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally substituted by 1-3 R i0A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 5A It is hydrogen; R 7A It is methyl; R 8A and R 9A Each independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, 3-6 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 are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or a 5-6 membered heteroaryl; R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH or C 1-6 alkoxy; and m is 0, 1, 2, 3 or 4.

26. The compound of claim 25, wherein: R 1A and R 2A Together with the nitrogen to which they are attached they have the following structure: R 3A is -CH3 or unsubstituted phenyl; R 4A yes R SA It is hydrogen; R 7A is methyl; and m is 0.

27. A compound of formula IVb: or a pharmaceutically acceptable form thereof, wherein: R 1A and R 2A combine to form a 4-6 membered heterocycloalkyl group including the nitrogen atom to which they are both attached; R 3A It is C 1-6 Alkyl or phenyl, wherein the C 1-6 The alkyl group and the phenyl group are each independently optionally substituted with 1 to 3 R 9A Substituent substitution; R 4A is a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally substituted by 1-3 R 10A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 5A It is hydrogen; R 7A It is methyl; R 8A and R 9A Each independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, 3-6 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 are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, -NR 12A R 13A or a 5-6 membered heteroaryl; R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, -OH or C 1-6 alkoxy; and m is 0, 1, 2, 3 or 4.

28. The compound of claim 27, wherein: R 1A and R 2A Combination Formation R 3A is -CH3 or phenyl; R 4A yes R 5A It is hydrogen; R 7A is methyl; and m is 0.

29. A compound of formula IVc: or a pharmaceutically acceptable form thereof, wherein: R 2A It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 heteroalkyl or 5-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 The heteroalkyl and 5-6 membered heteroaryl groups are each independently optionally substituted by 1-3 R 8A Substituent substitution; R 3A It is C 1-6 Alkyl, C 1-6 heteroalkyl, phenyl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R 9A Substituent substitution; R 4A is hydrogen, phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R 10A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 5A It is hydrogen; R 7A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 8A and R 9A Each independently selected from halogen, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 heteroalkyl, 3-6 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 are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, –OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, –NR 12A R 13A or a 5-6 membered heteroaryl; R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, –OH or C 1-6 alkoxy; and m is 0, 1, 2, 3 or 4.

30. The compound of claim 29, wherein: R 2A It is hydrogen; R 3A is -CH3; R 4A yes R 5A It is hydrogen; R 7A It is methyl; m is 0.

31. A compound as described in any one of claims 1 to 30, wherein R 4A and R 5A Not more than one of them is hydrogen.

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

33. A compound as described in any one of claims 1 to 32, wherein R 5A It's hydrogen.

34. A compound as described in any one of claims 1 to 33, wherein R 6A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, 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 , wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, aryl, C 5-10 Heteroaryl, C 3-7 Heterocycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution.

35. A compound as described in any one of claims 1 to 34, wherein R 6A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution.

36. A compound as described in any one of claims 1 to 35, wherein R 6A is methyl, ethyl or isopropyl, wherein the methyl, ethyl and isopropyl are each independently optionally substituted by 1-3 R 8A Substitution, where R 8A Yes -OH, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy.

37. A compound as described in any one of claims 1 to 36, wherein R 6A It is methyl, ethyl or isopropyl.

38. A compound as described in any one of claims 1 to 37, wherein R 6A It's methyl.

39. A compound as described in any one of claims 1 to 38, wherein R 7A It is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution.

40. A compound as described in any one of claims 1 to 39, wherein R 7A is methyl, ethyl or isopropyl, wherein the methyl, ethyl and isopropyl are each independently optionally substituted by 1-3 R 8A Substitution, where R 8A Yes -OH, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy.

41. A compound as described in any one of claims 1 to 40, wherein R 7A It is methyl, ethyl or isopropyl.

42. A compound as described in any one of claims 1 to 41, wherein R 7A It's methyl.

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

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

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

46. ​​A compound as described in any one of claims 1 to 44, wherein R 1A is hydrogen or C 1-3 alkyl.

47. A compound as described in any one of claims 1 to 44 or 46, wherein R 1A It is methyl, ethyl or isopropyl.

48. A compound as described in any one of claims 1 to 46, wherein R 1A It's hydrogen.

49. A compound as described in any one of claims 1 to 44 or 46 to 48, wherein R 2A It is C 1-4 Alkyl, C 4-5 Cycloalkyl, C 1-4 heteroalkyl or 5-6 membered heteroaryl, wherein the C 1-4 Alkyl, C 4-5 Cycloalkyl, C 1-4 The heteroalkyl and 5-6 membered heteroaryl groups are each independently optionally substituted by 1-3 R 8A Substituents are substituted, optionally wherein 2 independent R 8A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each is attached.

50. A compound as described in any one of claims 1 to 44 or 46 to 49, wherein R 2A is a 5-6 membered heteroaryl group, each of which is independently optionally substituted by 1-3 R 8A Substituents are substituted, optionally wherein 2 independent R 8A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each is attached.

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

52. The compound of claim 51, wherein the 5-6 membered heteroaryl is represented by 2 independent R 8A The cycloalkyl radical is substituted with substituents which combine to form a 5-6 membered cycloalkyl radical fused to the 5-6 membered heteroaryl radical including the one or more atoms to which each is attached.

53. The compound of claim 51, wherein the 5-6 membered heteroaryl is represented by 2 independent R 8A The alkylene group is substituted with substituents which combine to form a 5-6 membered heterocycloalkyl group fused to the 5-6 membered heteroaryl group including the one or more atoms to which each is attached.

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

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

56. The compound of claim 51, wherein R 8A Independently selected from 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 Cycloalkoxy, biotinamide or biotinylated substituents.

57. A compound as claimed in claim 51 or claim 56, wherein R 8A Independently selected from 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, 3-5 membered heterocycloalkyl, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, biotinamide or biotinylated substituents.

58. A compound as described in any one of claims 51 to 57, wherein R 8A are independently selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -NR 12A R 13A 、-(CO)R 11A , oxo, C 2-3 Hydroxyalkyl, C 2-4 heteroalkyl, methoxy, ethoxy, isopropoxy, cyclopropyloxy or cyclobutyloxy.

59. A compound as described in any one of claims 1 to 58, wherein X is: -OH、-NH2、 60. The compound of claim 59, wherein X is: -OH、-NH2、 61. A compound as described in any one of claims 1 to 60, wherein R 3A It is 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 , wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Heteroalkyl, phenyl and 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R 9A Substituent substitution.

62. The compound of claim 61, wherein R 9A Independently selected from 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 Cycloalkoxy.

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

64. The compound of any one of claims 1 to 63, wherein R 3A yes: -CH3, unsubstituted phenyl, (4-methoxy)-phenyl, isopropyl, cyclopropyl, 65. The compound of claim 64, wherein R 3A Yes: -CH3, unsubstituted phenyl, isopropyl, cyclopropyl, 66. A compound as described in any one of claims 1 to 65, wherein R 4A is phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl are each independently optionally substituted by 1-3 R 10A Substituents are substituted, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each is attached.

67. A compound as described in any one of claims 1 to 66, wherein R 4A is optionally replaced by 1-3 R 10A Substituent-substituted phenyl, optionally wherein two independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each is attached.

68. A compound as described in any one of claims 1 to 66, wherein R 4A is optionally replaced by 1-3 R 10A substituted 5-6 membered heteroaryl, optionally wherein 2 independent R 10A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each is attached.

69. A compound as described in any one of claims 66 to 68, wherein R 10A are independently selected from halo, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, –OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, –NR 12A R 13A or a 5-6 membered heteroaryl group.

70. A compound as described in any one of claims 66 to 69, wherein R 10A independently selected from halogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, 3-5 membered heterocycloalkyl, –OH, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, C 1-4 Haloalkoxy or –NR 12A R 13A .

71. A compound as described in any one of claims 66 to 70, wherein R 10A independently selected from halo, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, C 1-3 Haloalkyl, C 2-3 Hydroxyalkyl, C 2-4 Heteroalkyl, -OH, methoxy, ethoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, C 1-4 Haloalkoxy or –NR 12A R 13A .

72. The compound of any one of claims 69 to 71, wherein R 12A and R 13A are each independently selected from hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl, –OH or C 1-4 Alkoxy.

73. A compound as described in any one of claims 69 to 72, wherein R 12A and R 13A Each is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy or ethoxy.

74. A compound as described in any one of claims 69 to 73, wherein R 12A and R 13A are each independently selected from hydrogen or methyl.

75. A compound as described in any one of claims 69 to 74, wherein R 12A and R 13A Each is hydrogen.

76. A compound as described in any one of claims 1 to 75, wherein R 4A is: hydrogen, unsubstituted phenyl, 77. The compound of claim 76, wherein R 4A is: hydrogen, unsubstituted phenyl, 78. A compound of formula IIa(1): or a pharmaceutically acceptable form thereof, wherein: R 1A It is hydrogen; R 2A is a 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered heteroaryl group is optionally substituted by 1 to 3 R 8A Substituents are substituted, optionally wherein 2 independent R 8A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the one or more atoms to which each is attached; R 8A Selected from halogen, CN, C,-6 alkyl, C 3-6 Cycloalkyl, C,-6 haloalkyl, C,-6 hydroxyalkyl, C 1-6 Heteroalkyl, 3-6 membered heterocycloalkyl, -NR 12A R 13A 、-(CO)R 11A , oxo, -OH, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 A haloalkoxy group, a 5-6 membered heteroaryl group, a biotinamide group or a biotinylated substituent group; R 11A It is C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and C 1-6 The heteroalkyl groups are each independently optionally substituted with 1 to 3 R 8A Substituent substitution; R 12A and R 13A are each independently selected from 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 group including the nitrogen atom to which they are both attached; and R 18A It is C 1-3 Alkyl or C 3-6 Cycloalkyl.

79. The compound of claim 78, wherein R 18A It is methyl, ethyl, isopropyl or cyclopropyl.

80. The compound of claim 79, wherein R 18A It's methyl.

81. The compound of claim 79, wherein R 18A It is ethyl.

82. The compound of claim 79, wherein R 18A It is isopropyl.

83. The compound of claim 79, wherein R 18A It is cyclopropyl.

84. A compound as described in any one of claims 78-83, wherein R 8A Selected from 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 a 5-6 membered heteroaryl group.

85. A compound as described in any one of claims 78-84, wherein R 2A is pyridinyl, pyrimidinyl, pyrazolyl or pyrazolyl, wherein the pyridinyl, pyrimidinyl, pyrazolyl or pyrazolyl is optionally substituted by 1-3 R 8A Substituents are substituted, optionally wherein 2 independent R 8A The substituents combine to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each is attached.

86. The compound of claim 85, wherein R 2A is optionally replaced by 1-2 R 8A The substituent is substituted pyridinyl.

87. The compound of claim 86, wherein R 2A yes 88. The compound of claim 85, wherein R 2A is optionally replaced by 1-2 R 8A The substituent is substituted pyrimidinyl.

89. The compound of claim 88, wherein R 2A yes 90. The compound of claim 85, wherein R 2A is optionally replaced by 1-2 R 8A The substituent is substituted pyrazolyl.

91. The compound of claim 85, wherein R 2A is optionally replaced by 1-2 R 8A The substituent is substituted pyrazolyl.

92. The compound of claim 91, wherein R 2A yes 93. The compound of any one of claims 85-92, wherein the two independent R 8A The substituents combine to form a 5-membered cycloalkyl or 5-membered heterocycloalkyl group including the one or more atoms to which each is attached.

94. The compound of any one of claims 78-93, wherein R 1A and R 2A Together with the nitrogen to which they are attached they have the following structure:

95. The compound of any one of claims 78-94, wherein R 1A and R 2A Together with the nitrogen to which they are attached they have the following structure:

96. The compound of any one of claims 78-95, wherein the compound is selected from 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 of any one of claims 78-96, wherein the compound is selected from compounds 6, 84, 100, 102, 104, 124, 221, 222, 235, 238, 252, 255, 260, and 267.

98. The compound of any one of claims 1 to 97, wherein the compound has a MW of no more than 1,000 g / mol.

99. compounds as described in any one in claims 1 to 98, wherein said compound has a MW of no more than 900 g / mol, no more than 800 g / mol, no more than 700 g / mol, no more than 600 g / mol or no more than 500 g / mol.

100. A compound as described in any one of claims 1 to 99, wherein the compound has a MW of no more than 600 g / mol.

101. A compound as described in any one of claims 1 to 100, wherein the compound has a MW of no more than 500 g / mol.

102. The compound of any one of claims 1 to 101, wherein the compound is selected from 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 2, 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 06, 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 7, 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.

103. The compound of any one of claims 1 to 102, wherein the compound is selected from 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, 92, 93, 94, 95, 96, 97, 98, 99, 100. 1, 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 9, 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 8, 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.

104. The compound of any one of claims 1 to 103, wherein the compound is selected from 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, 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, 2 31, 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.

105. The compound of any one of claims 1 to 104, wherein the compound is selected from compound 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.

106. A compound as described in any one of claims 1 to 105, wherein the compound is selected from 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.

107. The compound of any one of claims 1 to 104, wherein the compound is selected from 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, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175 7, 165, 174, 175, 176, 177, 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.

108. A compound as described in any one of claims 1 to 104 or 107, wherein the compound is selected from 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 7, 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.

109. A compound as described in any one of claims 1 to 108, wherein the compound is selected from 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.

110. The compound of any one of claims 1 to 108, wherein the compound is selected from 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, 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.

111. A compound as described in any one of claims 1 to 110, wherein the compound is selected from 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.

112. A compound as described in any one of claims 1 to 111, wherein the compound is selected from 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.

113. A compound as described in any one of claims 1 to 110, wherein the compound is selected from 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.

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

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

116. The compound of any one of claims 1 to 115, wherein the compound is selected from compounds 29, 32 and 34 or a pharmaceutically acceptable form thereof.

117. The compound of any one of claims 1 to 113, wherein the compound is selected from Compound 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.

118. A compound as described in any one of claims 1 to 113 or 117, wherein the compound is selected from 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.

119. A compound as described in any one of claims 1 to 113, 117 or 118, wherein the compound is selected from 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.

120. The compound of any one of claims 1 to 119, wherein the compound is selected from 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.

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

122. A compound as described in any one of claims 1 to 119, wherein the compound is selected from Compound 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.

123. A compound as described in any one of claims 1 to 119 or 122, wherein the compound is selected from Compound 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.

124. A compound as described in any one of claims 1 to 119, 122 or 123, wherein the compound is selected from 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.

125. The compound of any one of claims 1 to 124, wherein the compound is selected from 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, 85 4, 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, 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, 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.

126. The compound of any one of claims 1 to 125, wherein the compound is selected from 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.

127. The compound of any one of claims 1 to 126, wherein the compound is selected from compound 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, 2 33, 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.

128. The compound of any one of claims 1 to 127, wherein the compound is selected from compound 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.

129. The compound of any one of claims 1 to 128, wherein the compound is selected from 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, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 199, 201 6, 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.

130. The compound of any one of claims 1 to 129, wherein the compound is selected from 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.

131. A compound as described in any one of claims 1 to 130, wherein the compound is selected from 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.

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

133. A compound as described in any one of claims 1 to 132, wherein the compound is selected from 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.

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

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

136. The compound of any one of claims 1 to 134, wherein the pharmaceutically acceptable form of the compound does not comprise 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 of any one of claims 1 to 137, wherein the compound is a tautomer of the compound.

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

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

143. A compound as described in any one of claims 140 to 142, wherein the compound has 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 enantiomeric excess of the (R)-enantiomer.

144. The compound of any one of claims 140 to 143, wherein the compound has about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% enantiomeric excess of the (R)-enantiomer.

145. 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 greater than 10% enantiomeric excess of the (S)-enantiomer.

147. The compound of any one of claims 140, 145 or 146, wherein the compound has an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more or 99% or more of the (S)-enantiomer.

148. The compound of any one of claims 140 or 145 to 147, wherein the compound has about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% enantiomeric excess of the (S)-enantiomer.

149. The compound of any one of claims 1 to 148, wherein the compound or a pharmaceutically 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 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 as determined by a Ras superfamily activity assay.

151. The compound of any one of claims 1 to 150, wherein the compound, or a pharmaceutically acceptable form thereof, inhibits phosphorylation of Erkl / 2 as determined by an Erkl / 2 phosphorylation assay.

152. The compound of claim 151, wherein 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 in an Erk1 / 2 phosphorylation assay.

153. The compound of any one of claims 1 to 150, wherein the compound, or a pharmaceutically acceptable form thereof, activates phosphorylation of Erkl / 2 as determined by an Erkl / 2 phosphorylation assay.

154. The compound of claim 153, wherein 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 equal to or greater than 100% 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 pharmaceutically acceptable form thereof, inhibits phosphorylation of Akt as determined by an Akt phosphorylation assay.

156. The compound of claim 155, wherein 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 as determined by an Akt phosphorylation assay.

157. The compound of any one of claims 1 to 154, wherein the compound, or a pharmaceutically acceptable form thereof, activates phosphorylation of Akt as determined by an Akt phosphorylation assay.

158. The compound of claim 157, wherein 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 equal to or greater than 100% 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 pharmaceutically acceptable form thereof, inhibits phosphorylation of Smad2 / 3 according to a phospho-Smad2 / 3 inhibition assay.

160. The compound of claim 159, wherein 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 in a phospho-Smad2 / 3 inhibition assay.

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

162. The compound of claim 161, wherein 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 equal to or greater than 100% 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 pharmaceutically acceptable form thereof, inhibits JNK as determined by a JNK activation assay.

164. The compound of claim 163, wherein 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.

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

166. The compound of claim 165, wherein the compound, or a pharmaceutically 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 equal to or greater than 100% 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 pharmaceutically acceptable form thereof, inhibits MAPK p38 as determined by a MAPK p38 activation assay.

168. The compound of claim 167, wherein 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 in a MAPK p38 activation assay.

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

170. The compound of claim 169, wherein the compound, or a pharmaceutically 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 equal to or greater than 100% 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 pharmaceutically acceptable form thereof, inhibits proliferation of MiaPaca2 according to a proliferation assay.

172. The compound of claim 171, wherein the compound or a pharmaceutically acceptable form thereof has an IC 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 according to a proliferation assay. 50 The value inhibits the proliferation of MiaPaca2.

173. The compound of any one of claims 1 to 172, wherein the compound, or a pharmaceutically acceptable form thereof, inhibits IL-6 as measured by IL-6 quantification.

174. The compound of claim 173, wherein 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 as measured by IL-6 quantification.

175. The compound of any one of claims 1 to 174, wherein the compound, or a pharmaceutically acceptable form thereof, inhibits TNF-alpha as measured by TNF-alpha quantification.

176. The compound of claim 175, wherein the compound, or a pharmaceutically acceptable form thereof, inhibits TNF-α 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 as measured by TNF-α quantification.

177. A compound as described in any one of claims 1 to 176, wherein the half-life of the compound, or a pharmaceutically acceptable form thereof, in mouse liver microsomes is 10 minutes or longer, 20 minutes or longer, 30 minutes or longer, 40 minutes or longer, or 50 minutes or longer, as determined by mouse liver microsomal metabolic stability.

178. A compound as described in any one of claims 1 to 177, wherein the kinetic solubility of the compound, or a pharmaceutically acceptable form thereof, in a pH 7.4 buffer comprising 2% DMSO as determined by kinetic solubility is 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.

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

180. The compound of claim 179, wherein the compound or a pharmaceutically acceptable form thereof has 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 according to a proliferation assay. 50 The values ​​inhibited the proliferation of NCI-H358, A375, GP2d, BT549 or MM.R1.

181. The compound of claim 180, wherein the compound or a pharmaceutically acceptable form thereof has an IC of 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to a proliferation assay. 50 The value inhibited the proliferation of MM.R1.

182. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 181, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

183. A method of regulating a Ras superfamily protein, comprising contacting the Ras superfamily protein with an effective amount of a compound as described in any one of claims 1-181, or a pharmaceutically acceptable form thereof.

184. A method for regulating 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 the Ras superfamily protein.

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

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 of 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 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 occurs 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 has cancer.

207. According to claim 183 至 The method of any one of claim 206 to 206, wherein the modulation occurs in a subject having 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, urethral cancer, glioblastoma, or multiple myeloma.

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

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

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

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

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

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

216. A method of modulating caspase activity comprising contacting the caspase with an effective amount of a compound of any one of claims 1-181, or a pharmaceutically 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 occurs in a cell.

221. The method of claim 220, wherein said modulating caspase activity induces apoptosis of said 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 has cancer.

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

227. The method of claim 225 or claim 226, wherein the cancer is a solid tumor or 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, urethral cancer, glioblastoma, or multiple myeloma.

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

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

231. 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. A method of treating cancer in a subject, comprising administering to the subject having cancer a therapeutically effective amount of a compound as described in any one of claims 1-181, or a pharmaceutically acceptable form thereof.

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

236. The method of claim 234 or claim 235, wherein the cancer is a solid tumor or 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, urethral cancer, glioblastoma, or multiple myeloma.

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

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

240. 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 that is dependent on a Ras superfamily protein.

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

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

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

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

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

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

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

258. The method of any one of claims 234 to 240, wherein the 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. A method for modulating Erk1 / 2 activity, comprising contacting Erk1 / 2 protein with an effective amount of a compound as described in any one of claims 1-181 or a pharmaceutically acceptable form thereof.

262. 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. A method for modulating Akt activity, comprising contacting an Akt protein with an effective amount of a compound as described in any one of claims 1-181 or a pharmaceutically acceptable form thereof.

266. A method for regulating 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. A method for 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 pharmaceutically acceptable form thereof.

270. 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. A method of modulating JNK activity, comprising contacting a JNK protein with an effective amount of a compound as described in any one of claims 1-181 or a pharmaceutically acceptable form thereof.

274. A method for 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. A method for modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of a compound as described in any one of claims 1-181 or a pharmaceutically acceptable form thereof.

278. A method for modulating MAPK p38 activity, comprising contacting the 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. A method for modulating IL-6 activity, comprising contacting an IL-6 protein with an effective amount of a compound as described in any one of claims 1-181 or a pharmaceutically acceptable form thereof.

282. 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. A method of modulating TNF-alpha activity, comprising contacting a TNF-alpha protein with an effective amount of a compound as described in any one of claims 1-181, or a pharmaceutically acceptable form thereof.

285. A method for 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. A method of treating a fibrotic disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-181, or a pharmaceutically acceptable form thereof.

288. 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. A method of treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound as described in any one of claims 1-181, or a pharmaceutically acceptable form thereof.

290. A method of 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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