This application is a continuation of International Application No. PCT/US2023/065530, filed Apr. 7, 2023, which designates the United States and was published in English, which further claims the benefit of priority from U.S. Provisional Application No. 63/384,905, filed Nov. 23, 2022, and U.S. Provisional Application No. 63/329,141, filed Apr. 8, 2022. Each of the foregoing related applications, in its entirety, is incorporated herein by reference.

1. FIELD

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

2. SUMMARY

Provided herein is a compound of Formula I:

or a pharmaceutically acceptable form thereof, wherein:

X is —NR 1A R 2A or OR 2A ; Y is an imidazolyl, a pyridinyl, or an 8-10-membered fused-heteroaryl; wherein the imidazolyl is optionally substituted with 1 R 6A substituent and optionally substituted with 1-2 R 7A substituents; and

the pyridinyl or the 8-10-membered fused-heteroaryl is optionally substituted with 1-4 R 7A substituents;

R 1A is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-4 R 8A substituents; R 2A is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 heteroalkyl, C 3-7 heterocycloalkyl, C 5-10 membered aryl, —S(O) 2 R 15A , —P(O)R 16A R 17A , or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 heteroalkyl, and 5-10 membered heteroaryl are each independently optionally substituted with 1-4 R 8A substituents, optionally wherein 2 independent R 8A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; or R 1A and R 2A are combined to form a 3-6 membered heterocycloalkyl including the nitrogen atom to which they are both attached, optionally wherein the 3-6 membered heterocycloalkyl formed by R 1A and R 2A is fused to a 5-6 membered heteroaryl; R 3A is C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 heteroalkyl, aryl, 5-10 membered heteroaryl, —(CO)R 11A , or —C(O)NR 12A R 13A 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 substituents; R 4A is hydrogen, aryl, or 5-10 membered heteroaryl, wherein the aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1-4 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen or C 1-6 alkyl; R 6A and R 7A are each independently C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, C 1-6 heteroalkyl, halo, —NR 12A R 13A , C 1-6 alkoxy, C 1-6 haloalkoxy, —C(O)NR 12A R 13A , —(CO)R 11A , —C(O)OR 14A , or CN, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, and C 1-6 heteroalkyl are each independently optionally substituted with 1-3 R 8A substituents; R 8A and R 9A are each independently selected from the group consisting of 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, —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 haloalkoxy, 5-6 membered heteroaryl, biotinamide, or a biotinylated substituent; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl, wherein the 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 haloalkoxy, or 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, —OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 heterocycloalkyl, aryl, or 5-10 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 haloalkoxy, C 3-7 heterocycloalkyl, aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 R 8A substituents, or R 12A and R 13A are combined to form a 3-7 membered heterocycloalkyl including the nitrogen atom to which they are both attached; R 14A is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or C 1-6 heteroalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 15A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 16A and R 17A are each independently selected from the group consisting 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents, or R 16A and R 17A are combined to form a 3-7 membered heterocycloalkyl including the phorphorus atom to which they are both attached; and wherein, when X is OH or

›CROSS REFERENCE · 2 of 63

Y is N-methyl imidazoyl, and R 5A is H, at least one of R 3A and R 4A is not unsubstituted phenyl.

Also provided herein is a compound of Formula II:

or a pharmaceutically acceptable form thereof, wherein:

X is —NR 1A R 2A or —OR 2A ; R 1A is hydrogen or C 1-6 alkyl; R 2A is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 heteroalkyl, —S(O) 2 R 15A , —P(O)R 16A R 17A , or 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, and 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents, optionally wherein 2 independent R 8A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; or R 1A and R 2A are combined to form a 3-6 membered heterocycloalkyl including the nitrogen atom to which they are both attached, optionally wherein the 3-6 membered heterocycloalkyl formed by R 1A and R 2A is fused to a 5-6 membered heteroaryl; R 3A is C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, phenyl, 5-10 membered heteroaryl, —(CO)R 11A , or —C(O)NR 12A R 13A , 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 with 1-3 R 9A substituents; R 4A is hydrogen, phenyl, or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen; R 6A and R 7A are each independently 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 8A and R 9A are each independently selected from the group consisting of 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, —NR 12A R 13A , —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, 5-6 membered heteroaryl, biotinamide, or a biotinylated substituent; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl, wherein the 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 haloalkoxy, or 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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 are combined to form a 3-6 membered heterocycloalkyl including the nitrogen atom to which they are both attached; R 15A is C 1-6 alkyl, C 3-6 cycloalkyl, or C 1-6 heteroalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 16A and R 17A are each independently selected from the group consisting 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents, or R 16A and R 17A are combined to form a 3-7 membered heterocycloalkyl including the phorphorus atom to which they are both attached; m is 0, 1 or 2; and wherein, when X is OH or

Y is N-methyl imidazoyl, and R 5A is H, at least one of R 3A and R 4A is not unsubstituted phenyl.

Also provided herein is a compound of Formula IIa:

or a pharmaceutically acceptable form thereof, wherein:

R 1A is hydrogen; R 2A is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, —S(O) 2 R 15A , or 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, and 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents, optionally wherein 2 independent R 8A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 3A is C 1-3 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, phenyl, 5-, 6- or 9-membered heteroaryl, —(CO)R 11A , or —C(O)NR 12A R 13A , 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 substituents; 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 with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen; R 6A is C 1-3 alkyl or C 1-3 heteroalkyl, wherein the C 1-3 alkyl or C 1-3 heteroalkyl is optionally substituted with biotinamide; R 7A is methyl; R 8A and R 9A are each independently selected from the group consisting of 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, —NR 12A R 13A , —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, 5-6 membered heteroaryl, biotinamide, or a biotinylated substituent; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl, wherein the C 1-6 alkyl or C 1-6 heteroalkyl is optionally substituted with biotinamide; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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 including the nitrogen atom to which they are both attached; R 15A is C 1-3 alkyl, C 3-6 cycloalkyl, or C 1-4 heteroalkyl; R 16A and R 17A are each independently selected from the group consisting C 1-3 alkyl or C 1-3 alkoxy, or R 16A and R 17A are combined to form a 5 membered heterocycloalkyl including the phorphorus atom to which they are both attached; and m is 0 or 1.

›CROSS REFERENCE · 3 of 63

Also provided herein is a compound of Formula IIa(1):

or a pharmaceutically acceptable form thereof, wherein:

R 1A is hydrogen; R 2A is 5 or 6 membered heteroaryl, wherein the 5 or 6 membered heteroaryl is optionally substituted with 1-3 R 8A substituents, optionally wherein 2 independent R 8A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 8A is selected from the group consisting of 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, —NR 12A R 13A , —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, 5-6 membered heteroaryl, biotinamide, or a biotinylated substituent; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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 including the nitrogen atom to which they are both attached; and R 18A is C 1-3 alkyl or C 3-6 cycloalkyl.

Also provided herein is 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 including the nitrogen atom to which they are both attached, optionally wherein the 4-6 membered heterocycloalkyl formed by R 1A and R 2A is fused to a 6 membered heteroaryl; R 3A is C 1-3 alkyl or phenyl, wherein the C 1-3 alkyl and phenyl are each independently optionally substituted with 1-3 R 9A substituents; R 4A is phenyl or 5 membered heteroaryl, wherein the phenyl and 5 membered heteroaryl are each independently optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen; R 6A is methyl; R 7A is methyl; R 9A is each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 11A and R 12A and R 13A are each independently selected from the group consisting of 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 wherein, when R 1A and R 2A are combined to form

R 6A is methyl, m is 0, and R 5A is H, at least one of R 3A and R 4A is not unsubstituted phenyl.

Also provided herein is a compound of Formula IIc:

or a pharmaceutically acceptable form thereof, wherein:

R 2A is hydrogen C 1-6 heteroalkyl, or 6 membered heteroaryl, wherein the C 1-6 heteroalkyl and 5-6 membered heteroaryl are each optionally substituted with 1-3 R 8A substituents; R 3A is C 1-3 alkyl or phenyl, wherein the C 1-3 alkyl or phenyl are each independently optionally substituted with 1-3 R 9A substituents; 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 with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen; R 6A is methyl; R 7A is methyl; R 8A and R 9A are each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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 wherein, when R 2A is H, R 6A is methyl, m is 0, and R 5A is H, at least one of R 3A and R 4A is not unsubstituted phenyl.

Also provided herein is a compound of Formula III:

or a pharmaceutically acceptable form thereof, wherein:

X is NR 1A R 2A or —OR 2A ; R 1A is hydrogen or C 1-6 alkyl; R 2A 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, and 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents, optionally wherein 2 independent R 8A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; or R 1A and R 2A are combined to form a 3-6 membered heterocycloalkyl including the nitrogen atom to which they are both attached; R 3A 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 with 1-3 R 9A substituents; R 4A is hydrogen, phenyl, or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen or C 1-6 alkyl; R 6A and R 7A are each independently 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 8A and R 9A are each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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.

›CROSS REFERENCE · 4 of 63

Also provided herein is a compound of Formula IIIa:

or a pharmaceutically acceptable form thereof, wherein:

R 1A is hydrogen; R 2A is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, and 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents, optionally wherein 2 independent R 8A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 3A 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 with 1-3 R 9A substituents; R 4A is hydrogen, phenyl, or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen or C 1-6 alkyl; R 6A and R 7A are each independently 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 8A and R 9A are each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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.

Also provided herein is a compound of Formula IIIb:

or a pharmaceutically acceptable form thereof, wherein:

R 1A and R 2A are combined to form a 4-6 membered heterocycloalkyl including the nitrogen atom to which they are both attached; R 3A 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 with 1-3 R 9A substituents; R 4A is hydrogen, phenyl, or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen or C 1-6 alkyl; R 6A and R 7A are each independently 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 8A and R 9A are each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; R 10A is independently selected from the group consisting of halo, CN, C 1-6 alkyl, R 10A 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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.

Also provided herein is a compound of Formula IIIc:

or a pharmaceutically acceptable form thereof, wherein:

R 2A is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, and 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents; R 3A 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 with 1-3 R 9A substituents; R 4A is hydrogen, phenyl, or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen or C 1-6 alkyl; R 6A and R 7A are each independently 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 8A and R 9A are each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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.

›CROSS REFERENCE · 5 of 63

Also provided herein is a compound of Formula IV:

or a pharmaceutically acceptable form thereof, wherein:

X is —NR 1A R 2A or —OR 2A ; R 1A is hydrogen or C 1-6 alkyl; R 2A 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, and 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents, optionally wherein 2 independent R 8A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; or R 1A and R 2A are combined to form a 3-6 membered heterocycloalkyl including the nitrogen atom to which they are both attached; R 3A 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 with 1-3 R 9A substituents; R 4A is hydrogen, phenyl, or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen or C 1-6 alkyl; R 7A is C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, C 1-6 heteroalkyl, halo, —NR 12A R 13A , C 1-6 alkoxy, C 1-6 haloalkoxy, —C(O)NR 12A R 13A , —(CO)R 11A , —C(O)OR 14A , or CN, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, and C 1-6 heteroalkyl are each independently optionally substituted with 1-3 R 8A substituents; R 8A and R 9A are each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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.

Also provided herein is a compound of Formula IVa:

or a pharmaceutically acceptable form thereof, wherein:

R 1A is hydrogen; R 2A is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, or 6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, and 6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents, optionally wherein 2 independent R 8A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 3A is C 1-6 alkyl or phenyl, wherein the C 1-6 alkyl and phenyl are each independently optionally substituted with 1-3 R 9A substituents; R 4A is 5 membered heteroaryl, wherein the 5 membered heteroaryl is optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen; R 7A is methyl; R 8A and R 9A are each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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.

Also provided herein is a compound of Formula IVb:

or a pharmaceutically acceptable form thereof, wherein:

R 1A and R 2A are combined to form a 4-6 membered heterocycloalkyl including the nitrogen atom to which they are both attached; R 3A is C 1-6 alkyl or phenyl, wherein the C 1-6 alkyl and phenyl are each independently optionally substituted with 1-3 R 9A substituents; R 4A is 5 membered heteroaryl, wherein the 5 membered heteroaryl is optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen; R 7A is methyl; R 8A and R 9A are each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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.

›CROSS REFERENCE · 6 of 63

Also provided herein is a compound of Formula IVc:

or a pharmaceutically acceptable form thereof, wherein:

R 2A is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, and 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents; R 3A 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 with 1-3 R 9A substituents; R 4A is hydrogen, phenyl, or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen; R 7A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 8A and R 9A are each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; is independently selected from the group consisting of 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, wherein the compound is a modulator of Ras superfamily activity according to a Ras Superfamily Activity Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 μM according to a Ras Superfamily Activity Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 20 μM according to a Ras Superfamily Activity Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, wherein the compound inhibits phosphorylation of Erk1/2 according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 μM according to Erk1/2 Phosphorylation Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, wherein the compound activates phosphorylation of Erk1/2 according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 μM according to Erk1/2 Phosphorylation Assay.

›CROSS REFERENCE · 7 of 63

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, wherein the compound inhibits phosphorylation of Akt according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 μM according to Akt Phosphorylation Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, wherein the compound activates phosphorylation of Akt according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 μM according to Akt Phosphorylation Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, wherein the compound inhibits phosphorylation of Smad2/3 according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 μM according to Phospho-Smad2/3 Inhibition Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, wherein the compound inhibits JNK according to JNK Activation Assay. In one embodiment, the compound or 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 JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits JNK by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 μM according to JNK Activation Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, wherein the compound activates JNK according to JNK Activation Assay. In one embodiment, the compound or 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 or greater than 100% at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 μM according to JNK Activation Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, wherein the compound inhibits MAPK p38 according to MAPK p38 Activation Assay. In one embodiment, the compound or 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 MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 μM according to MAPK p38 Activation Assay.

›CROSS REFERENCE · 8 of 63

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, wherein the compound activates MAPK p38 according to MAPK p38 Activation Assay. In one embodiment, the compound or 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 or greater than 100% at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 μM according to MAPK p38 Activation Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, II, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, wherein the compound inhibits proliferation in MiaPaca2 according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1 μM or less, 0.9 μM or less, 0.8 UM 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 UM or less, 0.2 μM or less, 0.15 μM or less, or 0.1 μM or less according to Proliferation Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, wherein the compound inhibits IL-6 according to IL-6 Quantification Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to IL-6 Quantification Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 μM according to IL-6 Quantification Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof inhibits TNF-alpha according to TNF-alpha Quantification Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to TNF-alpha Quantification Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 μM according to TNF-alpha Quantification Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof that has a half-life of 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, or 50 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof that has a kinetic solubility of 10 μM or more, 20 μM or more, 30 μM or more, 40 μM or more, 5 μM or more, 60 μM or more, 70 μM or more, 80 μM or more, 90 μM or more, 100 μM or more, 150 μM or more, or 200 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay.

Also provided herein is a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof that inhibits proliferation in NCI-H358, A375, GP2d, BT549, or MM.R1 according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in NCI-H358, A375, GP2d, BT549, or MM.R1 with an IC50 value of 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MM.R1 with an IC50 value of 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay.

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

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

Also provided herein are methods of 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 pharmaceutically acceptable form thereof.

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

›CROSS REFERENCE · 9 of 63

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

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

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

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

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

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

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

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

Also provided herein are methods of modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof.

Also provided herein are methods of modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of a pharmaceutical composition 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 pharmaceutically acceptable form thereof.

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

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

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

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

Also provided herein are methods of treating cancer in a subject, comprising administering a therapeutically effective amount of the compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, to the subject having cancer. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

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

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

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

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

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

Also provided herein are pharmaceutical compositions provided herein comprising therapeutically effective amounts of one or more of compounds provided herein (e.g. compounds of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc) and a pharmaceutically acceptable carrier, diluent or excipient.

3. DETAILED DESCRIPTION

3.1. Definitions

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

As used herein, “JNK” means the stress-activated MAPK protein c-Jun NH 2 -terminal kinase.

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

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

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

The GTP binding domains of one subfamily of the Ras superfamily having substantial sequence homology is commonly referred to as the Ras family or Ras.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Without being bound by theory, Ras is causally associated with inflammatory diseases including the following: rheumatoid arthritis (Abreu J R, de Launay D, Sanders M E, Grabiec A M, Sande van de M G, Tak P P, Reedquist K A: The Ras guanine nucleotide exchange factor RasGRF1 promotes matrix metalloproteinase-3 production in rheumatoid arthritis synovial tissue (Arthritis Res Ther. 2009, 11: R121-10.1186/ar2785), which is the most common cause of disability (Hootman J M, Brault M W, Helmick C G, Theis K A, Armour B S. 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 C S, Sandvik A K, Bruland T, Andreu-Ballester J C, J. Crohns Colitis, 2017 Mar. 16. doi: 10); ulcerative colitis; spondyloarthropathies; idiopathic pulmonary fibrosis; juvenile arthritis; psoriasis; psoriatic arthritis; and others.

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

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

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

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

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

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

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

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

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

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

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

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

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

Without being bound by theory, Rho subfamily associated kinases (ROCK1 and ROCK2) are implicated as mediators of multiple profibrotic processes including those associated with idiopathic pulmonary fibrosis. (Knipe R S, Tager E M, and Liao J K. “The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis.” Pharmacol Rev. 2015 67 (1): 103-17.)

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

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

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

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

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

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

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

As used herein, “alternative Tyr32 conformation” means the conformation of the GTP or GDP binding domain in the region of Tyr 32 in KRas crystal structure PDB code: 3gft in comparison to the KRas crystal structure PDB code: 4epr.

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

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

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

›CROSS REFERENCE · 14 of 63

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

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

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

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

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

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

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

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

›CROSS REFERENCE · 15 of 63

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

As used herein, “heteroalkyl” refers to a straight or branched aliphatic hydrocarbon group having, inserted in the hydrocarbon chain one or more oxygen, sulfur, including S(═O) and S(═O) 2 groups, or substituted or unsubstituted nitrogen atoms, including —NR— and —N + RR— groups, where the nitrogen substituent(s) is (are) alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, S(═O) 2 R′ or COR′, where R′ is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, —OY or —NYY′, where Y and Y′ are each independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, in one embodiment having from 1 to about 20 atoms, in another embodiment having from 1 to 12 atoms in the chain.

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

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

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

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

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

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

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

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

As used herein, “heteroaralkyl” refers to an alkyl group in which one of the hydrogen atoms of the alkyl is replaced by a heteroaryl group.

›CROSS REFERENCE · 16 of 63

As used herein, “halo”, “halogen” or “halide” refers to F, Cl, Br or I.

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

As used herein, “haloalkoxy” refers to RO in which R is a haloalkyl group.

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

As used herein, “cycloalkoxy” refers to an —OR group, in which R is a cycloalkyl group.

As used herein, “carboxy” refers to a divalent radical, —C(O)O—.

As used herein, “aminocarbonyl” refers to —C(O)NH 2 .

As used herein, “alkylaminocarbonyl” refers to —C(O)NHR in which R is alkyl, including lower alkyl. As used herein, “dialkylaminocarbonyl” refers to —C(O)NR′R in which R′ and R are independently alkyl, including lower alkyl; “carboxamide” refers to groups of formula —NR′COR in which R′ and R are independently alkyl, including lower alkyl.

As used herein, “arylalkylaminocarbonyl” refers to —C(O)NRR′ in which one of R and R′ is aryl, including lower aryl, such as phenyl, and the other of R and R′ is alkyl, including lower alkyl.

As used herein, “arylaminocarbonyl” refers to —C(O)NHR in which R is aryl, including lower aryl, such as phenyl.

As used herein, “hydroxycarbonyl” refers to —COOH.

As used herein, “alkoxycarbonyl” refers to —C(O)OR in which R is alkyl, including lower alkyl.

As used herein, “aryloxycarbonyl” refers to —C(O)OR in which R is aryl, including lower aryl, such as phenyl.

As used herein, “alkoxy” and “alkylthio” refer to RO— and RS—, in which R is alkyl, including lower alkyl.

As used herein, “aryloxy” and “arylthio” refer to RO— and RS—, in which R is aryl, including lower aryl, such as phenyl.

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

As used herein, “cyclic structure” may be a cycloalkyl, carbocyclic, heterocyclic, aryl or heteroaryl group.

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

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

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

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

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

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As used herein, a “pharmaceutically acceptable form” of compounds disclosed herein includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of compounds disclosed herein. In one embodiment, a “pharmaceutically acceptable form” includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, as disclosed herein.

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

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

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

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

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

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

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

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

Lower case r/s stereo descriptors are used to describe pseudo-asymmetric centers, according to Cahn-Ingold-Prelog Rules (see R. S. Cahn, C. K. Ingold and V. Prelog, Angew. Chem. Internat. Ed. Eng. 5, 385-415, 511 (1966); and V. Prelog and G. Helmchen, Angew. Chem Internat. Ed. Eng. 21, 567-583 (1982)). For example, Compound B below is named (1s,4s)-1-bromo-4-chlorocyclohexane.

Compound names included herein were generated from the corresponding chemical structures using ChemDraw® versions 20.0.0.38, 20.1.0.112, and 22.2.0.3348. If there is a discrepancy between the chemical structure and the name disclosed herein, the structure shall control.

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

›CROSS REFERENCE · 18 of 63

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

The phrase “an isotopic variant thereof; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof” has the same meaning as the phrase “an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable salt of the compound referenced therein; or a pharmaceutically acceptable salt of an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable solvate of the compound referenced therein; or a pharmaceutically acceptable solvate of an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of the compound referenced therein; or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of an isotopic variant of the compound referenced therein or its variant or its variant.”

3.2. Compounds

Provided herein is a compound of Formula I:

or a pharmaceutically acceptable form thereof, wherein:

the pyridinyl or the 8-10-membered fused-heteroaryl is optionally substituted with 1-4 R 7A substituents;

R 1A and R 2A are combined to form a 3-6 membered heterocycloalkyl including the nitrogen atom to which they are both attached, optionally wherein the 3-6 membered heterocycloalkyl formed by R 1A and R 2A is fused to a 5-6 membered heteroaryl;

R 3A is C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 heteroalkyl, aryl, 5-10 membered heteroaryl, —(CO)R 11A , or —C(O)NR 12A R 13A 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 substituents; R 4A is hydrogen, aryl, or 5-10 membered heteroaryl, wherein the aryl and 5-10 membered heteroaryl are each independently optionally substituted with 1-4 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen or C 1-6 alkyl; R 6A and R 7A are each independently C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, C 1-6 heteroalkyl, halo, —NR 12A R 13A , C 1-6 alkoxy, C 1-6 haloalkoxy, —C(O)NR 12A R 13A , —(CO)R 11A , —C(O)OR 14A , or CN, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, and C 1-6 heteroalkyl are each independently optionally substituted with 1-3 R 8A substituents; R 8A and R 9A are each independently selected from the group consisting of 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, —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 haloalkoxy, 5-6 membered heteroaryl, biotinamide, or a biotinylated substituent; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl, wherein the 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 haloalkoxy, or 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, —OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 heterocycloalkyl, aryl, or 5-10 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 haloalkoxy, C 3-7 heterocycloalkyl, aryl, and 5-10 membered heteroaryl are optionally substituted with 1-3 R 8A substituents, or R 12A and R 13A are combined to form a 3-7 membered heterocycloalkyl including the nitrogen atom to which they are both attached; R 14A is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or C 1-6 heteroalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 15A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 16A and R 17A are each independently selected from the group consisting 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents, or R 16A and R 17A are combined to form a 3-7 membered heterocycloalkyl including the phorphorus atom to which they are both attached; and wherein, when X is OH or

›CROSS REFERENCE · 19 of 63

Y is N-methyl imidazoyl, and R 5A is H, at least one of R 3A and R 4A is not unsubstituted phenyl.

In some embodiments, the compound of Formula I is such that Y is an imidazolyl optionally substituted with 1 R 6A substituent and optionally substituted with 1-2 R 7A substituents. In some embodiments, the compound of Formula I is such that Y is a C-linked imidazolyl that is substituted with 1 R 6A substituent at a nitrogen of the imidazolyl ring and optionally substituted with 1-2 R 7A substituents at carbons of the imidazolyl ring. In some embodiments, the compound of Formula I is a compound of Formula Ia:

or a pharmaceutically acceptable form thereof. In some embodiments, the compound of Formula I is a compound of Formula Ib:

or a pharmaceutically acceptable form thereof. In some embodiments, the compound of Formula I is such that Y is a pyridinyl optionally substituted with 1-4 R 7A substituents. In some embodiments, the compound of Formula I is a compound of Formula Ib:

or a pharmaceutically acceptable form thereof.

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

In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is such that R 6A is C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —C(O)NR 12A R 13A , —(CO)R 11A , or —C(O)OR 14A , wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, and C 1-6 heteroalkyl are each independently optionally substituted with 1-3 R 8A substituents. In some embodiments, the compound is such that R 6A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents. In some embodiments, the compound is such that R 6A is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R 8A , wherein R 8A is —OH, C 1-3 alkoxy, or C 1-3 haloalkoxy. In some embodiments, the compound is such that R 6A is methyl, ethyl, or isopropyl. In some embodiments, the compound is such that R 6A is methyl.

In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is such that R 7A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents. In some embodiments, the compound is such that R 7A is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R 8A , wherein R 8A is —OH, C 1-3 alkoxy, or C 1-3 haloalkoxy. In some embodiments, the compound is such that R 7A is methyl, ethyl, or isopropyl. In some embodiments, the compound is such that R 7A is methyl. In some embodiments, the compound is such that m is 4. In some embodiments, the compound is such that m is 3. In some embodiments, the compound is such that m is 2. In some embodiments, the compound is such that m is 1. In some embodiments, the compound is such that m is 0.

In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is such that X is —OR 2A . In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is such that X is —NR 1A R 2A . In some embodiments, the compound is such that X is —NR 1A R 2A , and R 1A and R 2A are combined to form a 3-6 membered heterocycloalkyl including the nitrogen atom to which they are both attached. In some embodiments, the compound is such that R 1A is hydrogen or C 1-3 alkyl. In some embodiments, the compound is such that R 1A is methyl, ethyl, or isopropyl. In some embodiments, the compound is such that R 14 is hydrogen. In some embodiments, the compound is such that R 2A 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, or 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents. In some embodiments, the compound is such that R 2A is a 5-6 membered heteroaryl, wherein each are independently optionally substituted with 1-3 R 8A substituents, optionally wherein 2 independent R 8A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached. In some embodiments, the compound is such that R 2A is a 5-6 membered heteroaryl selected from the group consisting of a pyridinyl, a pyrimidinyl, a pyrazinyl, a pyridazinyl, a triazinyl, an imidazolyl, a pyrazolyl, a triazolyl, a tetrazolyl, an oxazolyl, an isoxazolyl, an oxadiazolyl, a thiazolyl, a isothiazolyl, or a thiadiazolyl, wherein are each independently optionally substituted with 1-3 R 8A substituents. In some embodiments, the 5-6 membered heteroaryl is substituted with 2 independent R 8A substituents which are combined to form a 5-6 membered cycloalkyl fused to the 5-6 membered heteroaryl including the atom or atoms to which each are attached. In some embodiments, the 5-6 membered heteroaryl is substituted with 2 independent R 8A substituents which are combined to form a 5-6 membered heterocycloalkyl fused to the 5-6 membered heteroaryl including the atom or atoms to which each are attached. In some embodiments, the 2 R 8A substituents are combined to form a pyrazolo[5,1-b]oxazolyl ring. In some embodiments, the 2 R 8A substituents are combined to form a 2,3-dihydropyrazolo[5,1-b]oxazolyl ring. In some embodiments, the 5-6 membered heteroaryl is a pyrazolyl. In some embodiments, the compound is such that R 8A is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, —NR 12A R 13A , —(CO)R 11A , oxo, C 1 -6 hydroxyalkyl, C 1-6 heteroalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkoxy. In some embodiments, the compound is such that R 8A is independently selected from the group consisting of 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, or C 3-5 cycloalkoxy. In some embodiments, the compound is such that R 8A is independently selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, —NR 12A R 13A , —(CO)R 11A , oxo, C 2-3 hydroxyalkyl, C 2-4 heteroalkyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, or cyclobutoxy.

›CROSS REFERENCE · 20 of 63

In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is such that X is: —OH, —NH 2 ,

In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is such that R 3A 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, or 5-6 membered heteroaryl, are each independently optionally substituted with 1-3 R 9A substituents. In some embodiments, the compound is such that R 9A is independently selected from the group consisting of 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. In some embodiments, the compound is such that R 9A is independently selected from the group consisting of 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 such that R 3A is: —CH 3 , unsubstituted phenyl, (4-methoxy)-phenyl, ispropyl, cyclopropyl,

In some embodiments, the compound is such that R 3A is: —CH 3 , unsubstituted phenyl, isopropyl, cyclopropyl,

In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, or Formula Ic is such that R 4A is phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl are each independently optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached. In some embodiments, the compound is such that R 4A is phenyl optionally substituted with 1-3 R 10A substituents. In some embodiments, the compound is such that R 4A is 5-6 membered heteroaryl optionally substituted with 1-3 R 10A substituents. In some embodiments, the compound is such that R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl. In some embodiments, the compound is such that R 10A is independently selected from the group consisting of halo, 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 . In some embodiments, the compound is such that R 10A is independently selected from the group consisting of halo, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, C 1-3 haloalkyl, C 2-3 hydroxyalkyl, C 2-4 heteroalkyl, —OH, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, C 1-4 haloalkoxy, or —NR 12A R 13A . In some embodiments, the compound is such that R 12A and R 13A are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, —OH, or C 1-4 alkoxy. In some embodiments, the compound is such that R 12A and R 13A are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, or ethoxy. In some embodiments, the compound is such that R 12A and R 13A are each independently selected from the group consisting of hydrogen or methyl. In some embodiments, the compound is such that R 12A and R 13A are each hydrogen.

In some embodiments, the compound is such that R 4A is: hydrogen, unsubstituted phenyl.

In some embodiments, the compound of Formula I is a compound of Formula II:

or a pharmaceutically acceptable form thereof, wherein:

›CROSS REFERENCE · 21 of 63

Y is N-methyl imidazoyl, and R 5A is H, at least one of R 3A and R 4A is not unsubstituted phenyl.

In some embodiments, the compound of Formula I is a compound of Formula IIa:

or a pharmaceutically acceptable form thereof, wherein:

In some embodiments, the compound of Formula IIa is such that:

R 1A and R 2A together with the nitrogen to which they are attached, have a structure of: —NH 2 ,

In some embodiments, the compound of Formula IIa is such that:

R 1A and R 2A together with the nitrogen to which they are attached, have a structure of: —NH 2 ,

R 3A is —CH 3 , unsubstituted phenyl, isopropyl, cyclopropyl,

R 41 hydrogen, unsubstituted phenyl,

R 5A is hydrogen;

R 6A is methyl, —CH 2 CH 2 NH 2 , or

and

m is 0.

In some embodiments, the compound of Formula I is a compound of Formula IIa(1):

or a pharmaceutically acceptable form thereof, wherein:

In some embodiments, the compound of Formula IIa(1) is such that R 18A is methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, the compound of Formula IIa(1) is such that R 18A is methyl. In some embodiments, the compound of Formula IIa(1) is such that R 18A is ethyl. In some embodiments, the compound of Formula IIa(1) is such that R 18A is isopropyl. In some embodiments, the compound of Formula IIa(1) is such that R 18A is cyclopropyl.

In some embodiments, the compound of Formula IIa(1) is such that R 8A is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkoxy, —NR 12A R 13A , or 5-6 membered heteroaryl.

In some embodiments, the compound of Formula IIa(1) is such that R 2A is pyridyl, pyrimidyl, pyrazyl, or pyrazolyl, wherein the pyridyl, pyrimidyl, pyrazyl, or pyrazolyl is optionally substituted with 1-3 R 8A substituents, optionally wherein 2 independent R 8A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached. In some embodiments, the compound of Formula IIa(1) is such that R 2A is pyridyl, optionally substituted with 1-2 R 8A substituents. In some embodiments, the compound of Formula IIa(1) is such that R 2A is

›CROSS REFERENCE · 22 of 63

In some embodiments, the compound of Formula IIa(1) is such that R 2A is pyrimidyl, optionally substituted with 1-2 R 8A substituents. In some embodiments, the compound of Formula IIa(1) is such that R 2A is

In some embodiments, the compound of Formula IIa(1) is such that R 2A is pyrazyl, optionally substituted with 1-2 R 8A substituents. In some embodiments, the compound of Formula IIa(1) is such that R 2A is pyrazolyl, optionally substituted with 1-2 R 8A substituents. In some embodiments, the compound of Formula IIa(1) is such that R 2A is

In some embodiments, the compound of Formula IIa(1) is such that the 2 independent R 8A substituents are combined to form a 5 membered cycloalkyl or 5 membered heterocycloalkyl including the atom or atoms to which each are attached.

In some embodiments, the compound of Formula IIa(1) is such that R 1A and R 2A together with the nitrogen to which they are attached have a structure of:

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

In some embodiments, the compound of Formula I is 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 including the nitrogen atom to which they are both attached, optionally wherein the 4-6 membered heterocycloalkyl formed by RA and R 2A is fused to a 6 membered heteroaryl; R 3A is C 1-3 alkyl or phenyl, wherein the C 1-3 alkyl and phenyl are each independently optionally substituted with 1-3 R 9A substituents; R 4A is phenyl or 5 membered heteroaryl, wherein the phenyl and 5 membered heteroaryl are each independently optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen; R 6A is methyl; R 7A is methyl; R 9A is each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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 wherein, when R 1A and R 2A are combined to form

R 6A is methyl, m is 0, and R 5A is H, at least one of R 3A and R 4A is not unsubstituted phenyl.

In some embodiments, the compound of Formula IIb is such that:

R 1A and R 2A are combined to form

In some embodiments, the compound of Formula IIb is such that:

R 1A and R 2A are combined to form

In some embodiments, the compound of Formula I is a compound of Formula IIc:

or a pharmaceutically acceptable form thereof, wherein:

In some embodiments, the compound of Formula IIc is such that:

R 2A together with the oxygen to which it is attached have a structure of: —OH,

In some embodiments, the compound of Formula I is a compound of Formula III:

or a pharmaceutically acceptable form thereof, wherein:

›CROSS REFERENCE · 23 of 63

In some embodiments, the compound of Formula I is a compound of Formula IIIa:

or a pharmaceutically acceptable form thereof, wherein:

In some embodiments, the compound of Formula I is a compound of Formula IIIb:

or a pharmaceutically acceptable form thereof, wherein:

R 1A and R 2A are combined to form a 4-6 membered heterocycloalkyl including the nitrogen atom to which they are both attached; R 3A 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 with 1-3 R 9A substituents; R 4A is hydrogen, phenyl, or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen or C 1-6 alkyl; R 6A and R 7A are each independently 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 8A and R 9A are each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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.

›CROSS REFERENCE · 24 of 63

In some embodiments, the compound of Formula I is a compound of Formula IIIc:

or a pharmaceutically acceptable form thereof, wherein:

In some embodiments, the compound of Formula I is a compound of Formula IV:

or a pharmaceutically acceptable form thereof, wherein:

In some embodiments, the compound of Formula I is a compound of Formula IVa:

or a pharmaceutically acceptable form thereof, wherein:

R 1A is hydrogen; R 2A is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, or 6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, and 6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents, optionally wherein 2 independent R 8A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 3A is C 1-6 alkyl or phenyl, wherein the C 1-6 alkyl and phenyl are each independently optionally substituted with 1-3 R 9A substituents; R 4A is 5 membered heteroaryl, wherein the 5 membered heteroaryl is optionally R 10A substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen; R 7A is methyl; R 8A and R 9A are each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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.

›CROSS REFERENCE · 25 of 63

In some embodiments, the compound of Formula IVa is such that:

R 1A and R 2A together with the nitrogen to which they are attached have a structure of:

In some embodiments, the compound of Formula I is a compound of Formula IVb:

or a pharmaceutically acceptable form thereof, wherein:

In some embodiments, the compound of Formula IVb is such that:

In some embodiments, the compound of Formula I is a compound of Formula IVc:

or a pharmaceutically acceptable form thereof, wherein:

R 2A is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, or 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, and 5-6 membered heteroaryl are each independently optionally substituted with 1-3 R 8A substituents; R 3A 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 with 1-3 R 9A substituents; R 4A is hydrogen, phenyl, or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl are each independently optionally substituted with 1-3 R 10A substituents, optionally wherein 2 independent R 10A substituents are combined to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl including the atom or atoms to which each are attached; R 5A is hydrogen; R 7A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 8A and R 9A are each independently selected from the group consisting of 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, —(CO)R 11A , oxo, —OH, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkoxy, or 5-6 membered heteroaryl; R 10A is independently selected from the group consisting of 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 5-6 membered heteroaryl; R 11A 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 heteroalkyl, are each independently optionally substituted with 1-3 R 8A substituents; R 12A and R 13A are each independently selected from the group consisting of 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.

In some embodiments, the compound of Formula IVc is such that:

R 2A is hydrogen; R 3A is —CH 3 ; R 4A is

R 5A is hydrogen;

R 7A is methyl;

m is 0.

In one embodiment, the compound of Formula I, Ia, II, or IIb is such that the combination of Y, X, R 1A , R 2A , R 3A , R 4A , and R 5A substituents do not form:

In one embodiment, the compound of Formula I, Ia, II, or IIb is not

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 no more than 1000 g/mol. In one embodiment, the compound has a MW of no more than 900 g/mol, no more than 800 g/mol, no more than 700 g/mol, no more than 600 g/mol, or no more than 500 g/mol. In one embodiment, the compound has a MW of no more than 900 g/mol. In one embodiment, the compound has a MW of no more than 800 g/mol. In one embodiment, the compound has a MW of no more than 700 g/mol. In one embodiment, the compound has a MW of no more than 600 g/mol. In one embodiment, the compound has a MW of no more than 500 g/mol. In one embodiment, the compound has a MW of no more than 450 g/mol.

In one embodiment, the compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc is selected from the group consisting of 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, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 26 of 63

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 pharmaceutically acceptable form thereof is a modulator of Ras superfamily activity according to a Ras Superfamily Activity Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase 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 pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 20 μM according to a Ras Superfamily Activity Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 45% or more at 20 μM according to a Ras Superfamily Activity Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more at 20 μM according to a Ras Superfamily Activity Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 75% or more at 20 μM according to a Ras Superfamily Activity Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 90% or more at 20 μM according to a Ras Superfamily Activity Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 95% or more at 20 μM according to a Ras Superfamily Activity Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 50% to about 60% at 20 μM according to a Ras Superfamily Activity Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 60% to about 70% at 20 μM according to a Ras Superfamily Activity Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 70% to about 80% at 20 μM according to a Ras Superfamily Activity Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 80% to about 90% at 20 μM according to a Ras Superfamily Activity Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 90% to about 100% at 20 μM according to a Ras Superfamily Activity Assay. In one embodiment, the compound is selected from the group consisting of Compounds 6, 17, 22, 32, 34, 37, 42, 43, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 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 a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of Compounds 6, 17, 22, 37, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 149, 150, 151, 152, 153, 154, 156, 157, 158, 165, 166, 169, 170, 173, 175, 176, 177, 178, 179, 186, 187, 188, 196, 202, 208, 211, 212, 213, 214, 215, 216, 217, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 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.

›CROSS REFERENCE · 27 of 63

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 pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 50% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 75% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 85% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 90% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 95% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by equal or greater than 100% at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 50% to about 60% at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 60% to about 70% at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 70% to about 80% at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 80% to about 90% at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 90% to about 100% at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 100% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In one embodiment, the compound is selected from the group consisting of Compounds 49, 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 130, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 183, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of Compounds 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 183, 190, 191, 192, 193, 194, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 28 of 63

In one embodiment, the compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, II, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof activates phosphorylation of Akt according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 75% or more at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 85% or more at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 90% or more at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 95% or more at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by equal or greater than 100% at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 50% to about 60% at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 60% to about 70% at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 70% to about 80% at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 80% to about 90% at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 90% to about 100% at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 100% or more at 10 μM according to Akt Phosphorylation Assay. In one embodiment, the compound is selected from the group consisting of 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.

›CROSS REFERENCE · 29 of 63

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 pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 50% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 75% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 85% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 90% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 95% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by equal or greater than 100% at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 50% to about 60% at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 60% to about 70% at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 70% to about 80% at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 80% to about 90% at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 90% to about 100% at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 100% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In one embodiment, the compound is selected from the group consisting of Compounds 56, 63, 84, 88, 89, 90, 95, 100, 101, 103, 104, 106, 108, 109, 111, 112, 113, 114, 129, 166, 173, 179, 183, 186, 216, 241, 247, 248, 250, 255, 256, 257, and 266, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 30 of 63

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 pharmaceutically acceptable form thereof activates JNK according to JNK Activation Assay. In one embodiment, the compound or 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 or greater than 100% at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by 25% or more at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by 30% or more at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by 50% or more at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by 75% or more at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by 85% or more at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by 90% or more at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by 95% or more at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by equal or greater than 100% at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by about 50% to about 60% at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by about 60% to about 70% at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by about 70% to about 80% at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by about 80% to about 90% at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by about 90% to about 100% at 10 μM according to JNK Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates JNK by about 100% or more at 10 μM according to JNK Activation Assay. In one embodiment, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 6, 7, 8, 9, 11, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of Compounds 3, 4, 6, 7, 11, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of Compounds 3, 6, 7, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 31 of 63

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 pharmaceutically acceptable form thereof activates MAPK p38 according to MAPK p38 Activation Assay. In one embodiment, the compound or 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 or greater than 100% at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 25% or more at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 30% or more at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 75% or more at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 85% or more at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 90% or more at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 95% or more at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by equal or greater than 100% at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 50% to about 60% at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 60% to about 70% at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 70% to about 80% at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 80% to about 90% at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 90% to about 1000% at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 100% or more at 10 μM according to MAPK p38 Activation Assay. In one embodiment, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, 93, and 218, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of Compounds 1, 2, 3, 7, 8, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof.

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 pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.25 μM or less, 1.1 μM or less, 1 μM or less, 0.9 μM or less, 0.8 μM or less, 0.75 μM or less, 0.7 μM or less, 0.6 μM or less, 0.5 μM or less, 0.4 μM or less, 0.3 μM or less, 0.25 μM or less, 0.2 μM or less, 0.15 μM or less, or 0.1 μM or less according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 1.25 μM to about 1.1 μM, about 1.1 μM to about 1 μM, about 1.0 μM to about 0.9 μM, about 0.9 μM to about 0.8 μM, about 0.8 μM to about 0.75μ, about 0.75μ M to about 0.7μ, about 0.7μ M to about 0.6μ, about 0.6μ M to about 0.5 μM, about 0.5 μM to about 0.4 μM, about 0.4 μM to about 0.3 μM, about 0.3 μM to about 0.25 μM, about 0.25 μM to about 0.2 μM, about 0.2 μM to about 0.15 μM, about 0.15 μM to about 0.1 μM, about 0.1 μM to about 0.01 μM, about 0.01 μM to about 0.001 μM, about 0.001 μM to about 0.0001 μM, or less than about 0.0001 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.25 μM or less according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1 μM or less according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.6 μM or less according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.5 μM or less according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.4 μM or less according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.3 μM or less according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.25 μM or less according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.20 μM or less according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.15 μM or less according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.10 μM or less according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 1.25 μM to about 1.1 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 1.1 μM to about 1 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 1.0 μM to about 0.9 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.9 μM to about 0.8 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.8 μM to about 0.75 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.75 μM to about 0.7 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.7 μM to about 0.6 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.6 μM to about 0.5 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.5 μM to about 0.4 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.4 μM to about 0.3 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.3 μM to about 0.25 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.25 μM to about 0.2 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.2 μM to about 0.15 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.15 μM to about 0.1 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value about 0.1 μM to about 0.01 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.01 μM to about 0.001 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.001 μM to about 0.0001 μM according to Proliferation Assay. In one embodiment, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of less than about 0.0001 μM according to Proliferation Assay. In one embodiment, the compound is selected from the group consisting of 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 a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of Compounds 6, 13, 22, 26, 29, 30, 32, 33, 34, 42, 48, 49, 50, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 68, 72, 73, 74, 76, 78, 79, 81, 82, 83, 84, 86, 89, 91, 93, 94, 95, 96, 97, 98, 100, 101, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 122, 123, 124, 125, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 149, 156, 157, 158, 165, 169, 170, 173, 174, 175, 176, 196, 203, 209, 210, 213, 217, 219, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 255, 257, 263, 264, 265, 266, 267, 268, 269, 270, 271, 274, and 276, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of Compounds 6, 13, 22, 32, 34, 48, 49, 50, 53, 54, 55, 56, 57, 58, 59, 62, 63, 64, 65, 68, 73, 74, 76, 78, 79, 81, 82, 83, 84, 86, 89, 91, 93, 94, 95, 96, 97, 98, 100, 101, 102, 104, 106, 107, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 122, 123, 124, 125, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 156, 157, 158, 165, 169, 170, 174, 175, 196, 209, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 243, 244, 245, 246, 247, 248, 249, 250, 252, 255, 257, 263, 264, 265, 266, 267, 268, 270, 271, 274, and 276, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of Compounds 6, 48, 49, 50, 53, 54, 55, 57, 58, 62, 63, 64, 65, 68, 73, 76, 79, 82, 84, 89, 91, 94, 95, 97, 98, 100, 102, 104, 106, 107, 110, 112, 113, 114, 115, 117, 118, 120, 122, 123, 124, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 156, 157, 158, 165, 169, 170, 196, 221, 222, 224, 226, 227, 228, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 243, 244, 245, 248, 249, 250, 252, 255, 257, 263, 265, 266, 267, and 268, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 32 of 63

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 pharmaceutically acceptable form thereof has a kinetic solubility of 10 μM or more, 20 μM or more, 30 μM or more, 40 μM or more, 50 μM or more, 60 μM or more, 70 μM or more, 80 μM or more, 90 μM or more, 100 μM or more, 150 μM or more, or 200 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In one embodiment, the compound has a kinetic solubility of 10 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In one embodiment, the compound has a kinetic solubility of 20 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In one embodiment, the compound has a kinetic solubility of 30 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In one embodiment, the compound has a kinetic solubility of 40 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In one embodiment, the compound has a kinetic solubility of 50 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In one embodiment, the compound has a kinetic solubility of 60 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In one embodiment, the compound has a kinetic solubility of 70 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In one embodiment, the compound has a kinetic solubility of 80 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In one embodiment, the compound has a kinetic solubility of 90 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In one embodiment, the compound has a kinetic solubility of 100 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In one embodiment, the compound has a kinetic solubility of 150 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In one embodiment, the compound has a kinetic solubility of 200 μM or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In one embodiment, the compound is selected from the group consisting of Compounds 53, 55, 57, 58, 84, 91, 100, 102, 116, 118, 124, 137, 141, 142, 145, 158, 221, 222, 255, and 267, or a pharmaceutically acceptable form thereof. In one embodiment, the compound is selected from the group consisting of Compounds 91, 102, 118, and 255, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 33 of 63

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 pharmaceutically acceptable form thereof has a half-life of 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, or 50 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In one embodiment, the compound has a half-life of 10 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In one embodiment, the compound has a half-life of 20 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In one embodiment, the compound has a half-life of 30 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In one embodiment, the compound has a half-life of 40 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In one embodiment, the compound has a half-life of 50 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In one embodiment, the compound is selected from the group consisting of Compounds 6, 102, 104, 124, 126, 128, 129, 137, 141, 142, 144, 145, 156, 157, 224, 226, 227, 235, 238, 248, 255, 265, and 267, or a pharmaceutically acceptable form thereof.

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 pharmaceutically acceptable form thereof inhibits proliferation in NCI-H358, A375, GP2d, BT549, or MM.R1 according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in NCI-H358 according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in A375 according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in GP2d according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in MM.R1 according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in NCI-H358, A375, GP2d, BT549, or MM.R1 with an IC 50 value of 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in NCI-H358, A375, GP2d, BT549, or MM.R1 with an IC 50 value of 50 nM or less according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in NCI-H358, A375, GP2d, BT549, or MM.R1 with an IC 50 value of 40 nM or less according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in NCI-H358, A375, GP2d, BT549, or MM.R1 with an IC50 value of 30 nM or less according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in NCI-H358, A375, GP2d, BT549, or MM.R1 with an IC 50 value of 20 nM or less according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in NCI-H358, A375, GP2d, BT549, or MM.R1 with an IC50 value of 10 nM or less according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in NCI-H358, A375, GP2d, BT549, or MM.R1 with an IC50 value of 1 nM or less according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in NCI-H358, A375, GP2d, BT549, or MM.R1 with an IC 50 value of 0.1 nM or less according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in NCI-H358, A375, GP2d, BT549, or MM.R1 with an IC 50 value of 0.01 nM or less according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in MM.R1 with an IC 50 value of 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in MM.R1 with an IC 50 value of 1 nM or less according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in MM.R1 with an IC 50 value of 0.1 nM or less according to Proliferation Assay. In one embodiment, the compound inhibits proliferation in MM.R1 with an IC 50 value of 0.01 nM or less according to Proliferation Assay. In one embodiment, the compound is selected from the group consisting of Compounds 6, 58, 84, 100, 102, 104, 124, 221, 222, 235, 238, 252, 255, and 267, or a pharmaceutically acceptable form thereof.

In one embodiment, the pharmaceutically acceptable form of 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 isomer, isotopic variant, pharmaceutically acceptable salt, polymorph, or solvate of said compound. In one embodiment, the pharmaceutically acceptable form of the compound is exclusive of a salt form. In one embodiment, the isomer of the compound is a diastereomer or enantiomer of the compound.

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.

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

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 diasteromer.

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 greater 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 an enantiomeric excess of 25% or more of the (R) enantiomer. In one embodiment, the compound has an enantiomeric excess of 50% or more of the (R) enantiomer. In one embodiment, the compound has an enantiomeric excess of 75% or more of the (R) enantiomer. In one embodiment, the compound has an enantiomeric excess of 90% or more of the (R) enantiomer. In one embodiment, the compound has an enantiomeric excess of 95% or more of the (R) enantiomer. In one embodiment, the compound has an enantiomeric excess of 98% or more of the (R) enantiomer. In one embodiment, the compound has an enantiomeric excess of 99% or more of the (R) enantiomer. In one embodiment, the compound has an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (R) enantiomer.

›CROSS REFERENCE · 34 of 63

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 enantiomeric excess of greater than 10% of the(S) 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(S) enantiomer. In one embodiment, the compound has an enantiomeric excess of 15% or more of the(S) enantiomer. In one embodiment, the compound has an enantiomeric excess of 25% or more of the(S) enantiomer. In one embodiment, the compound has an enantiomeric excess of 50% or more of the(S) enantiomer. In one embodiment, the compound has an enantiomeric excess of 75% or more of the(S) enantiomer. In one embodiment, the compound has an enantiomeric excess of 90% or more of the(S) enantiomer. In one embodiment, the compound has an enantiomeric excess of 95% or more of the(S) enantiomer. In one embodiment, the compound has an enantiomeric excess of 98% or more of the(S) enantiomer. In one embodiment, the compound has an enantiomeric excess of 99% or more of the(S) enantiomer. In one embodiment, the compound has an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the(S) enantiomer.

3.3. Methods of Modulating Activity of Cellular Targets

Provided herein are methods of modulating a Ras superfamily protein, comprising contacting the Ras superfamily protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating a Ras superfamily protein, comprising contacting the Ras superfamily protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

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

In some embodiments, the method comprises contacting the Ras superfamily protein with a compound or pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily proteins by 45% or more at 20 μM according to a Ras Superfamily Activity Assay. In some embodiments, the method comprises contacting the Ras superfamily protein with a compound or pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily proteins by 50% or more at 20 μM according to a Ras Superfamily Activity Assay. In some embodiments, the compound is selected from the group consisting of Compounds 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 a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 6, 17, 22, 37, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 149, 150, 151, 152, 153, 154, 156, 157, 158, 165, 166, 169, 170, 173, 175, 176, 177, 178, 179, 186, 187, 188, 196, 202, 208, 211, 212, 213, 214, 215, 216, 217, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 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.

›CROSS REFERENCE · 35 of 63

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

In some embodiments of the methods provided herein, the Ras superfamily protein is a Ras protein, or a mutant thereof. In some embodiments, the Ras protein is DIRAS I; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRASI; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASLIOA; RASLIOB; RASLI IA; RASLIIB; RASL12; REMI; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2. In some embodiments, the Ras protein is HRAS; KRAS; or NRAS, or a mutant thereof. In some embodiments, the Ras protein is a KRAS mutant. In some embodiments, the KRAS mutant is a KRas G12D mutant, KRas G12C mutant, or KRas Q61H mutant. In some embodiments, the Ras protein is HRAS or a mutant thereof. In some embodiments, the Ras protein is NRAS or a mutant thereof.

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.

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.

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

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

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

In some embodiments of the methods provided herein, the modulation takes place in a subject suffering from a cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a blood borne tumor (or a hematological cancer). In some embodiments, the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, or multiple myeloma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is triple negative breast cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is a cancer dependent on a Ras superfamily protein.

Provided herein are methods of 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 pharmaceutically acceptable form thereof. Also provided herein are methods of modulating caspase activity, comprising contacting the caspase with an effective amount of a pharmaceutical composition comprising a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

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

In some embodiments of the methods provided herein, the contacting of the caspase takes place in a cell. In some embodiments, the modulation of caspase activity induces apoptosis of the cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the subject suffers from a cancer. In some embodiments, the modulation takes place in a subject suffering from a cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a blood borne tumor (or a hematological cancer). In some embodiments, the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, 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.

›CROSS REFERENCE · 36 of 63

Provided herein are methods of modulating Erk1/2 activity, comprising contacting an Erk1/2 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating Erk1/2 activity, comprising contacting an Erk1/2 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276 or a pharmaceutically acceptable form thereof.

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

In certain embodiments of the methods of of modulating Erk1/2 activity described herein, the method activates phosphorylation of the Erk1/2 protein. In some embodiments, the method comprises contacting the Erk1/2 protein with a compound or pharmaceutically acceptable form thereof that activates phosphorylation of the Erk1/2 protein by 45% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the method comprises contacting the Erk1/2 protein with a compound or pharmaceutically acceptable form thereof that activates phosphorylation of the Erk1/2 protein by 50% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 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 a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 183, 190, 191, 192, 193, 194, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharmaceutically acceptable form thereof.

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

Provided herein are methods of modulating Akt activity, comprising contacting an Akt protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating Akt activity, comprising contacting an AKT protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 37 of 63

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

In certain embodiments of the methods of of modulating Akt activity described herein, the method activates phosphorylation of the Akt protein. In some embodiments, the method comprises contacting the Akt protein with a compound or pharmaceutically acceptable form thereof that activates phosphorylation of the Akt protein by 50% or more at 10 μM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 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.

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

Provided herein are methods of modulating Smad2/3 activity, comprising contacting a Smad2/3 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating Smad2/3 activity, comprising contacting a Smad2/3 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

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

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

›CROSS REFERENCE · 38 of 63

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

Provided herein are methods of modulating JNK activity, comprising contacting a JNK protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating JNK activity, comprising contacting a JNK protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

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

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

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

Provided herein are methods of modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating MAPK p38 activity, comprising contacting a MAPK p38 protein with an effective amount of a pharmaceutical composition 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 pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 39 of 63

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

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

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

Provided herein are methods of modulating IL-6 activity, comprising contacting a IL-6 protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating IL-6 activity, comprising contacting a IL-6 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

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

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

›CROSS REFERENCE · 40 of 63

Provided herein are methods of modulating TNF-alpha activity, comprising contacting a TNF-alpha protein with an effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof. Also provided herein are methods of modulating TNF-alpha activity, comprising contacting a TNF-alpha protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, as disclosed herein below. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

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

In some embodiments of the methods provided herein, the contacting of the TNF-alpha protein takes place in a cell. In some embodiments, the cell is in a subject. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell.

3.4. Methods of Treating Cancer

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

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

a) Tumor evolution commences when a cell within a normal population sustains a genetic mutation that expands its tendency to proliferate. b) Such genetically altered cells and their offspring continue to appear normal, but they reproduce excessively and lead to a condition termed hyperplasia. The altered cells may also secrete signaling factors or other molecules that cause changes in their local cellular and extracellular environment, including without limitation, the response of the immune system to them. Such environmental effects may in turn affect the viability, proliferation, and further mutations of the altered cells. After some time (months or years) a very small fraction of these altered cells may sustain additional mutation with subsequent loss of control of cell growth and further potential effects on their environment. c) The offspring of these cells not only proliferate excessively but also appear abnormal in shape and in orientation. The tissue is now said to exhibit a condition termed dysplasia. After some time, one or more additional mutations may further alter cell behavior and the effect of the cells on their environment. d) The influenced and genetically altered cells turn still more abnormal in growth and appearance. If the tumor mass does not invade through any boundaries between tissues, it is termed an in situ tumor. This tumor may stay contained indefinitely, however, some cells may acquire still more mutations. e) A malignant or invasive tumor results if the genetic changes allow the tumor mass to initiate invading underlying tissue and to cast off cells into the blood or lymph. The defector cells may install new tumors loci (metastases) throughout the body.

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

›CROSS REFERENCE · 41 of 63

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

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

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

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

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

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

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

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

Provided herein are methods of treating cancer in a subject, comprising administering a therapeutically effective amount of the compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, to the subject having cancer. Also provided herein are methods of treating cancer in a subject, comprising administering a therapeutically effective amount of a pharmaceutical comprising a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, as disclosed herein below, to the subject having cancer. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily protein. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 μM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits the activity one or more Ras superfamily protein. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 45% or more at 20 μM according to a Ras Superfamily Activity. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 50% or more at 20 μM according to a Ras Superfamily Activity. In some embodiments, the compound is selected from the group consisting of Compounds 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 a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 6, 17, 22, 37, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 149, 150, 151, 152, 153, 154, 156, 157, 158, 165, 166, 169, 170, 173, 175, 176, 177, 178, 179, 186, 187, 188, 196, 202, 208, 211, 212, 213, 214, 215, 216, 217, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 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.

›CROSS REFERENCE · 42 of 63

In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Erk1/2 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein by 80% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein by 85% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 36, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein by 45% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein by 50% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 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 a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 183, 190, 191, 192, 193, 194, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharmaceutically acceptable form thereof.

In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Akt activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein by 85% or more at 10 μM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 17, 20, 23, 25, 29, 30, 31, 32, 33, 34, 42, 203, 209, 210, 219, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein by 50% or more at 10 μM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 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.

›CROSS REFERENCE · 43 of 63

In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Smad2/3 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein by 80% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein by 85% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound is selected from the group consisting of Compounds 27, 29, 30, 31, 32, 33, 36, 43, 44, 47, 51, 52, 55, 59, 85, 96, 97, 98, 99, 116, 141, 144, 156, 203, 205, 207, 208, 209, 210, 211, 214, 219, 230, 269, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 29, 30, 31, 32, 33, 36, 44, 47, 59, 85, 97, 98, 99, 116, 141, 144, 156, 203, 205, 207, 208, 209, 210, 211, 214, 219, 230, 269, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2/3 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2/3 protein by 50% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound is selected from the group consisting of Compounds 56, 63, 84, 88, 89, 90, 95, 100, 101, 103, 104, 106, 108, 109, 111, 112, 113, 114, 129, 166, 173, 179, 183, 186, 216, 241, 247, 248, 250, 255, 256, 257, and 266, or a pharmaceutically acceptable form thereof.

In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form that modulates JNK activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 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 JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by 30% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by 75% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by about 100% at 10 μM according to JNK Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 29, 30, 32, 33, and 34, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 29, 32, 33, and 34, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 29, 32, and 34, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 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 or greater than 100% at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by 30% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by 75% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by about 100% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 6, 7, 8, 9, 11, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 3, 4, 6, 7, 11, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 3, 6, 7, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 44 of 63

In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates MAPK p38 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 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 MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 by 30% or more at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 by about 100% at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 29, 30, 32, 33, 34, 46, 47, 188, 196, 197, 203, 205, 207, 208, 209, 210, 212, 213, 214, 215, 217, and 220, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 29, 32, 33, 34, 46, 207, and 209, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 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 or greater than 100% at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 by 30% or more at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 by 75% or more at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 by about 100% or more at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, 93, and 218, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 7, 8, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof.

In some embodiments, the compounds disclosed herein inhibit cell proliferation, such as inhibit cell proliferation in a cell viability assay. In some embodiments, the anti-proliferative activity of the compounds disclosed herein are administered according to the methods of treating disclosed herein to treat cancer, including solid, soft and blood-born tumors. In some embodiments of the methods of treating cancer provided herein, the method administering a compound or pharmaceutically acceptable form thereof that inhibits proliferation in MiaPaca2. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.25 μM or less, 1.1 μM or less, 1 μM or less, 0.9 μM or less, 0.8 μM or less, 0.75 μM or less, 0.7 μM or less, 0.6 μM or less, 0.5 μM or less, 0.4 μM or less, 0.3 μM or less, 0.25 μM or less, 0.2 μM or less, 0.15 μM or less, or 0.1 μM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.1 μM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.0 μM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.60 μM or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.15 μM or less according to Proliferation Assay. In some embodiments, the compound is selected from the group consisting of 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 a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 6, 13, 22, 26, 29, 30, 32, 33, 34, 42, 48, 49, 50, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 68, 72, 73, 74, 76, 78, 79, 81, 82, 83, 84, 86, 89, 91, 93, 94, 95, 96, 97, 98, 100, 101, 102, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 122, 123, 124, 125, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 149, 156, 157, 158, 165, 169, 170, 173, 174, 175, 176, 196, 203, 209, 210, 213, 217, 219, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 255, 257, 263, 264, 265, 266, 267, 268, 269, 270, 271, 274, and 276, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 6, 13, 22, 32, 34, 48, 49, 50, 53, 54, 55, 56, 57, 58, 59, 62, 63, 64, 65, 68, 73, 74, 76, 78, 79, 81, 82, 83, 84, 86, 89, 91, 93, 94, 95, 96, 97, 98, 100, 101, 102, 104, 106, 107, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 122, 123, 124, 125, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 156, 157, 158, 165, 169, 170, 174, 175, 196, 209, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 243, 244, 245, 246, 247, 248, 249, 250, 252, 255, 257, 263, 264, 265, 266, 267, 268, 270, 271, 274, and 276, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 6, 48, 49, 50, 53, 54, 55, 57, 58, 62, 63, 64, 65, 68, 73, 76, 79, 82, 84, 89, 91, 94, 95, 97, 98, 100, 102, 104, 106, 107, 110, 112, 113, 114, 115, 117, 118, 120, 122, 123, 124, 126, 127, 128, 129, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 156, 157, 158, 165, 169, 170, 196, 221, 222, 224, 226, 227, 228, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 243, 244, 245, 248, 249, 250, 252, 255, 257, 263, 265, 266, 267, and 268, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 45 of 63

In some embodiments of the methods provided herein, the cancer is a solid tumor. In some embodiments, the cancer is a blood borne tumor (or a hematological cancer). In some embodiments, the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, 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 of the methods provided herein, the cancer is a cancer dependent on a Ras superfamily protein. In some embodiments, the Ras superfamily protein is a Ras protein, or a mutant thereof. In some embodiments, the Ras protein is DIRAS I; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRASI; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; 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, KRas G12C mutant, or KRas Q61H mutant. In some embodiments, the Ras protein is HRAS or a mutant thereof. In some embodiments, the Ras protein is NRAS or a mutant thereof. In some embodiments, the Ras superfamily protein is a Rac protein, or a mutant thereof. In some embodiments, the Rac protein is RAC1; RAC2; RAC3; RHOG, or a mutant thereof. In some embodiments, the the Rac protein is wild-type RAC1. In some embodiments, the Ras superfamily protein is a Rho protein, or a mutant thereof. In some embodiments, the Rho protein is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; CDC42, or a mutant thereof. In some embodiments, the Rho protein is wild-type RHOA. In some embodiments, the Ras superfamily protein is a Cdc42 protein, or a mutant thereof. In some embodiments, the Ras superfamily protein is a Rheb protein, or a mutant thereof.

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

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

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

In certain embodiments, the cancer is a solid tumor. In certain embodiments, the solid tumor is metastatic. In certain embodiments, the solid tumor is drug-resistant. In certain embodiments, the solid tumor is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, or multiple myeloma.

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

›CROSS REFERENCE · 46 of 63

In one embodiment, methods provided herein encompass treating, preventing or managing various types of leukemias such as chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acute myeloblastic leukemia (AML) by administering a therapeutically effective amount of a compound provided herein or a derivative thereof.

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

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

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

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

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

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

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

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

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

As discussed herein, Ras signaling is causally implicated in rasopathies. Thus, the compounds provided herein, which inhibit the function of one or more members of the Ras superfamily, are useful in the treatment of rasopathies including neurofibromatosis type 1, Noonan's syndrome, and Costello syndrome.

3.5. Methods of Treating Fibrosis

Fibrosis, or the accumulation of extracellular matrix molecules that constitute scar tissue, is a common result of tissue injury. Fibrosis can occur in many tissues within the body, typically as a result of inflammation or damage. Pulmonary fibrosis, renal fibrosis, and hepatic cirrhosis are among the common fibrotic diseases which altogether represent a large unmet medical need. (Friedman S L, Sheppard D, Duffield J S, Violette S. Sci Transl Med 2013 Jan. 9; 5(167): 167sr1).

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

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

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

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

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

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

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

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

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

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

DMD primarily affects boys, but in rare cases it can affect girls. In Europe and North America, the prevalence of DMD is approximately 6 per 100,000 individuals.

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

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

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

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

Without being bound by theory, a growing number of published studies also suggest that pharmacological activation of the stress-activated MAPK proteins p-38 MAPK and c-Jun NH 2 -terminal kinase (JNK) may also represent a therapeutic approach for the treatment of DMD related fibrosis.

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

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

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

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

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

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

Provided herein are methods of treating a fibrotic disease in a subject, comprising administering a therapeutically effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, to the subject. Also provided herein are methods treating a fibrotic disease in a subject, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, to the subject. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 49 of 63

In some embodiments of the methods of treating a fibrotic disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily protein. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 μM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits the activity one or more Ras superfamily protein. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 45% or more at 20 μM according to a Ras Superfamily Activity. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 50% or more at 20 μM according to a Ras Superfamily Activity. In some embodiments, the compound is selected from the group consisting of Compounds 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 a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 6, 17, 22, 37, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 149, 150, 151, 152, 153, 154, 156, 157, 158, 165, 166, 169, 170, 173, 175, 176, 177, 178, 179, 186, 187, 188, 196, 202, 208, 211, 212, 213, 214, 215, 216, 217, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 254, 255, 256, 257, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, and 276, or a pharmaceutically acceptable form thereof.

In some embodiments of the methods of treating a fibrotic disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Erk1/2 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein by 80% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein by 85% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 36, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein by 45% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein by 50% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 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 a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 183, 190, 191, 192, 193, 194, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 50 of 63

In some embodiments of the methods of treating a fibrotic disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Akt activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein by 85% or more at 10 μM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 17, 20, 23, 25, 29, 30, 31, 32, 33, 34, 42, 203, 209, 210, 219, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein by 50% or more at 10 μM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 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.

In some embodiments of the methods of treating a fibrotic disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Smad2/3 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein by 80% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein by 85% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound is selected from the group consisting of Compounds 27, 29, 30, 31, 32, 33, 36, 43, 44, 47, 51, 52, 55, 59, 85, 96, 97, 98, 99, 116, 141, 144, 156, 203, 205, 207, 208, 209, 210, 211, 214, 219, 230, 269, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 29, 30, 31, 32, 33, 36, 44, 47, 59, 85, 97, 98, 99, 116, 141, 144, 156, 203, 205, 207, 208, 209, 210, 211, 214, 219, 230, 269, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2/3 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2/3 protein by 50% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound is selected from the group consisting of Compounds 56, 63, 84, 88, 89, 90, 95, 100, 101, 103, 104, 106, 108, 109, 111, 112, 113, 114, 129, 166, 173, 179, 183, 186, 216, 241, 247, 248, 250, 255, 256, 257, and 266, or a pharmaceutically acceptable form thereof.

In some embodiments of the methods of treating a fibrotic disease provided herein, the method administering a compound or pharmaceutically acceptable form that modulates JNK activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 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 JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by 30% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by 75% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by about 100% at 10 μM according to JNK Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 29, 30, 32, 33, and 34, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 29, 32, 33, and 34, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 29, 32, and 34, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 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 or greater than 100% at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by 30% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by 75% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by about 100% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 6, 7, 8, 9, 11, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 3, 4, 6, 7, 11, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 3, 6, 7, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 51 of 63

In some embodiments of the methods of treating a fibrotic disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates MAPK p38 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 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 MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 by 30% or more at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 by about 100% at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 29, 30, 32, 33, 34, 46, 47, 188, 196, 197, 203, 205, 207, 208, 209, 210, 212, 213, 214, 215, 217, and 220, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 29, 32, 33, 34, 46, 207, and 209, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 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 or greater than 100% at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 by 30% or more at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 by 75% or more at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 by about 100% or more at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, 93, and 218, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 7, 8, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof.

In some embodiments, the compound of Formula I administered according to any of the methods disclosed herein treats, prevents, or inhibits fibrosis in the subject. In some embodiments, the compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, administered according to any of the methods disclosed herein inhibits fibrosis in the liver, lung, skin, soft tissue, tendons, lymph nodes, lung, kidney, heart, eye, or retroperitoneum of said subject. In some embodiments, the compound administered according to any of the methods disclosed herein treats, prevents, or ameliorates one or more symptoms of a fibrotic disease in the subject. In some embodiments, the compound administered according to any of the methods disclosed herein treats, prevents, or ameliorates the fibrotic disease in the subject. In some embodiments, the fibrotic disease is selected from the group consisting of fibrosis of kidney, fibrosis of cardiovascular system, pulmonary fibrosis, cystic fibrosis, idiopathic fibrosis, fibrosis of the lung, bridging fibrosis, fibrosis of the liver, fibrosis of the intestine, fibrosis of the muscular system, fibrosis of the brain, fibrosis of the joints, fibrosis of the skin, fibrosis of the bone marrow, fibrosis of the heart, fibrosis of the soft tissue, fibrosis of the tendons, fibrosis of the lymph nodes, fibrosis of the eyes, retroperitoneum, scleroderma and surgical scarring. In some embodiments, the fibrotic disease is fibrosis of the kidney. In some embodiments, the fibrosis of the kidney is progressive kidney disease. In some embodiments, the fibrotic disease is fibrosis of the cardiovascular system. In some embodiments, the fibrosis of the cardiovascular system is atherosclerosis or restenosis. In some embodiments, the fibrotic disease is pulmonary fibrosis. In some embodiments, the fibrotic disease is cystic fibrosis. In some embodiments, the fibrotic disease is idiopathic fibrosis. In some embodiments, the idiopathic fibrosis is idiopathic pulmonary fibrosis. In some embodiments, the fibrotic disease is fibrosis of the lung. In some embodiments, the fibrosis of the lung is progressive massive fibrosis and radiation-induced lung injury. In some embodiments, the fibrotic disease is bridging fibrosis. In some embodiments, the fibrotic disease is fibrosis of the liver. In some embodiments, the fibrosis of the liver is cirrhosis. In some embodiments, the fibrotic disease is fibrosis of the intestine. In some embodiments, the fibrosis of the intestine is Crohn's disease. In some embodiments, the fibrotic disease is fibrosis of the muscular system. In some embodiments, the fibrosis of the muscular system is Duchenne muscular dystrophy (DMD). In some embodiments, the Duchenne muscular dystrophy is Becker Muscular Dystrophy (BMD), an intermediate clinical presentation between DMD and BMD, or DMD-associated dilated cardiomyopathy. In some embodiments, the fibrotic disease is fibrosis of the brain. In some embodiments, the fibrosis of the brain is glial scar. In some embodiments, the fibrotic disease is fibrosis of the joints. In some embodiments, the fibrosis of the joints is arterial stiffness. In some embodiments, the fibrosis of the joints is fibrosis of the knee. In some embodiments, the fibrosis of the joints is fibrosis of the shoulder. In some embodiments, the fibrotic disease is fibrosis of the skin. In some embodiments, the fibrosis of the skin is Keloid. In some embodiments, the fibrotic disease is fibrosis of the bone marrow. In some embodiments, the fibrosis of the bone marrow is Myelofibrosis. In some embodiments, the fibrotic disease is fibrosis of the heart. In some embodiments, the fibrosis of the heart is Myocardial fibrosis. In some embodiments, the fibrotic disease is fibrosis of the soft tissue. In some embodiments, the fibrotic disease is fibrosis of the tendons. In some embodiments, the fibrotic disease is fibrosis of the lymph nodes. In some embodiments, the fibrotic disease is fibrosis of the eyes. In some embodiments, the fibrotic disease is retroperitoneum. In some embodiments, the fibrotic disease is scleroderma. In some embodiments, the fibrotic disease is surgical scarring.

›CROSS REFERENCE · 52 of 63

3.6. Methods of Treating Inflammation

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

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

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

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

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

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

Provided herein are methods treating an inflammatory disease in a subject, comprising administering a therapeutically effective amount of a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, to the subject. Also provided herein are methods of treating an inflammatory disease in a subject, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, Ia, Ib, Ic, II, IIa, IIa(1), IIb, IIc, III, IIIa, IIIb, IIIc, IV, IVa, IVb, or IVc, or pharmaceutically acceptable form thereof, to the subject. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, and 276, or a pharmaceutically acceptable form thereof.

In some embodiments of the methods of treating an inflammatory disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily protein. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 μM according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits the activity one or more Ras superfamily protein. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 45% or more at 20 μM according to a Ras Superfamily Activity. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 50% or more at 20 μM according to a Ras Superfamily Activity. In some embodiments, the compound is selected from the group consisting of Compounds 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 a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 6, 17, 22, 37, 44, 45, 46, 48, 49, 50, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 86, 89, 90, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 104, 105, 107, 108, 109, 110, 111, 113, 114, 116, 118, 119, 120, 121, 122, 123, 124, 125, 127, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 149, 150, 151, 152, 153, 154, 156, 157, 158, 165, 166, 169, 170, 173, 175, 176, 177, 178, 179, 186, 187, 188, 196, 202, 208, 211, 212, 213, 214, 215, 216, 217, 221, 222, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 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.

›CROSS REFERENCE · 53 of 63

In some embodiments of the methods of treating an inflammatory disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Erk1/2 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein by 80% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein by 85% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 36, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 3, 4, 20, 23, 26, 29, 30, 31, 32, 33, 34, 42, 43, 53, 58, 67, 93, 203, 209, 210, 219, 266, 269, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein by 45% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein by 50% or more at 10 μM according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 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 a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 83, 84, 86, 87, 89, 90, 91, 94, 95, 97, 98, 99, 100, 104, 107, 113, 116, 118, 120, 121, 124, 126, 127, 128, 129, 135, 136, 138, 143, 145, 148, 149, 151, 154, 156, 157, 165, 174, 175, 176, 177, 178, 179, 183, 190, 191, 192, 193, 194, 196, 197, 198, 199, 200, 201, 202, 204, 205, 207, 208, 213, 216, 217, 218, 224, 227, 230, 231, 233, 234, 236, 239, 243, 247, 248, 249, 250, 253, 254, 257, 267, 268, and 276, or a pharmaceutically acceptable form thereof.

In some embodiments of the methods of treating an inflammatory disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Akt activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein by 85% or more at 10 μM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 17, 20, 23, 25, 29, 30, 31, 32, 33, 34, 42, 203, 209, 210, 219, 270, 271, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein by 50% or more at 10 μM according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 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.

›CROSS REFERENCE · 54 of 63

In some embodiments of the methods of treating an inflammatory disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates Smad2/3 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein by 80% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein by 85% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound is selected from the group consisting of Compounds 27, 29, 30, 31, 32, 33, 36, 43, 44, 47, 51, 52, 55, 59, 85, 96, 97, 98, 99, 116, 141, 144, 156, 203, 205, 207, 208, 209, 210, 211, 214, 219, 230, 269, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 29, 30, 31, 32, 33, 36, 44, 47, 59, 85, 97, 98, 99, 116, 141, 144, 156, 203, 205, 207, 208, 209, 210, 211, 214, 219, 230, 269, 272, 273, and 274, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2/3 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2/3 protein by 50% or more at 10 μM according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound is selected from the group consisting of Compounds 56, 63, 84, 88, 89, 90, 95, 100, 101, 103, 104, 106, 108, 109, 111, 112, 113, 114, 129, 166, 173, 179, 183, 186, 216, 241, 247, 248, 250, 255, 256, 257, and 266, or a pharmaceutically acceptable form thereof.

In some embodiments of the methods of treating an inflammatory disease provided herein, the method administering a compound or pharmaceutically acceptable form that modulates JNK activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 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 JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by 30% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by 75% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by about 100% at 10 μM according to JNK Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 29, 30, 32, 33, and 34, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 29, 32, 33, and 34, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 29, 32, and 34, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 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 or greater than 100% at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by 30% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by 75% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by about 100% or more at 10 μM according to JNK Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 6, 7, 8, 9, 11, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 3, 4, 6, 7, 11, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 3, 6, 7, 13, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 46, 47, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof.

›CROSS REFERENCE · 55 of 63

In some embodiments of the methods of treating an inflammatory disease provided herein, the method administering a compound or pharmaceutically acceptable form thereof that modulates MAPK p38 activity. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 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 MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 by 30% or more at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 by about 100% at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 29, 30, 32, 33, 34, 46, 47, 188, 196, 197, 203, 205, 207, 208, 209, 210, 212, 213, 214, 215, 217, and 220, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 29, 32, 33, 34, 46, 207, and 209, or a pharmaceutically acceptable form thereof. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 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 or greater than 100% at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 by 30% or more at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 by 75% or more at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 by about 100% or more at 10 μM according to MAPK p38 Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, 93, and 218, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 7, 8, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 36, 42, 43, 44, 45, 51, 53, 54, 55, 56, 59, 60, 61, 62, 63, 64, 65, 66, 67, 69, 70, 71, 72, and 93, or a pharmaceutically acceptable form thereof.

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

›CROSS REFERENCE · 56 of 63

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

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

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

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

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

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

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

›CROSS REFERENCE · 57 of 63

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

›CROSS REFERENCE · 58 of 63

3.7. Pharmaceutical Compositions

The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of 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 a pharmaceutically acceptable carrier, diluent or excipient.

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

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

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

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

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

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

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

›CROSS REFERENCE · 59 of 63

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

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

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

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

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

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

The pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable salts thereof. The pharmaceutically therapeutically active compounds and salts thereof are formulated and administered in unit dosage forms or multiple dosage forms. Unit dose forms as used herein refer to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dose forms include ampules and syringes and individually packaged tablets or capsules. Unit dose forms may be administered in fractions or multiples thereof. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in segregated unit dose form. Examples of multiple dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit doses which are not segregated in packaging.

Sustained-release preparations can also be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound provided herein, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include iontophoresis patches, polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated compound remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37° C., resulting in a loss of biological activity and possible changes in their structure. Rational strategies can be devised for stabilization depending on the mechanism of action involved. For example, if the aggregation mechanism is discovered to be intermolecular S—S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

›CROSS REFERENCE · 60 of 63

Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non toxic carrier may be prepared. For oral administration, a pharmaceutically acceptable non toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain about 0.001% to 100% active ingredient, in certain embodiments, about 0.1 85% or about 75-95%.

The active compounds or pharmaceutically acceptable salts may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.

The compositions may include other active compounds to obtain desired combinations of properties. The compounds provided herein, or pharmaceutically acceptable salts thereof as described herein, may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinabove, such as diseases related to oxidative stress. It is to be understood that such combination therapy constitutes a further aspect of the compositions and methods of treatment provided herein.

Lactose-free compositions provided herein can contain excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-free compositions contain an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose-free dosage forms contain an active ingredient, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate.

Further encompassed are anhydrous pharmaceutical compositions and dosage forms containing a compound provided herein. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs and strip packs.

Articles of Manufacture

The 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, provided herein, and the pharmaceutical compositions comprising the same with a pharmaceutically acceptable carrier, diluent or excipient, can be contained in a pharmaceutical kit or pharmaceutical packaging (sometimes referred to as articles of manufacture). Such articles of manufacture can be used for treatment, prevention or amelioration of one or more symptoms or progression of a disease or disorder disclosed herein, and a label that indicates that the compound or pharmaceutically acceptable salt thereof is used for treatment, prevention or amelioration of one or more symptoms or progression of a disease or disorder disclosed herein.

In certain embodiments, provided herein is a a pharmaceutical kit, which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject. In certain embodiments, the pharmaceutical kit provided herein includes a container and a dosage form of a compound provided herein, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In certain embodiments, the pharmaceutical kit includes a container comprising a dosage form of the compound provided herein, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a container comprising one or more other therapeutic agent(s) described herein.

Pharmaceutical kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle-less injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.

›CROSS REFERENCE · 61 of 63

Pharmaceutical kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

3.8. Dosing

The 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, and pharmaceutical compositions comprising the same, provided herein may be dosed in certain therapeutically or prohylactically effective amounts, certain time intervals, certain dosage forms, and certain dosage administration methods as described below.

In certain embodiments, a therapeutically or prophylactically effective amount of the compound is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day, from about 0.05 to about 10 mg per day, from about 0.05 to about 5 mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 to about 5 mg per day.

In certain embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day.

In one embodiment, the recommended daily dose range of the compound provided herein, or a derivative thereof, for the conditions described herein lie within the range of from about 0.5 mg to about 50 mg per day, in one embodiment given as a single once-a-day dose, or in divided doses throughout a day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage ranges from about 0.5 to about 5 mg per day. Specific doses per day include 0.1, 0.2, 0.5, 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 or 50 mg per day.

In a specific embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4, or 5 mg per day. The dose may be escalated to 15, 20, 25, 30, 35, 40, 45 and 50 mg/day. In a specific embodiment, the compound can be administered in an amount of about 25 mg/day. In a particular embodiment, the compound can be administered in an amount of about 10 mg/day. In a particular embodiment, the compound can be administered in an amount of about 5 mg/day. In a particular embodiment, the compound can be administered in an amount of about 4 mg/day. In a particular embodiment, the compound can be administered in an amount of about 3 mg/day.

In certain embodiments, the therapeutically or prophylactically effective amount is from about 0.001 to about 100 mg/kg/day, from about 0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, from about 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day, 0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, from about 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day, from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3 mg/kg/day, from about 0.01 to about 2 mg/kg/day, from about 0.01 to about 1 mg/kg/day, or from about 0.01 to about 0.05 mg/kg/day.

The administered dose can also be expressed in units other than mg/kg/day. For example, doses for parenteral administration can be expressed as mg/m 2 /day. One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m 2 /day to given either the height or weight of a subject or both (see, e.g., Nair A B, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharma 2016; 7:27-31). For example, a dose of 1 mg/kg/day for a 60 kg human is approximately equal to 37 mg/m 2 /day.

In certain embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 0.001 to about 500 μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, from about 1 to about 50 μM, about 0.02 to about 25 μM, from about 0.05 to about 20 μM, from about 0.1 to about 20 μM, from about 0.5 to about 20 μM, or from about 1 to about 20 μM.

In other embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 5 to about 100 nM, about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM or from about 50 to about 100 nM.

As used herein, the term “plasma concentration at steady state” is the concentration reached after a period of administration of a compound provided herein, or a derivative thereof. Once steady state is reached, there are minor peaks and troughs on the time dependent curve of the plasma concentration of the compound.

›CROSS REFERENCE · 62 of 63

In certain embodiments, the amount of the compound administered is sufficient to provide a maximum plasma concentration (peak concentration) of the compound, ranging from about 0.001 to about 500 μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, from about 1 to about 50 μM, about 0.02 to about 25 μM, from about 0.05 to about 2 μM, from about 0.1 to about 20 μM, from about 0.5 to about 20 μM, or from about 1 to about 20 μM.

In certain embodiments, the amount of the compound administered is sufficient to provide a minimum plasma concentration (trough concentration) of the compound, ranging from about 0.001 to about 500 μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, from about 1 to about 50 μM, about 0.01 to about 25 μM, from about 0.01 to about 20 μM, from about 0.02 to about 20 μM, from about 0.02 to about 20 μM, or from about 0.01 to about 20 μM.

In certain embodiments, the amount of the compound administered is sufficient to provide an area under the curve (AUC) of the compound, ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 to about 50,000 ng*hr/mL, from about 5,000 to about 25,000 ng*hr/mL, or from about 5,000 to about 10,000 ng*hr/mL.

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

Depending on the disease to be treated and the subject's condition, the compound provided herein, or a derivative thereof, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. The compound provided herein, or a derivative thereof, may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration.

In one embodiment, the compound provided herein, or a derivative thereof, is administered orally. In another embodiment, the compound provided herein, or a derivative thereof, is administered parenterally. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered intravenously.

The compound provided herein, or a derivative thereof, can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time, such as, e.g., continuous infusion over time or divided bolus doses over time. The compound can be administered repeatedly if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity. For example, stable disease for solid tumors generally means that the perpendicular diameter of measurable lesions has not increased by 25% or more from the last measurement. Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92 (3): 205 216 (2000). Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.

The compound provided herein, or a derivative thereof, can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID). In addition, the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug). As used herein, the term “daily” is intended to mean that a therapeutic compound, such as the compound provided herein, or a derivative thereof, is administered once or more than once each day, for example, for a period of time. The term “continuous” is intended to mean that a therapeutic compound, such as the compound provided herein or a derivative thereof, is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of the compound provided herein or a derivative thereof is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days. The term “cycling” as used herein is intended to mean that a therapeutic compound, such as the compound provided herein or a derivative thereof, is administered daily or continuously but with a rest period. In some such embodiments, administration is once a day for two to six days, then a rest period with no administration for five to seven days.

In some embodiments, the frequency of administration is in the range of about a daily dose to about a monthly dose. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the compound provided herein, or a derivative thereof, is administered once a day. In another embodiment, the compound provided herein, or a derivative thereof, is administered twice a day. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered three times a day. In still another embodiment, the compound provided herein, or a derivative thereof, is administered four times a day.

In certain embodiments, the compound provided herein, or a derivative thereof, is administered once per day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks. In certain embodiments, the compound provided herein, or a derivative thereof, is administered once per day for one week, two weeks, three weeks, or four weeks. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 4 days. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 5 days. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 6 days. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for one week. In another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for two weeks. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for three weeks. In still another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for four weeks.

›CROSS REFERENCE · 63 of 63

Combination Therapy with a Second Active Agent

The compound provided herein, or a derivative thereof, can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of cancers, inflammatory diseases, rasopathies, or fibrotic disease.

In one embodiment, provided herein is a method of treating, preventing, or managing cancers, inflammatory diseases, rasopathies, and fibrotic disease, comprising administering to a subject a compound provided herein, or a derivative thereof; in combination with one or more second active agents.

As used herein, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein, a compound provided herein, e.g., the compound provided herein, or a derivative thereof) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein.

Administration of the compound provided herein, or a derivative thereof and one or more second active agents to a subject can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease or disorder being treated.

The route of administration of the compound provided herein, or a derivative thereof, is independent of the route of administration of a second therapy. In one embodiment, the compound provided herein, or a derivative thereof, is administered orally. In another embodiment, the compound provided herein, or a derivative thereof, is administered intravenously. Thus, in accordance with these embodiments, the compound provided herein, or a derivative thereof, is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, the compound provided herein, or a derivative thereof, and a second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, the compound provided herein, or a derivative thereof, is administered by one mode of administration, e.g., by IV, whereas the second agent is administered by another mode of administration, e.g., orally.

In one embodiment, the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount of the compound provided herein, or a derivative thereof, and any optional additional active agents concurrently administered to the subject.

One or more second active ingredients or agents can be used together with the compound provided herein, or a derivative thereof, in the methods and compositions provided herein. Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, particularly, therapeutic antibodies to cancer antigens. Typical large molecule active agents are biological molecules, such as naturally occurring or synthetic or recombinant proteins.

In one embodiment, the compound provided herein, or a derivative thereof, can be administered in an amount ranging from about 0.1 to about 150 mg, from about 1 to about 25 mg, or from about 2 to about 10 mg orally and daily alone, or in combination with a second active agent, prior to, during, or after the use of conventional therapy.

4. EXAMPLES

The present disclosure will now be described with reference to specific example(s) which should not be construed as in any way limiting.

Analytical Methods:

NMR: Proton nuclear magnetic resonance spectra (NMR) were recorded at 400 MHz or 500 MHz. 13 C NMR spectra were recorded at 100 MHz or 125 MHz. Chemical shifts (δ) are given in parts per million (ppm) and are listed upfield with tetramethylsilane as a reference. Peaks are described as singlets(s), doublets (d), triplets (t), quartets (q), quintets (quint) multiplets (m) and broad (br.). All assignments of NMR spectra were based on 1D NMR data.

LCMS Specifications and Method Details:

4.1 Synthetic Examples

Example A1: Synthesis of Intermediate A1

›Step A: tert-Butyl (5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)carbamate A1b

To a stirred solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid A1a (2.00 g, 13.15 mmol) in mixture of t-BuOH (50 mL), DMF (1 mL) were added Et 3 N (3.64 mL, 26.3 mmol) followed by DPPA (5.42 g, 19.7 mmol) at room temperature and resulting reaction mixture slowly heated to 90° C. for 12 h. The reaction mixture was concentrated under reduced pressure to afford crude product, which was quenched with H 2 O (20 mL), and the aqueous layer extracted with ethyl acetate (2×20 mL), washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure afforded crude material. Obtained crude material was purified by reverse phase C-18 column chromatography (50% CH 3 CN in H 2 O) afforded tert-butyl (5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl) carbamate A1b (0.80 g, 27% yield) as an off white solid. 1 H NMR (400 MHZ, DMSO-d 6 ) δ 9.38 (s, 1H), 5.97 (s, 1H), 3.91 (t, J=7.20 Hz, 2H), 2.78 (t, J=7.60 Hz, 2H), 2.46-2.40 (m, 2H), 1.43 (s, 9H).

›Step B: 5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol-2-amine A1

To a stirred solution of tert-butyl (5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)carbamate A1b (0.8 g, 3.58 mmol) in CF 3 CH 2 OH (8 mL) was added TMSC1 (0.67 mL, 5.38 mmol) at 0° C. and slowly warmed to room temperature and stirred for 2 h. The solvent was evaporated under reduced pressure to crude which was neutralized with saturated NaHCO 3 solution (10 mL), extracted with CH 2 Cl 2 (2×20 mL). The organic layer washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and the combined organic layer was evaporated under reduced pressure to afford 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-amine A1 (0.35 g, 79% yield) as an off white solid. 1H-NMR (400 MHZ, CDCl 3 ) δ 5.34 (s, 1H), 3.96 (t, J=7.20 Hz, 2H), 3.17 (brs, 2H), 2.80 (t, J=8.04 Hz, 2H), 2.51-2.44 (m, 2H). MS (ESI+APCI; multimode): Calculated [M+1] 124. Found [M+1] 124.

Example A2: Synthesis of Intermediate A2

›Step A: 2-((6-Aminopyrimidin-4-yl)oxy)ethan-1-ol A2

To a mixture of 6-chloropyrimidin-4-amine A2a (1.00 g, 7.75 mmol) in ethane-1,2-diol (15 mL) was added 1-KOBu (1.30 g, 11.62 mmol) and resulting reaction mixture was heated to 110° C. for 16 h. The reaction mixture was quenched with H 2 O (10 mL), an aqueous layer extracted with CH 2 Cl 2 (2×20 mL), washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and the combined organic layer was evaporated under reduced pressure to afford crude material. The crude material was purified using silica gel combi-flash column chromatography (10% MeOH in CH 2 Cl 2 ) afforded impure material, which was re-purified using reverse phase C-18 column chromatography using (30-50% CH 3 CN in H 2 O) to afford 2-((6-aminopyrimidin-4-yl)oxy)ethan-1-ol A2 (0.50 g, 41.6% yield) as white solid. 1 H-NMR (400 MHZ, DMSO-d 6 ) δ 8.07 (d, J=0.80 Hz, 1H), 6.61 (s, 2H), 5.68 (d, J=0.80 Hz, 1H), 4.82 (t, J=5.60 Hz, 1H), 4.18 (t, J=5.20 Hz, 2H), 3.66-3.62 (m, 2H). MS (ESI+APCI; multimode): Calculated [M+1] 156. Found [M+1] 156.

Example A3: Synthesis of Intermediate A3

›Step A: 4-Chloropyrimidin-2-amine A3b

To a stirred solution of 2-aminopyrimidin-4 (3H)-one A3a (10.0 g, 90.09 mmol) in toluene (200 mL) was added POCl 3 at 0° C. and slowly heated to 120° C. for 5 h. The reaction mixture was concentrated under reduced pressure to afford crude residue, which was quenched with saturated NaHCO 3 solution (20 mL) and resulting solid was filtered and washed with H 2 O (30 mL) and dried under vacuum to afford 4-chloropyrimidin-2-amine A3b (4.60 g, crude) as brown solid which was directly used as such in next step without any purification.

›Step B: 4-(2-(Dimethylamino)ethoxy)pyrimidin-2-amine A3

A mixture of 4-chloropyrimidin-2-amine A3b (4.60 g, 35.65 mmol) and 2-(dimethylamino) ethan-1-ol in DMF (50 mL) was added K 2 CO 3 (9.84 g, 71.31 mmol) and heated to 80° C. for 16 h. The reaction mixture was poured into crushed ice and resulting solid was filtered, washed with H 2 O (30 mL) followed by MTBE (30 mL): Hexane (30 mL) and dried under vacuum to afford 4-(2-(dimethylamino) ethoxy)pyrimidin-2-amine A3 (0.90 g, 14% yield {over 2 steps}) as light brown solid. 1H-NMR (400 MHZ, DMSO-d 6 ) δ 7.94 (d, J=5.60 Hz, 1H), 6.53 (s, 2H), 5.98 (d, J=5.60 Hz, 1H), 4.28 (t, J=5.60 Hz, 2H), 2.56 (t, J=5.60 Hz, 2H), 2.20 (s, 6H).

Example A4: Synthesis of Intermediate A4

›Step A: 4-(Difluoromethoxy)pyridin-2-amine A4

Sodium hydroxide (18.16 g, 454.06 mmol) was added in one portion to a stirred solution of 2-aminopyridin-4-ol A4a (10.0 g, 90.82 mmol) in dioxane (150 mL) and water (50 mL) causing an exotherm to 50° C. Chlorodifluoromethane was then rapidly bubbled into the reaction over 9 minutes, causing a gradual exotherm to 70° C. After the reaction had cooled to room temperature, it was diluted with ether (150 mL) and water (150 mL) and the layers separated. The organic phase washed with water, brine and dried over Na 2 SO 4 and concentrated in vacuo to give 4-(difluoromethoxy)pyridin-2-amine A4 (700.0 mg, 90.0% purity, 3.93 mmol, 4.3% yield) as brown solid.

Example A5: Synthesis of Intermediate A5

›Step A: 4-(2,2,2-Trifluoroethoxy)pyridin-2-amine A5

Sodium hydride (0.21 g, 5.25 mmol) (60% on mineral oil) was added portionwise to the solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.05 g, 4.54 mmol) and 2-aminopyridin-4-ol A4a (500.0 mg, 4.54 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 16 h, then diluted with water (45 mL) and extracted 3 times by EtOAc (3*15 mL). The organic phase washed with water, brine and dried over Na 2 SO 4 and concentrated in vacuo to give 4-(2,2,2-trifluoroethoxy)pyridin-2-amine A5 (410.0 mg, 90.0% purity, 1.92 mmol, 42.3% yield) as a brown solid.

Example A6: Synthesis of Intermediate A6

›Step A: 3-Bromo-1-cyclopropyl-1H-pyrazole (A6a)

A suspension of 2-(pyridin-2-yl)pyridine (21.25 g, 136.08 mmol) and copper II) acetate (24.72 g, 136.08 mmol) in DCE (320 mL) was warmed to 50° C. and stirred for 10 minutes. Then, the mixture of 3-bromo-1H-pyrazole (A6a) (20.0 g, 136.08 mmol), cyclopropylboronic acid (35.07 g, 408.24 mmol) and sodium carbonate (31.73 g, 299.38 mmol) in DCE (100 mL) was added. The reaction mixture was stirred at 65° C. for 18 hr. Then, the obtained mixture was allowed to cool to room temperature, filtered through celite frit, and rinsed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc and NH 4 Cl (aqueous solution) and the organic layer was washed with NH 4 Cl (aqueous solution), Na 2 CO 3 (aqueous solution) and brine and dried over Na 2 SO 4 . The residue was dried in vacuo and purified by flash column chromatography (m=30 g Interchim; 330 g SiO 2 , hexane/methyl t-butyl ether (MtBE) with MtbE from 0˜20%, flow rate 100 mL/min, Rv=6.2-8.5 CV) to give 3-bromo-1-cyclopropyl-1H-pyrazole (A6a) (10.7 g, 95.0% purity, 54.35 mmol, 39.9% yield).

›Step B: 1-Cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (A6)

The mixture of 3-bromo-1-cyclopropyl-1H-pyrazole (A6a) (10.7 g, 57.21 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (15.25 g, 60.07 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (2.34 g, 2.86 mmol) and potassium acetate (11.23 g, 114.42 mmol) in dioxane (150 mL) was degassed, warmed to 100° C., and stirred for 18 h. The volatiles were removed in vacuo. The residue was suspended in EtOAc, filtered through a pad of Celite, rinsed with EtOAc. The filtrate was concentrated under reduced pressure to give 1-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (A6) (21.0 g, 51.0% purity, 45.75 mmol, 80% yield) and used without further purification.

Example 1: Synthesis of Compound 1

›Step A: Methyl 4-iodo-3-methyl-1H-pyrrole-2-carboxylate 1b

1-Iodopyrrolidine-2,5-dione (33.95 g, 150.91 mmol) was added portionwise to the solution of methyl 3-methyl-1H-pyrrole-2-carboxylate 1a (20.0 g, 143.73 mmol) in DMF (100.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 h. Then, the mixture was poured in ice water. The formed precipitate was collected by filtration, washed with water (2×50 mL) and dried in vacuo to afford methyl 4-iodo-3-methyl-1H-pyrrole-2-carboxylate 1b (29.0 g, 109.41 mmol, 76.1% yield) as yellow powder.

›Step B: Methyl 4-(1-isopropyl-1H-pyrazol-3-yl)-3-methyl-1H-pyrrole-2-carboxylate 1d

Methyl 4-iodo-3-methyl-1H-pyrrole-2-carboxylate 1b (26.94 g, 101.64 mmol), 1-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1c (24.0 g, 101.64 mmol), cesium carbonate (66.24 g, 203.29 mmol) and Pd(dppf)Cl 2 (8.3 g, 10.16 mmol) were dissolved in degassed dioxane (80 mL) under Ar atmosphere. 3.8 mL of water was added via syringe and the reaction mixture was stirred at 80° C. for 16 h. The mixture was cooled to room temperature, filtered through celite pad and concentrated under reduced pressure. The residue was purified by column chromatography (eluted by Hex:EtOAc 20:1 to 1:2) to afford methyl 4-(1-isopropyl-1H-pyrazol-3-yl)-3-methyl-1H-pyrrole-2-carboxylate 1d (7.5 g, 30.33 mmol, 29.8% yield) as dark-yellow powder.

›Step C: Methyl 1-amino-4-(1-isopropyl-1H-pyrazol-3-yl)-3-methyl-1H-pyrrole-2-carboxylate 1e

To a solution of methyl 4-(1-isopropyl-1H-pyrazol-3-yl)-3-methyl-1H-pyrrole-2-carboxylate 1d (5.8 g, 22.19 mmol) in DMF (75 mL), sodium hydride (1.15 g, 48.09 mmol) was added at 0° C. The resulting mixture was stirred for 1 h at room temperature and the solution of O-(2,4-dinitrophenyl) hydroxylamine (5.75 g, 28.85 mmol) in DMF (50 mL) was added dropwise at 0° C. The reaction mixture was stirred at RT overnight. Then, the aqueous solution of NH 4 Cl (20 mL) was added dropwise to reaction mixture at cooling to 0° C. The product was extracted with EtOAc (3×35 mL) and combined organic layers was washed with water (5×20 mL). The organic extracts were dried over Na 2 SO 4 and concentrated in vacuo to afford methyl 1-amino-4-(1-isopropyl-1H-pyrazol-3-yl)-3-methyl-1H-pyrrole-2-carboxylate 1e (4.9 g, 73.5% purity, 13.03 mmol, 58.7% yield).

Step D: 6-(1-Isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol 1f

Sodium hydride (1.77 g, 73.71 mmol) (60% in mineral oil) was added portionwise (over 3 min) to the solution of methyl 1-amino-4-(1-isopropyl-1H-pyrazol-3-yl)-3-methyl-1H-pyrrole-2-carboxylate 1e (5.8 g, 22.11 mmol) and 1-methyl-1H-imidazole-2-carbonitrile (2.37 g, 22.11 mmol) in dioxane (20 mL). The reaction mixture was heated under reflux for 16 h. Then, the mixture was cooled to the room temperature, poured in ice water and neutralized by acetic acid (6.64 g, 110.56 mmol). The formed participate was collected by filtration, washed with water (2×10 mL) and purified by column chromatography (eluted Hex:EtOAc 10:1 to EtOAc 100%) to afford 6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol 1f (1.8 g, 5.34 mmol, 24.1% yield) as dark-yellow solid.

Step E: 4-Chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 1g

6-(1-Isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol 1f (1.8 g, 5.34 mmol) was dissolved in phosphoryl trichloride (9.81 g, 64.01 mmol, 5.97 ml, 12.0 equiv). The mixture was stirred at 100° C. for 16 h. The reaction mixture was concentrated in vacuo, poured in ice water (5 mL) and neutralized by K 2 CO 3 (pH˜9!). The mixture was extracted three times with DCM, dried over Na 2 SO 4 and concentrated under reduced pressure to afford 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 1g (1.3 g, 3.65 mmol, 68.5% yield) as dark-brown oil.

Step G: rac 6-(1-Isopropyl-1H-pyrazol-3-yl)-N-((1R,3S)-3-methoxycyclopentyl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1)

General Procedure: DIPEA (163.29 mg, 1.26 mmol, 220.0 μl, 3.0 equiv) was added in one portion to the solution of 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 1g (150.0 mg, 421.56 μmol) and the appropriate corresponding amine (505.37 μmol, 1.2 eq) in DMF (2 mL). The mixture was stirred at 100° C. for 16 h. The mixture was purified by HPLC. Starting with 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 1g (150.0 mg, 421.56 μmol) and using the General Procedure with rac (1R,3S)-3-methoxycyclopentan-1-amine (505.37 μmol, 1.2 eq) produced rac 6-(1-isopropyl-1H-pyrazol-3-yl)-N-((1R,3S)-3-methoxycyclopentyl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1) (16.9 mg, 9% yield, 100% purity). LCMS(ESI): Calculated [M+1] 435.3 Found [M+1] 435.2 1 H NMR (DMSO-d 6 , 600 MHz): δ (ppm) 1.45 (m, 6H), 1.95 (m, 6H), 2.67 (s, 3H), 3.24 (s, 3H), 3.92 (m, 4H), 4.51 (m, 1H), 4.73 (m, 1H), 6.50 (d, 1H), 6.84 (m, 1H), 6.93 (d, 1H), 7.23 (d, 1H), 7.76 (d, 1H), 7.87 (s, 1H).

›Examples9

›Example 2-Example 5: Synthesis of Compounds 2-5

Following the general procedure described in Example 1, Step G, 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 1g (150.0 mg, 421.56 μmol) was treated with the appropriate corresponding amine (505.37 μmol, 1.2 eq) to produce the Example compounds (2)-(5) shown in Table 1. Analytical data for compounds (2)-(5) is also shown in Table 1.

›Example 6: Synthesis of Compound 6

Step A: 6-(1-Isopropyl-1H-pyrazol-3-yl)-N-(6-methoxypyrimidin-4-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (6)

General Procedure: Sodium hydride (25.32 mg, 1.06 mmol, 1.5 eq) (60% in mineral oil) was added portionwise (over 3 min) to the solution of 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 1g (prepared as described in Example 1, Step E (150.0 mg, 421.56 μmol) and the appropriate corresponding amine (633.12 μmol, 1.5 eq) in DMF (2 mL). The reaction mixture was stirred at 100° C. for 16 h. Then, the mixture was cooled to the room temperature, poured in cold solution of ammonium chloride (67.73 mg, 1.27 mmol) in water. The formed participate was collected by filtration, washed by water (2×2 mL) and purified by HPLC. Following the general procedure starting with 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 1g (150.0 mg, 421.56 μmol) (prepared as described in Example 1, Step E) and using 6-methoxypyrimidin-4-amine (633.12 μmol, 1.5 eq), produced 6-(1-isopropyl-1H-pyrazol-3-yl)-N-(6-methoxypyrimidin-4-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (6) (14.6 mg, 7.20% yield, 100% purity). LCMS(ESI): Calculated [M+1] 445.2 Found [M+1] 445.2 1 H NMR (DMSO-d 6 , 400 MHz) § 1.74 (dd, 6H), 3.06 (s, 3H), 4.28 (s, 3H), 4.50 (s, 3H), 4.76-4.85 (m, 1H), 6.82 (t, 1H), 7.74 (s, 1H), 7.89 (d, 1H), 7.91-7.98 (m, 1H), 8.02 (t, 1H), 8.54 (s, 1H), 8.89 (s, 1H).

›Example 7: Synthesis of Compound 7

Step A: 6-(1-Isopropyl-1H-pyrazol-3-yl)-N-(6-methoxypyridin-2-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (7)

Using 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 1g (prepared as described in Example 1, Step E, and 6-methoxypyridin-2-amine as the corresponding amine in the General Procedure described above in Example 6, Step A, produced 6-(1-isopropyl-1H-pyrazol-3-yl)-N-(6-methoxypyridin-2-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (7) (3.7 mg, 2.0% yield, 97% purity). LCMS(ESI): Calculated [M+1] 444.2 Found [M+1] 444.2.

›Example 8: Synthesis of Compound 8

Step A: 6-(1-Isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (8)

Sodium hydride (30.38 mg, 1.27 mmol) (60% in mineral oil) was added portionwise (over 3 min) to the solution of methyl 1-amino-4-(1-isopropyl-1H-pyrazol-3-yl)-3-methyl-1H-pyrrole-2-carboxylate 1e (prepared as described in Example 1, Step C (100.0 mg, 381.23 μmol) and pyridine-2-carbonitrile (39.54 mg, 379.81 μmol) in dioxane (20 mL). The reaction mixture was heated under reflux for 16 h. Then, the mixture was cooled to the room temperature, poured in ice water and neutralized by acetic acid. The obtained precipitate was collected by filtration, washed with water (2×10 mL) and purified by column chromatography (eluted hexane: EtOAc 10:1 to EtOAc 100%) to afford 6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (8) (13.0 mg, 38.88 μmol, 10.2% yield, 100% purity) as dark-yellow solid. LCMS(ESI): Calculated [M+1] 335.2 Found [M+1] 335.2 1 H NMR (DMSO-d6, 400 MHz) δ1.43 (m, 6H), 2.67 (s, 3H), 4.49 (m, 1H), 6.51 (d, 1H), 7.62 (m, 1H), 7.78 (m, 1H), 7.91 (s, 1H), 8.04 (dd, 1H), 8.20 (m, 1H), 8.80 (m, 1H), 11.02 (br s, 1H).

›Example 9: Synthesis of Compound 9

Step A: 4-Chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine 9a

6-(1-Isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (8) (prepared as described in Example 8, Step A (2.99 g, 8.96 mmol) was dissolved in phosphoryl trichloride (16.48 g, 107.48 mmol, 10.02 mL, 12.0 equiv). The mixture was heated to 100° C. and stirred at this temperature for 16 h. The reaction mixture was concentrated in vacuo, poured in ice water (5 mL) and neutralized by K 2 CO 3 (pH˜9!). The mixture was extracted three times with DCM, dried over Na 2 SO 4 and concentrated under reduced pressure to afford 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine 9a (2.5 g, 7.09 mmol, 79.1% yield) as dark-brown oil. The obtained material was used in next step without further purification.

Step B: rac 6-(1-Isopropyl-1H-pyrazol-3-yl)-N-((1R,3S)-3-methoxycyclopentyl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (9)

General Procedure: DIPEA (148.4 mg, 1.15 mmol, 200.0 μl, 4.0 equiv) was added in one portion to the solution of 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine 9a (101.38 mg, 287.35 μmol) and the appropriate corresponding amine (431.02 μmol, 1.5 eq) in DMF (2 mL). The mixture was heated to 100° C. and stirred at this temperature for 16 h. The mixture was purified by HPLC. Following the General Procedure with 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine 9a (101.38 mg, 287.35 μmol) and using rac (1R,3S)-3-methoxycyclopentan-1-amine (431.02 μmol, 1.5 eq) as the corresponding amine, produced rac 6-(1-isopropyl-1H-pyrazol-3-yl)-N-((1R,3S)-3-methoxycyclopentyl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (9) (15.8 mg, 12.7% yield, 100% purity). LCMS(ESI): Calculated [M+1] 432.3 Found [M+1] 432.2 1 H NMR (DMSO-d 6 , 400 MHz) δ 1.46 (d, 6H), 1.83-2.00 (m, 4H), 2.02-2.13 (m, 2H), 2.71 (s, 3H), 3.29 (s, 3H), 3.93-4.01 (m, 1H), 4.53 (p, 1H), 4.84-4.95 (m, 1H), 6.52 (d, 1H), 6.88 (d, 1H), 7.43-7.51 (m, 1H), 7.80 (d, 1H), 7.88-7.98 (m, 2H), 8.27 (d, 1H), 8.68 (d, 1H).

›Example 10-Example 12: Synthesis of Compounds 10-12

Following the general procedure described in Example 9, Step B, 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine 9a (101.38 mg, 287.35 μmol) and the appropriate corresponding amine (431.02 μmol, 1.5 eq) to produce the Example compounds (10)-(12) shown in Table 1. Analytical data for compounds 10-12 is also presented in Table 1.

›Example 13: Synthesis of Compound 13

Step A: 6-(1-Isopropyl-1H-pyrazol-3-yl)-N-(6-methoxypyrimidin-4-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (13)

General Procedure: Sodium hydride (25.55 mg, 1.06 mmol) (60% in mineral oil) was added portionwise (over 3 min) to the solution of 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine 9a (prepared as described in Example 9, Step A) (150.0 mg, 425.15 μmol) and the appropriate corresponding amine (638.75 μmol, 1.5 eq) in DMF (2 mL). The reaction mixture was heated 100° C. and stirred at this temperature for 16 h. Then the mixture was cooled to the room temperature, poured in cold solution of ammonium chloride (68.34 mg, 1.28 mmol) in water. The formed participate was collected by filtration, washed by water (2×10 mL) and purified by HPLC. Following the General Procedure with 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine 9a (150.0 mg, 425.15 μmol) and 6-methoxypyrimidin-4-amine (638.75 μmol, 1.5 eq) as the corresponding amine, produced 6-(1-isopropyl-1H-pyrazol-3-yl)-N-(6-methoxypyrimidin-4-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (13) (30.8 mg, 16.4% yield, 100% purity). LCMS(ESI): Calculated [M+1] 442.2 Found [M+1] 442.2 1 H NMR (DMSO-d 6 , 400 MHz) § 1.47 (d, 6H), 2.86 (s, 3H), 3.94 (s, 3H), 4.47-4.65 (m, 1H), 6.47 (s, 1H), 6.56 (s, 1H), 7.63 (s, 1H), 7.81 (d, 1H), 7.89-8.11 (m, 2H), 8.21 (d, 1H), 8.52-8.85 (m, 2H), 14.85 (s, 1H).

›Example 14: Synthesis of Compound 14

Step A: 6-(1-Isopropyl-1H-pyrazol-3-yl)-N-(6-methoxypyridin-2-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (14)

Following the in the General Procedure described above in Example 13, Step A, 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine 9a (prepared as described in Example 9, Step A) (150.0 mg, 425.15 μmol) and 6-methoxypyridin-2-amine (638.75 μmol, 1.5 eq) as the corresponding amine, produced 6-(1-Isopropyl-1H-pyrazol-3-yl)-N-(6-methoxypyridin-2-yl)-5-methyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (14) (30.8 mg, 16.4% yield, 100% purity). LCMS(ESI): Calculated [M+1] 441.2 Found [M+1] 441.2 1 H NMR (DMSO-d 6 , 400 MHz) § 1.47 (d, 6H), 2.86 (s, 3H), 3.94 (s, 3H), 4.47-4.65 (m, 1H), 6.47 (s, 1H), 6.56 (s, 1H), 7.63 (s, 1H), 7.81 (d, 1H), 7.89-8.11 (m, 2H), 8.21 (d, 1H), 8.52-8.85 (m, 2H), 14.85 (s, 1H).

Example 15: Synthesis of Compound 15

›Step A: Methyl 4-(2-chloro-3-methoxyphenyl)-3-methyl-1H-pyrrole-2-carboxylate 15b

A mixture of methyl 4-iodo-3-methyl-1H-pyrrole-2-carboxylate 1b (prepared as described in Example 1, Step A (5.0 g, 18.86 mmol), 2-(2-chloro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 15a (6.08 g, 22.64 mmol), cesium carbonate (12.29 g, 37.73 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.54 g, 1.89 mmol) in dioxane/H 2 O (100/5 mL) was heated at 100° C. overnight under Argon atmosphere. The reaction mixture was concentrated, and crude compound was purified by flash chromatography to give methyl 4-(2-chloro-3-methoxyphenyl)-3-methyl-1H-pyrrole-2-carboxylate 15b (3.05 g, 57.8% yield).

›Step B: Methyl 1-amino-4-(2-chloro-3-methoxyphenyl)-3-methyl-1H-pyrrole-2-carboxylate 15c

To solution of methyl 4-(2-chloro-3-methoxyphenyl)-3-methyl-1H-pyrrole-2-carboxylate 15b (2.4 g, 8.58 mmol) in DMF (70 mL), sodium hydride (686.39 mg, 28.6 mmol) was added at 0° C. After 30 min, O-(diphenylphosphinyl) hydroxylamine (4.0 g, 17.16 mmol) was added portionwise at 0° C. Reaction mixture was stirred at 60° C. overnight. Then, the mixture was cooled, filtered and filtrate was evaporated under reduce pressure to give methyl 1-amino-4-(2-chloro-3-methoxyphenyl)-3-methyl-1H-pyrrole-2-carboxylate 15c (1.7 g, 65.4% yield).

Step C: 6-(2-Chloro-3-methoxyphenyl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (15)

To solution of methyl 1-amino-4-(2-chloro-3-methoxyphenyl)-3-methyl-1H-pyrrole-2-carboxylate 15c (499.72 mg, 1.7 mmol) and 1-methyl-1H-imidazole-2-carbonitrile (217.93 mg, 2.03 mmol) in dioxane (20 mL), sodium hydride (169.53 mg, 7.06 mmol) was added at 0° C. Reaction mixture was heated at 100° C. overnight. Solution of NH 4 Cl (5 mL) was added dropwise to reaction mixture after cooling to 0° C., then extracted with EtOAc (3×15 mL). The organic extracts were dried over Na 2 SO 4 , concentrated in vacuo to give 6-(2-chloro-3-methoxyphenyl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (15) (610.0 mg, 64% purity, 1.06 mmol, 62.3% yield). A small amount was purified by HPLC for bioassay (100% purity). LCMS(ESI): Calculated [M+1] 370.1 Found [M+1] 370.0 1 H NMR (DMSO-d 6 , 400 MHz) § 2.30 (s, 1H), 3.87 (s, 3H), 3.98 (s, 3H), 6.95 (d, 1H), 7.10 (s, 1H), 7.29 (d, 1H), 7.35 (dd, 1H), 7.45 (s, 1H), 7.58 (s, 1H), 11.05 (br s, 1H).

›Example 16: Synthesis of Compound 16

Step A: 4-Chloro-6-(2-chloro-3-methoxyphenyl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 16a

To solution of 6-(2-chloro-3-methoxyphenyl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (15) (prepared as described in Example 15, Step C, used without purification) (926.77 mg, 2.51 mmol) in phosphoryl trichloride (3.84 g, 25.06 mmol, 2.34 ml, 10.0 equiv) DIPEA (972.02 mg, 7.52 mmol, 1.31 mL, 3.0 equiv) was added. Reaction mixture was stirred at 100° C. overnight then concentrated in vacuo, washed with aqueous solution of NaHCO 3 to pH 7 and extracted with CHCl 3 (3×15 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo to give 4-chloro-6-(2-chloro-3-methoxyphenyl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 16a (1.1 g, 50.0% purity, 1.42 mmol, 56.5% yield).

Step B: 6-(2-Chloro-3-methoxyphenyl)-N-(2-methoxyethyl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (16)

The 4-chloro-6-(2-chloro-3-methoxyphenyl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 16a (355.6 mg, 915.91 μmol) was dissolved in DMSO (7 mL) and 2-methoxyethylamine (137.6 mg, 1.83 mmol, 160.0 μL, 2.0 equiv) followed by DIPEA (355.12 mg, 2.75 mmol, 480.0 μL, 3.0 equiv) were added at room temperature. The mixture was heated at 100° C. overnight. Then, the mixture was cooled and purified by HPLC (20-80% 0-6 min H 2 O/MeOH, flow: 30 mL/min; column: SunFire C18) to afford 6-(2-chloro-3-methoxyphenyl)-N-(2-methoxyethyl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (16) (34.0 mg, 8.7% yield, 100% purity) as yellow gum. LCMS(ESI): Calculated [M+1] 427.2 Found [M+1] 427.0 1 H NMR (DMSO-d 6 , 400 MHz) § 2.32 (s, 3H), 3.30 (s, 3H), 3.59 (t, 2H), 3.74-3.80 (m, 2H), 3.90 (s, 3H), 3.96 (s, 3H), 6.94-7.00 (m, 2H), 7.16-7.21 (m, 2H), 7.28 (s, 1H), 7.37 (t, 1H), 7.72 (s, 1H).

Example 17: Synthesis of Compound 17

›Step A: Methyl 4-bromo-3-phenyl-1H-pyrrole-2-carboxylate 17b

To a solution of methyl 3-phenyl-1H-pyrrole-2-carboxylate 17a (5.0 g, 24.85 mmol) in THF/H 2 O 4:1 (100 mL) was added N-bromosuccinimide (4.42 g, 24.85 mmol). The reaction mixture was stirred vigorously at room temperature for 15 min following by the addition of water (50 mL) and EtOAc (200 mL). The reaction mixture was extracted with two portions of EtOAc (100 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Methyl 4-bromo-3-phenyl-1H-pyrrole-2-carboxylate 17b (5.0 g, 70.0% purity, 12.49 mmol, 50.3% yield) was used in next step without purification.

›Step B: Methyl 4-(1-isopropyl-1H-pyrazol-3-yl)-3-phenyl-1H-pyrrole-2-carboxylate 17c

Methyl 4-bromo-3-phenyl-1H-pyrrole-2-carboxylate 17b (5.0 g, 17.85 mmol), 1-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1c (5.06 g, 21.42 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.46 g, 1.78 mmol), cesium carbonate (11.63 g, 35.7 mmol) were suspended in degassed dioxane: water (50 mL: 10 mL). The mixture was heated under argon at 100° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL), the organic layer was washed with water (100 mL) and saturated brine (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the methyl 4-(1-isopropyl-1H-pyrazol-3-yl)-3-phenyl-1H-pyrrole-2-carboxylate 17c (5.7 g, 56.0% purity, 10.32 mmol, 57.8% yield).

›Step C: Methyl 1-amino-4-(1-isopropyl-1H-pyrazol-3-yl)-3-phenyl-1H-pyrrole-2-carboxylate 17d

The mixture of methyl 4-(1-isopropyl-1H-pyrazol-3-yl)-3-phenyl-1H-pyrrole-2-carboxylate 17c (3.2 g, 10.34 mmol) sodium hydride (620.52 mg, 25.86 mmol) in DMF (50 mL) was cooled to 0° C. and O-(diphenylphosphinyl) hydroxylamine (2.89 g, 12.41 mmol) was added. The mixture was allowed to warm up to 60° C. and stirred for 16 h. The mixture was poured into the ice-cold water (150 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (100 mL), dried over Na 2 SO 4 and evaporated under reduced pressure to obtain methyl 1-amino-4-(1-isopropyl-1H-pyrazol-3-yl)-3-phenyl-1H-pyrrole-2-carboxylate 17d after crystallization in methyl tert-butyl ether and hexane (10/3) (3.1 g, 90.0% purity, 6.69 mmol, 64.7% yield).

Step D: 6-(1-Isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-ol (17)

1-Methyl-1H-imidazole-2-carbonitrile (990.77 mg, 9.25 mmol) and 1-amino-4-(1-isopropyl-1H-pyrazol-3-yl)-3-phenyl-1H-pyrrole-2-carboxylate 17d (2.5 g, 7.71 mmol) was dissolved in DMF (50 mL) and sodium hydride (616.59 mg, 25.69 mmol) was added. The mixture was stirred at 80° C. 16 h. Then mixture was evaporated, and the residue was diluted with water (80 mL). The product was extracted with EtOAc (80 mL). Organic layer was dried over Na 2 SO 4 and evaporated to give 6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-ol (17) (2.6 g, 60.0% purity, 3.91 mmol, 50.7% yield). A small amount of material was purified by HPLC for bioassay (100% purity). LCMS(ESI): Calculated [M+1] 400.2 Found [M+1] 400.2 1 H NMR (DMSO-d 6 , 400 MHz) § 1.32 (m, 6H), 4.00 (s, 3H), 4.32 (m, 1H), 5.65 (s, 1H), 7.08 (s, 1H), 7.30 (m, 5H), 7.42 (s, 1H), 7.51 (s, 1H), 7.88 (s, 1H), 11.22 (br s, 1H).

›Examples7

›Example 18: Synthesis of Compound 18

Step A: 4-Chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 18a

The starting material 6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-ol (17) (crude product prepared as described in Example 17, Step D (2.5 g, 6.26 mmol) was suspended in phosphoryl trichloride (9.59 g, 62.58 mmol, 5.83 mL, 10.0 equiv) and DIPEA (2.43 g, 18.77 mmol, 3.27 mL, 3.0 equiv) was added at RT. The reaction mixture was heated at 100° C. for 16 h. The solution was cooled to RT, evaporated under reduced pressure, poured in ice (25 mL) and diluted with ice-cold ammonia (20 mL, 20-25% of ammonia), the product was extracted with chloroform (2×50 mL) and evaporated. 4-Chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 18a (2.8 g, 52.0% purity, 3.48 mmol, 55.7% yield) was obtained as brown slurry.

Step B: rac 6-(1-Isopropyl-1H-pyrazol-3-yl)-N-((1R,3S)-3-methoxycyclopentyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (18)

General Procedure: The 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 18a (202.8 mg, 485.29 μmol) was dissolved in DMSO (2 mL) and triethylamine (196.02 mg, 1.94 mmol, 270.0 μl, 4.0 equiv) and the appropriate corresponding amine (1.5 equiv) was added at room temperature. The mixture was heated at 100° C. overnight (16 hours), cooled and purified by HPLC.

Following the General Procedure using 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 18a (202.8 mg, 485.29 μmol) and rac (1R,3S)-3-methoxycyclopentan-1-amine (1.5 equiv) as the corresponding amine, produced (after conversion to the HCl salt) rac 6-(1-isopropyl-1H-pyrazol-3-yl)-N-((1R,3S)-3-methoxycyclopentyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride salt (18) (7.00 mg, 1.70% yield, 97% purity). LCMS(ESI): Calculated [M+1] 497.3 Found [M+1] 497.2 1 H NMR (cd 3 od, 400 MHZ,) δ 1.46-1.53 (m, 7H), 1.60-1.79 (m, 3H), 1.92-2.01 (m, 1H), 2.03-2.16 (m, 1H), 3.01 (s, 3H), 3.73-3.80 (m, 1H), 4.39 (s, 3H), 4.55 (p, 1H), 4.81-4.86 (m, 1H), 5.65 (d, 1H), 7.42-7.49 (m, 2H), 7.54-7.60 (m, 4H), 7.68 (d, 1H), 7.75 (d, 1H), 8.17 (s, 1H).

›Example 19-Example 21: Synthesis of Compounds 19-21

Following the General Procedure described in Example 18, Step B, chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 18a (202.8 mg, 485.29 μmol) and the appropriate corresponding amine (1.5 equiv) produced the Example compounds (19)-(21) shown in Table 1. Analytical data for compounds (19)-(21) is also presented in Table 1.

›Example 22: Synthesis of Compound 22

Step A: 6-(1-Isopropyl-1H-pyrazol-3-yl)-N-(6-methoxypyrimidin-4-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (22)

General Procedure: To a solution of 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 18a (prepared as described in Example 18, (259.87 mg, 621.87 μmol) and the appropriate corresponding amine (518.22 μmol, 1 equiv) in dry DMF (5.0 mL), sodium hydride (31.09 mg, 1.3 mmol) was added under Ar atmosphere. The reaction mixture was stirred at 80° C. for 15 h. The mixture was cooled, diluted with water (20 mL) and concentrated to dryness. The residue was purified by HPLC (20-80% 0-6 min H 2 O/MeOH, flow: 30 mL/min; column: SunFire C18) to afford product. Following the General Procedure using 4-chloro-6-(1isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 18a (259.87 mg, 621.87 μmol) and 6-methoxypyrimidin-4-amine amine (518.22 μmol, 1 equiv) as the corresponding amine, produced 6-(1-isopropyl-1H-pyrazol-3-yl)-N-(6-methoxypyrimidin-4-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (22) (4.60 mg, 2.30% yield, 99% purity). LCMS(ESI): Calculated [M+1] 507.3 Found [M+1] 507.2 1 H NMR (cd 3 od, 400 MHz) § 1.49 (d, 6H), 3.95 (s, 3H), 4.12 (s, 3H), 4.44-4.57 (m, 1H), 5.66 (d, 1H), 7.19 (s, 1H), 7.32 (s, 1H), 7.48 (d, 1H), 7.52-7.65 (m, 5H), 8.12 (s, 1H), 8.25 (s, 2H).

›Example 23: Synthesis of Compound 23

Step A: 6-(1-Isopropyl-1H-pyrazol-3-yl)-N-(6-methoxypyridin-2-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (23)

Following the General Procedure described in Example 22, Step A, using 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 18a (prepared as described in Example 18, Step A) (259.87 mg, 621.87 μmol) and 6-methoxypyridin-2-amine (518.22 μmol, 1 equiv) as the corresponding amine, produced 6-(1-isopropyl-1H-pyrazol-3-yl)-N-(6-methoxypyridin-2-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (23) (6.00 mg, 2.30% yield, 100% purity). LCMS(ESI): Calculated [M+1] 506.3 Found [M+1] 506.2.

›Example 24: Synthesis of Compound 24

Step A: 6-(1-Isopropyl-1H-pyrazol-3-yl)-5-phenyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol 24a

Pyridine-2-carbonitrile (1.44 g, 13.87 mmol) and methyl 1-amino-4-(1-isopropyl-1H-pyrazol-3-yl)-3-phenyl-1H-pyrrole-2-carboxylate 17b (prepared as described in Example 17, Step A (3.75 g, 11.56 mmol) was dissolved in DMF (15 mL) and sodium hydride (1.16 g, 48.17 mmol) was added. The mixture was stirred and heated at 80° C. for 16 h. Then mixture was diluted with water (40 mL) and extracted with EtOAc (3×50 mL). Organic layer dried and evaporated to give 6-(1-isopropyl-1H-pyrazol-3-yl)-5-phenyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol 24a (5.0 g, 34.0% purity, 4.29 mmol, 37.1% yield).

Step B: 4-Chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-phenyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine 24b

The starting material 6-(1-isopropyl-1H-pyrazol-3-yl)-5-phenyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol 24a (5.0 g, 12.61 mmol) was suspended in phosphoryl trichloride (19.34 g, 126.13 mmol, 11.76 ml, 10.0 equiv) and DIPEA (4.89 g, 37.84 mmol, 6.59 mL, 3.0 equiv) was added at room temperature. The reaction mixture was heated at 100° C. for 16 h. The solution was cooled to RT, evaporated under reduced pressure, poured in ice (100 mL) and diluted with ice-cold ammonia (20 mL, 20-25% of ammonia). The product was extracted with chloroform (2×100 mL) and evaporated under reduced pressure to afford 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-phenyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine 24b (6.0 g, 48.0% purity, 6.94 mmol, 55% yield) as brown slurry.

Step C: rac 6-(1-Isopropyl-1H-pyrazol-3-yl)-N-((1R,3S)-3-methoxycyclopentyl)-5-phenyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (24)

General Procedure: The 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-phenyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine 24b (400.0 mg, 964.11 μmol) was dissolved in DMSO (7 mL) and DIPEA (415.8 mg, 3.22 mmol, 560.0 μL, 4.0 equiv) with the appropriate corresponding amine (1.0 equiv) were added at room temperature. The mixture was heated at 100° C. overnight, cooled and purified by HPLC to produce product.

Following the General Procedure using 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-phenyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine 24b and rac (1R,3S)-3-methoxycyclopentan-1-amine (1.0 equiv) as the corresponding amine, produced rac 6-(1-isopropyl-1H-pyrazol-3-yl)-N-((1R,3S)-3-methoxycyclopentyl)-5-phenyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (24) (7.30 mg, 1.80% yield, 98% purity). LCMS(ESI): Calculated [M+1] 494.3 Found [M+1] 494.4 1 H NMR (cd 3 od, 400 MHz) δ 1.40-1.51 (m, 7H), 1.56 (d, 1H), 1.66-1.74 (m, 2H), 1.99-2.13 (m, 2H), 3.04 (s, 3H), 3.72-3.81 (m, 1H), 4.49 (hept, 1H), 4.85-4.86 (m, 1H), 5.61 (d, 1H), 7.37-7.48 (m, 3H), 7.48-7.58 (m, 4H), 7.97 (td, 1H), 8.07 (s, 1H), 8.44 (d, 1H), 8.65-8.70 (m, 1H).

›Example 25-Example 27: Synthesis of Compounds 25-27

Following the general procedure described in Example 24, Step C, 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-phenyl-2-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine 24b (400.0 mg, 964.11 μmol) and the appropriate corresponding amine (1.0 equiv) produced the Example compounds (25)-(27) shown in Table 1. Analytical data for compounds (25)-(27) is shown is also presented in Table 1.

Example 28: Synthesis of Compound 28

›Step A: Methyl 4-(2-chloro-3-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carboxylate 28a

A mixture of methyl 4-bromo-3-phenyl-1H-pyrrole-2-carboxylate 17b (prepared as described in Example 17, Step A) (8.5 g, 30.34 mmol), 2-(2-chloro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 15a (9.78 g, 36.41 mmol), cesium carbonate (19.77 g, 60.69 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (2.48 g, 3.03 mmol) in Dioxane/H 2 O (170/10 mL) was heated at 100° C. under Argon atmosphere overnight. Reaction mixture was evaporated, and crude compound was purified by flash chromatography (Hexane-EtOAc as a solvent mixture) to give methyl 4-(2-chloro-3-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carboxylate 28a (7.7 g, 85.56% purity, 19.28 mmol, 63.5% yield).

›Step B: Methyl 1-amino-4-(2-chloro-3-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carboxylate 28b

To solution of methyl 4-(2-chloro-3-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carboxylate 28a (7.7 g, 22.53 mmol) in DMF (70 mL) sodium hydride (1.8 g, 75.09 mmol) was added at 0° C. After 30 min, amino diphenylphosphinate (10.51 g, 45.06 mmol) was added portionwise at 0° C. Reaction mixture was stirred at 60° C. overnight then cooled, filtered and filtrate was evaporated under reduce pressure to give methyl 1-amino-4-(2-chloro-3-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carboxylate 28b (6.5 g, 80.22% purity, 14.61 mmol, 64.9% yield).

Step C: 6-(2-Chloro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-ol (28)

1-Methyl-1H-imidazole-2-carbonitrile (3.24 g, 30.27 mmol) and methyl 1-amino-4-(2-chloro-3-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carboxylate 28b (9.0 g, 25.22 mmol) was dissolved in DMF (40 mL) and sodium hydride (2.52 g, 105.1 mmol) was added. The mixture was stirred heated at 80° C. 16 h. Then mixture was evaporated, diluted with water (100 mL) and extracted with EtOAc (3×150 mL). Organic layer dried and evaporated to give a 6-(2-chloro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-ol (28) (13.0 g, 50% purity, 15.05 mmol, 59.7% yield). A small amount was purified by HPLC for bioassay (100% purity). LCMS(ESI): Calculated [M+1] 432.1 Found [M+1] 432.5 1 H NMR (DMSO-d 6 , 400 MHz) δ 3.82 (s, 3H), 4.00 (s, 3H), 6.77 (m, 1H), 7.07 (m, 1H), 7.20 (m, 7H), 7.52 (m, 1H), 7.88 (s, 1H), 11.30 (br s, 1H).

›Examples3

›Example 29: Synthesis of Compound 29

Step A: 4-Chloro-6-(2-chloro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 29a

The 6-(2-chloro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-ol (28) (prepared as described in Example 28, Step C; crude product) (13.0 g, 30.1 mmol) was suspended in phosphoryl trichloride (46.15 g, 301.01 mmol, 28.06 mL, 10.0 equiv) and DIPEA (11.67 g, 90.3 mmol, 15.73 ml, 3.0 equiv) was added at room temperature. The reaction mixture was heated at 100° C. for 16 h. Then, the solution was cooled to room temperature, evaporated under reduced pressure, poured in ice (200 mL) and diluted with ice-cold ammonia (200 mL, 20-25% of ammonia). The product was extracted with chloroform (2×200 mL) and evaporated under reduced pressure to afford 4-chloro-6-(2-chloro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 29a (17.0 g, 36.42% purity, 13.75 mmol, 45.7% yield) as brown slurry.

Step B: 6-(2-Chloro-3-methoxyphenyl)-N-(2-methoxyethyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (29)

General Procedure: The 4-chloro-6-(2-chloro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 29a (500.08 mg, 1.11 mmol) was dissolved in DMSO (7 mL) and DIPEA (430.36 mg, 3.33 mmol, 580.0 μL, 3.0 equiv) with the appropriate corresponding amine (1.33 mmol) was added at room temperature. The mixture was heated at 100° C. overnight, cooled and purified by HPLC ((20-80% 0-6 min H 2 O/MeOH, flow: 30 mL/min; column: SunFire C18) to afford pure product. Following the general procedure, 6-(2-chloro-3-methoxyphenyl)-N-(2-methoxyethyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (29) was prepared (30.00 mg, 5.50% yield, 97% purity). LCMS(ESI): Calculated [M+1] 489.2 Found [M+1] 489.2 1 H NMR (DMSO-d 6 , 400 MHz) δ 3.14 (s, 3H), 3.37-3.43 (m, 2H), 3.59-3.64 (m, 2H), 3.83 (s, 3H), 3.98 (s, 3H), 5.83-5.90 (m, 1H), 6.81 (d, 1H), 7.01 (s, 1H), 7.05 (d, 1H), 7.19 (t, 1H), 7.26 (d, 2H), 7.31 (s, 1H), 7.34-7.42 (m, 3H), 7.93 (s, 1H).

›Example 30-Example 34: Synthesis of Compounds 30-34

Following the general procedure described in Example 29, Step B, 4-chloro-6-(2-chloro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 29a (500.08 mg, 1.11 mmol) and the appropriate corresponding amine (1.33 mmol) produced the Example compounds (30)-(34) shown in Table 1. Analytical data for compounds (30)-(34) is also presented in Table 1.

Example 35: Synthesis of Compound 35

›Step A: 1-(tert-Butyl) 2-methyl 3-bromo-1H-pyrrole-1,2-dicarboxylate 35b

To solution of 1-tert-butyl 2-methyl (R)-pyrrolidine-1,2-dicarboxylate (40.0 g, 174.46 mmol) in CCl 4 (500 mL) N-bromosuccinimide (108.68 g, 610.62 mmol) was added in one portion. Reaction mixture was refluxed for 1 h, then cooled and filtered. Filtrate was evaporated and crude compound was purified by flash chromatography to give 1-(tert-butyl) 2-methyl 3-bromo-1H-pyrrole-1,2-dicarboxylate 35b (6.37 g, 20.94 mmol, 12% yield).

›Step B: 1-(tert-Butyl) 2-methyl 3-(prop-1-en-2-yl)-1H-pyrrole-1,2-dicarboxylate 35c

A mixture of 1-(tert-butyl) 2-methyl 3-bromo-1H-pyrrole-1,2-dicarboxylate 35b (6.37 g, 20.96 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.28 g, 31.44 mmol, 5.91 mL, 1.5 equiv), sodium carbonate (4.44 g, 41.92 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (855.87 mg, 1.05 mmol) in Dioxane/H 2 O (120/10 mL) was heated at 100° C. under Argon atmosphere overnight. Reaction mixture was evaporated, and crude compound was purified by flash chromatography to give 1-(tert-butyl) 2-methyl 3-(prop-1-en-2-yl)-1H-pyrrole-1,2-dicarboxylate 35c (4.2 g, 80.0% purity, 12.66 mmol, 60.4% yield).

›Step C: 1-(ter-Butyl) 2-methyl 3-isopropyl-1H-pyrrole-1,2-dicarboxylate 35d

1-(tert-butyl) 2-methyl 3-(prop-1-en-2-yl)-1H-pyrrole-1,2-dicarboxylate 35c (2.1 g, 7.92 mmol) was dissolved in MeOH (30 mL) and stirred with 10% Pd/C (0.42 g) under H 2 atmosphere at room temperature for 3 h. Reaction mixture was degassed and filtered. Filtrate was concentrated under reduced pressure to give 1-(tert-butyl) 2-methyl 3-isopropyl-1H-pyrrole-1,2-dicarboxylate 35d (2.05 g, 78.6% purity, 6.03 mmol, 76.1% yield).

›Step D: Methyl 3-isopropyl-1H-pyrrole-2-carboxylate 35e

To solution of 1-(ter-butyl) 2-methyl 3-isopropyl-1H-pyrrole-1,2-dicarboxylate 35d (5.0 g, 18.7 mmol) in DCM (40 mL) 2,2,2-trifluoroacetic acid (31.99 g, 280.52 mmol, 21.66 mL, 15.0 equiv) was added at 0° C. Reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure to give methyl 3-isopropyl-1H-pyrrole-2-carboxylate 35e (2.9 g, 44.3% purity, 7.68 mmol, 41.1% yield).

›Step E: Methyl 4-bromo-3-isopropyl-1H-pyrrole-2-carboxylate 35f

To solution of methyl 3-isopropyl-1H-pyrrole-2-carboxylate 35e (2.9 g, 17.34 mmol) in DMF (25 mL) N-bromosuccinimide (3.09 g, 17.34 mmol) was added at 0° C. Reaction mixture was stirred at room temperature overnight then poured into water, extracted with EtOAc three times. Combined EtOAc was washed with water and brine, dried over Na 2 SO 4 , and concentrated in vacuo to give methyl 4-bromo-3-isopropyl-1H-pyrrole-2-carboxylate 35f (1.26 g, 73.0% purity, 3.74 mmol, 21.6% yield).

›Step F: Methyl 3-isopropyl-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxylate 35g

A mixture of methyl 4-bromo-3-isopropyl-1H-pyrrole-2-carboxylate 35f (1.26 g, 5.12 mmol), 1-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1c (1.21 g, 5.12 mmol), cesium carbonate (3.34 g, 10.24 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (418.19 mg, 512.08 μmol) in Dioxane/H 2 O (25/3 mL) was heated at 100° C. under Argon atmosphere overnight. Reaction mixture was evaporated and crude compound was purified by flash chromatography (Hexane-EtOAc as a solvent mixture) to give methyl 3-isopropyl-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxylate 35g (1.28 g, 68.1% purity, 3.17 mmol, 61.8% yield).

›Step G: Methyl 1-amino-3-isopropyl-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxylate 35h

To solution of methyl 3-isopropyl-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxylate 35g (513.97 mg, 1.87 mmol) in DMF (20 mL) sodium hydride (149.32 mg, 6.22 mmol) was added at 0° C. After 30 min amino diphenylphosphinate (870.61 mg, 3.73 mmol) was added portionwise at 0° C. Reaction mixture was stirred at 60° C. overnight then cooled, filtered and filtrate was evaporated under reduce pressure to give methyl 1-amino-3-isopropyl-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxylate 35h (550.0 mg, 63.31% purity, 1.2 mmol, 64.2% yield).

Step H: 5-Isopropyl-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol 35i

Methyl 1-amino-3-isopropyl-4-(1-isopropyl-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxylate 35h (549.84 mg, 1.89 mmol) and 1-methyl-1H-imidazole-2-carbonitrile (243.4 mg, 2.27 mmol) were dissolved in Dioxane (20 mL) and sodium hydride (189.35 mg, 7.89 mmol) was added at 0° C. Reaction mixture was heated at 80° C. overnight. Solution of NH 4 Cl (5 mL) was added dropwise to reaction mixture after cooling to 0° C., then extracted with EtOAc (3×15 mL). The organic extracts were dried over Na 2 SO 4 , concentrated in vacuo to give 5-isopropyl-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol 35i (620.0 mg, 58.7% purity, 995.92 μmol, 52.6% yield).

Step I: 4-Chloro-5-isopropyl-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 35j

To 5-isopropyl-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol 35i (622.57 mg, 1.7 mmol) in phosphoroyl trichloride (2.61 g, 17.04 mmol, 1.59 mL, 10.0 equiv) DIPEA (660.38 mg, 5.11 mmol, 890.0 μL, 3.0 equiv) was added. Reaction mixture was stirred at 100° C. overnight then concentrated in vacuo, washed with solution of NaHCO 3 to pH 7 and extracted with CHCl 3 (3×15 mL). Combined CHCl 3 was dried over Na 2 SO 4 , and concentrated in vacuo to give 4-chloro-5-isopropyl-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 35j (800.0 mg, 43.7% purity, 910.71 μmol, 53.5% yield).

Step J: 5-Isopropyl-6-(1-isopropyl-1H-pyrazol-3-yl)-N-(2-methoxyethyl)-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (35)

General Procedure: To a solution of 4-chloro-5-isopropyl-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 35j (411.56 mg, 1.07 mmol) and the appropriate corresponding amine (1.5 equiv) in DMSO (5 mL) DIPEA (415.52 mg, 3.22 mmol, 560.0 μl, 3.0 equiv) was added. Reaction mixture was stirred at 90° C. overnight. Product was purified by HPLC (2-10 min 60-75% methanol flow 30 mL/min (loading pump 4 mL/min methanol), Column Sun Fire C18 100×19 mm) to give product. Following the general procedure, 5-isopropyl-6-(1-isopropyl-1H-pyrazol-3-yl)-N-(2-methoxyethyl)-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (35) was prepared (13.20 mg, 2.80% yield, 100% purity). LCMS(ESI): Calculated [M+1] 423.3 Found [M+1] 423.4 1 H NMR (DMSO-d 6 , 400 MHz) δ 1.30-1.39 (m, 6H), 1.46 (d, 6H), 3.31 (s, 3H), 3.61 (t, 2H), 3.70-3.83 (m, 3H), 3.94-4.01 (m, 3H), 4.46-4.60 (m, 1H), 6.40 (d, 1H), 6.97 (s, 1H), 7.27 (s, 1H), 7.77 (d, 1H), 7.82 (s, 1H).

›Example 36: Synthesis of Compound 36

Step A: rac 5-Isopropyl-6-(1-isopropyl-1H-pyrazol-3-yl)-N-((1R,3S)-3-methoxycyclopentyl)-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (36)

Following the General Procedure described in Example 35, Step J, 5-isopropyl-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 35j (prepared as described in Example 35, Step I) was converted to rac 5-isopropyl-6-(1-isopropyl-1H-pyrazol-3-yl)-N-((1R,3S)-3-methoxycyclopentyl)-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (36) (12.70 mg, 2.60% yield, 100% purity). LCMS(ESI): Calculated [M+1] 463.3 Found [M+1] 463.4 1 H NMR (DMSO-d 6 , 400 MHz) δ 1.33-1.40 (m, 6H), 1.46 (d, 6H), 1.80-2.03 (m, 6H), 3.29 (s, 3H), 3.61-3.74 (m, 1H), 3.94-4.00 (m, 4H), 4.46-4.61 (m, 1H), 4.84-4.92 (m, 1H), 6.40 (d, 1H), 6.98 (s, 1H), 7.28 (s, 1H), 7.77 (d, 1H), 7.81 (s, 1H).

Example 37: Synthesis of Compound 37

›Step A: Methyl 1-amino-3-methyl-1H-pyrrole-2-carboxylate 37a

To solution of methyl 3-methyl-1H-pyrrole-2-carboxylate (15.0 g, 107.8 mmol) in DMF (200 mL) sodium hydride (8.62 g, 359.33 mmol) was added at 0° C. After 1 h, amino diphenylphosphinate (50.28 g, 215.6 mmol) was added. Reaction mixture was stirred at 60° C. overnight then cooled, filtered and filtrate was evaporated under reduce pressure to give methyl 1-amino-3-methyl-1H-pyrrole-2-carboxylate 37a (12.9 g, 80.0% purity, 66.94 mmol, 62.1% yield).

›Step B: 5-Methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol 37b

Sodium hydride (6.23 g, 259.45 mmol) (60% on mineral oil) was added portionwise (during 3 min) to the solution of methyl 1-amino-3-methyl-1H-pyrrole-2-carboxylate 37a (12.0 g, 77.84 mmol) and 1-methyl-1H-imidazole-2-carbonitrile (8.34 g, 77.84 mmol, 8.34 mL, 1.0 equiv) in dioxane (20 mL). The reaction mixture was heated to reflux and stirred at this temperature for 16 h. Then the mixture was cooled to the room temperature, poured in ice water and neutralized by acetic acid. The formed participate was collected by filtration, washed by water (2×10 mL) and dried in vacuo. 5-Methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol 37b (9.5 g, 41.44 mmol, 53.2% yield) was obtained.

›Step C: 4-Chloro-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 37c

5-Methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol 37b (1.0 g, 4.36 mmol) was dissolved in phosphoroyl trichloride (8.02 g, 52.32 mmol, 4.88 mL, 12.0 equiv). The mixture was heated to 100° C. and stirred at this temperature for 16 h. The reaction mixture was concentrated in vacuo, poured in ice water (5 mL) and neutralized by aqueous solution of K 2 CO 3 . The formed participate was collected by filtration, washed by water (2×5 mL) and dried in vacuo. 4-Chloro-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 37c (450.0 mg, 1.82 mmol, 41.7% yield) was obtained.

Step D: 5-Methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine trifluoroacetic acid salt (37)

4-Chloro-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 37c (250.0 mg, 1.01 mmol) was dissolved in 20 mL 10% solution NH 3 in iPA. The mixture was heated in sealed tube for 48 h, then evaporated and the residue was triturated in water. The solid was filtered and purified on HPLC (2-10 min 10-50% MeOH+TFA flow 30 mL/min (loading pump 4 mL/min water), Column Sun Fire C18 100×19 mm). 5-Methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine trifluoroacetic acid salt (37) (5.4 mg, 23.66 μmol, 2.3% yield, 100% purity) was obtained. LCMS(ESI): Calculated [M+1] 229.1 Found [M+1] 229.1 1 H NMR (DMSO-d 6 , 400 MHz) § 2.55 (s, 3H), 4.31 (s, 3H), 6.61 (s, 1H), 7.62 (m, 3H).

›Example 38: Synthesis of Compound 38

Step A: N-(6-Methoxypyridin-2-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (38)

Sodium hydride (24.15 mg, 1.01 mmol) (60% on mineral oil) was added portionwise (over 3 min) to the solution of 4-chloro-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine 37c (prepared as described in Example 37, Step C) (99.7 mg, 402.55 μmol) and 6-methoxypyridin-2-amine (74.96 mg, 603.82 μmol) in DMF (2 mL). The reaction mixture was heated 100° C. and stirred at this temperature for 16 h. Then, the mixture was cooled to the room temperature, poured in clod solution of ammonium chloride (64.6 mg, 1.21 mmol) in water. The formed participate was collected by filtration, washed by water (2×10 mL) and purified by HPLC (2-10 min 55-80% methanol+NH 3 flow 30 mL/min (loading pump 4 mL/min methanol), Column Sun Fire C18 100×19 mm). N-(6-Methoxypyridin-2-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (38) (15.8 mg, 47.11 μmol, 11.7% yield) was obtained (15.80 mg, 11.70% yield, 100% purity). LCMS(ESI): Calculated [M+1] 336.2 Found [M+1] 336.2 1 H NMR (DMSO-d 6 , 400 MHz): δ (ppm) 2.56 (s, 3H), 4.00 (s, 3H), 4.12 (s, 3H), 6.40 (m, 1H), 6.50 (d, 1H), 6.75 (d, 1H), 7.08 (m, 1H), 7.50 (m, 2H), 7.68 (dd, 1H), 13.10 (m, 1H).

Example 39: Synthesis of Compound 39

›Step A: Ethyl 1-amino-3-phenyl-1H-pyrrole-2-carboxylate 39b

To solution of ethyl 1-amino-3-phenyl-1H-pyrrole-2-carboxylate 39a (12.0 g, 55.75 mmol) in DMF (150 mL) sodium hydride (4.46 g, 185.82 mmol) was added at 0° C. After 30 min, amino diphenylphosphinate (26.0 g, 111.49 mmol) was added portionwise at 0° C. Reaction mixture was stirred at 60° C. overnight then cooled, filtered and filtrate was evaporated under reduce pressure to give ethyl 1-amino-3-phenyl-1H-pyrrole-2-carboxylate 39b (15.9 g, 45.28% purity, 31.27 mmol, 56.1% yield).

›Step B: 2-(1-Methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-ol (39)

Ethyl 1-amino-3-phenyl-1H-pyrrole-2-carboxylate 39b (15.0 g, 65.14 mmol) and 1-methyl-1H-imidazole-2-carbonitrile (8.37 g, 78.17 mmol) were dissolved in Dioxane (150 mL) and sodium hydride (6.51 g, 271.43 mmol) was added at 0° C. Reaction mixture was heated at 100° C. overnight. Solution of NH 4 Cl (25 mL) was added dropwise to reaction mixture after cooling to 0° C., then extracted with EtOAc (3×75 mL). The organic extracts were dried over Na 2 SO 4 , concentrated in vacuo. Product was recrystallized from MTBE to give 2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-ol (39) (7.9 g, 85% purity, 23.14 mmol, 35.5% yield). A small amount was purified by HPLC for bioassay (100% purity). Calculated [M+1] 292.1 Found [M+1] 292.0 1 H NMR (DMSO-d 6 , 400 MHz): δ (ppm) 4.03 (s, 3H), 6.83 (d, 1H), 7.14 (d, 1H), 7.32 (m, 1H), 7.39 (m, 2H), 7.50 (d, 1H), 7.72 (m, 1H), 7.82 (m, 2H).

Example 40: Synthesis of Compound 40

›Step A: 4-Chloro-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 40a

To 2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-ol (39) (prepared as described in Example 39, Step B; crude product) (500.32 mg, 1.72 mmol) phosphoroyl trichloride (2.63 g, 17.17 mmol, 1.6 mL, 10.0 equiv) was added. Reaction mixture was stirred at 100° C. overnight then concentrated in vacuo, washed with aqueous solution of NaHCO 3 to pH 7 and extracted with CHCl 3 (3×15 mL). Combined CHCl 3 was dried over Na 2 SO 4 , and concentrated in vacuo to give 4-chloro-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 40a (500.0 mg, 92.0% purity, 1.49 mmol, 86.5% yield).

Step B: N-(6-Methoxypyridin-2-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (40)

General Procedure: To the appropriate corresponding amine (1.1 equiv) in DMF (10 mL) sodium hydride (52.23 mg, 2.18 mmol) was added at 0° C. After 30 min, 4-chloro-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 40a (269.67 mg, 870.59 μmol) was added. Reaction mixture was stirred at 50° C. overnight. Product was purified by HPLC (2-10 min 60-85% methanol+NH 3 flow 30 mL/min (loading pump 4 mL/min methanol), Column Sun Fire C18 100×19 mm) to give pure product. Following the general procedure, N-(6-methoxypyridin-2-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (40) was obtained (32.90 mg, 9.00% yield, 100% purity). LCMS(ESI): Calculated [M+1] 398.2 Found [M+1] 398.2 1 H NMR (DMSO-d 6 , 400 MHz): δ (ppm) 3.68 (s, 3H), 4.00 (s, 3H), 6.53 (d, 1H), 6.95 (m, 1H), 7.12 (m, 1H), 7.41 (m, 1H), 7.52 (m, 1H), 7.65 (m, 4H), 7.75 (dd, 1H), 8.03 (m, 2H), 8.33 (d, 1H).

›Example 41: Synthesis of Compound 41

Step A: 2-(1-Methyl-1H-imidazol-2-yl)-5-phenyl-4-(2-(pyrrolidin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazine (41)

Following the general procedure described in Example 40, Step B, except using 2-(pyrrolidin-1-yl) ethan-1-ol in place of an amine, 4-chloro-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 40a (prepared as described in Example 40, Step A) produced 2-(1-methyl-1H-imidazol-2-yl)-5-phenyl-4-(2-(pyrrolidin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazine (41) (12.90 mg, 4.90% yield, 97% purity). LCMS(ESI): Calculated [M+2]/2=195.1 Found [M+2]/2=195.2 1 H NMR (DMSO-d 6 , 400 MHz) δ 1.60-1.66 (m, 4H), 2.39-2.44 (m, 4H), 2.81 (t, 2H), 4.02 (s, 3H), 4.65 (t, 2H), 7.05 (d, 1H), 7.06 (d, 1H), 7.32 (t, 1H), 7.37 (s, 1H), 7.40 (t, 2H), 7.69 (s, 1H), 7.71 (d, 1H), 8.08 (d, 1H).

Example 42: Synthesis of Compound 42

›Step A: Ethyl 3-phenyl-1H-pyrrole-2-carboxylate 42b

To a solution of ethynylbenzene 42a (40.0 g, 391.65 mmol) in NMP (400 mL), silver carbonate (10.8 g, 39.16 mmol) and ethyl 2-isocyanoacetate (66.45 g, 587.47 mmol) were added under Ar. The reaction mixture was stirred at 80° C. overnight, then cooled and filtered. Water (400 mL) was added to filtrate and extracted with DCM once (400 mL). DCM was washed with water (10*150 mL). The organic layer dried and evaporated under reduce pressure. Crude compound was purified by flash chromatography (SiO 2 , Hexane-MtBE as a solvent mixture) to give ethyl 3-phenyl-1H-pyrrole-2-carboxylate 42b (5.4 g, 89.0% purity, 22.33 mmol, 5.7% yield).

›Step B: Ethyl 4-bromo-3-phenyl-1H-pyrrole-2-carboxylate 42c

To a solution of ethyl 3-phenyl-1H-pyrrole-2-carboxylate 42b (5.4 g, 25.09 mmol) in DMF (50 mL) N-bromosuccinimide (4.46 g, 25.09 mmol) was added cooling with ice. The reaction mixture was stirred at RT overnight and then poured into water (150 mL). The product was extracted with TBME (3*75 mL). Combined TBME was washed with water (5*50 mL), dried and evaporated under reduce pressure to give ethyl 4-bromo-3-phenyl-1H-pyrrole-2-carboxylate 42c (5.8 g, 70.9% purity, 13.98 mmol, 55.7% yield).

›Step C: Ethyl 4-(2-fluoro-3-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carboxylate 42d

A mixture of 4-bromo-3-phenyl-1H-pyrrole-2-carboxylate 42c (5.7 g, 19.38 mmol), 2-fluoro-3-methoxyphenylboronic acid (3.29 g, 19.38 mmol), cesium carbonate (12.63 g, 38.76 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.58 g, 1.94 mmol) was heated at 100° C. under Argon atmosphere overnight. The reaction mixture was evaporated and crude compound was purified by flash chromatography (SiO 2 , Hexane-MtBE as a solvent mixture) to give ethyl 4-(2-fluoro-3-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carboxylate 42d (3.3 g, 82.5% purity, 8.02 mmol, 41.4% yield).

›Step D: Ethyl 1-amino-4-(2-fluoro-3-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carboxylate 42e

To a solution of ethyl 4-(2-fluoro-3-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carboxylate 42d (2.2 g, 6.48 mmol) in DMF (30 mL) sodium hydride (337.02 mg, 14.04 mmol) was added at 0° C. After 1 hour, O-(2,4-dinitrophenyl) hydroxylamine (1.68 g, 8.43 mmol) in DMF was added dropwise. The reaction mixture was stirred at RT overnight. An aqueous solution of NH 4 Cl was added to reaction mixture, extracted with EtOAc (3*25 mL), combined EtOAc was washed with water (7*15 mL), dried and evaporated under reduce pressure to give ethyl 1-amino-4-(2-fluoro-3-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carboxylate 42e (2.3 g, 78.1% purity, 5.07 mmol, 78.2% yield).

Step E: 6-(2-Fluoro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-ol 42f

To a mixture of ethyl 1-amino-4-(2-fluoro-3-methoxyphenyl)-3-phenyl-1H-pyrrole-2-carboxylate 42e (3.3 g, 9.31 mmol) and 1-methyl-1H-imidazole-2-carbonitrile (997.34 mg, 9.31 mmol) in dioxane (35 mL), sodium hydride (744.81 mg, 31.04 mmol) was added at cooling with ice. The reaction mixture was stirred at 80° C. overnight. An aqueous solution of NH 4 Cl was added to reaction mixture, extracted with EtOAc (3*20 mL), dried and evaporated under reduce pressure to give 6-(2-fluoro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-ol 42f (4.0 g, 51.6% purity, 4.97 mmol, 53.4% yield).

Step F: 4-Chloro-6-(2-fluoro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 42g

The starting material 6-(2-fluoro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-ol 42f (4.0 g, 9.62 mmol) was suspended in phosphoroyl trichloride (14.76 g, 96.23 mmol, 8.97 mL, 10.0 equiv) and ethylbis(propan-2-yl)amine (3.73 g, 28.87 mmol, 5.03 ml, 3.0 equiv) was added at RT. The reaction mixture was heated at 100° C. overnight. The solution was cooled to RT, evaporated under reduced pressure, poured into aqueous solution of NaHCO 3 and the product was extracted with chloroform (3*50 mL), evaporated to give 4-chloro-6-(2-fluoro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 42g (3.1 g, 53.5% purity, 3.82 mmol, 39.7% yield).

Step H: 6-(2-Fluoro-3-methoxyphenyl)-N-((1r,3r)-3-methoxycyclobutyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (42)

A mixture of 4-chloro-6-(2-fluoro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 42g (248.89 mg, 573.66 μmol), (1r,3r)-3-methoxycyclobutan-1-amine hydrochloride (78.94 mg, 573.66 μmol) and ethylbis(propan-2-yl)amine (222.6 mg, 1.72 mmol, 300.0 μL, 3.0 equiv) in DMSO (5 mL) was heated at 100° C. 18h then cooled and purified by HPLC (2-10 min 30-60H 2 O-MeOH+NH 3 ; Flow 30 mL/min; (loading pump 4.0 mL methanol), column: sun fire C18) to give 6-(2-fluoro-3-methoxyphenyl)-N-((1r,3r)-3-methoxycyclobutyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (42) (20.3 mg, 95.0% purity, 38.68 μmol, 6.7% yield) as yellow gum. LCMS(ESI): Calculated [M+1] 499.3 Found [M+1] 499.2.

›Example 43: Synthesis of Compound 43

Step A: rac 6-(2-Fluoro-3-methoxyphenyl)-N-((1R,3R)-3-methoxycyclopentyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (43)

A mixture of 4-chloro-6-(2-fluoro-3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-phenylpyrrolo[2,1-f][1,2,4]triazine 42g (prepared as described in Example 42, Step F) (198.91 mg, 458.47 μmol), rac (1R,3R)-3-methoxycyclopentan-1-amine hydrochloride (69.52 mg, 458.47 μmol) and ethylbis(propan-2-yl)amine (178.08 mg, 1.38 mmol, 240.0 μL, 3.0 equiv) in DMSO (5.0 mL) was heated at 100° C. for 18 h, then cooled and purified by HPLC (2-10 min 30-60H 2 O-MeOH+NH 3 ; Flow 30 mL/min; (loading pump 4.0 mL methanol), column: sun fire C18) to give

›Tables in the description — 24

R 3A is —CH 3 , unsubstituted phenyl, isopropyl, cyclopropyl, R 4A hydrogen, unsubstituted phenyl,

R 5A is hydrogen;	R 6A is methyl, —CH 2 CH 2 NH 2 , or
R 7A is methyl; and	m is 0 or 1.

R 3A is —CH 3 , unsubstituted phenyl, (4-methoxy)-phenyl, or isopropyl;	R 4A is
R 5A is hydrogen;	R 6A is methyl; and	m is 0.

R 3A is —CH 3 or unsubstituted phenyl;	R 4A is
R 5A is hydrogen;	R 6A is methyl; and	m is 0.

R 3A is —CH 3 or unsubstituted phenyl;	R 4A hydrogen, unsubstituted phenyl,
R 5A is hydrogen;	R 6A is methyl; and	m 0.

R 3A is —CH 3 or phenyl;	R 4A
R 5A is hydrogen;	R 7A is methyl; and	m is 0.

R 1A and R 2A are combined to form	R 3A is —CH 3 or phenyl;	R 4A is
R 5A is hydrogen;	R 7A is methyl; and	m is 0.

TABLE A 1-methyl-1H-

Example	173i	CH 3 CN	imidazole	TCFH	Amine
174	148.06 mg,	20 mL	100.98 mg,	139.9 mg,	42.91 mg,
	332.6 μmol		1.23 mmol	499.57 μmol	433.28 μmol
					30.0 μL
175	201.34 mg,	20 mL	92.7 mg,	190.23 mg,	38.71 mg,
	452.28 μmol		1.13 mmol	679.32 μmol	678.43 μmol
					50.0 μL
176	148.91 mg,	20 mL	68.62 mg,	140.7 mg,	32.68 mg,
	334.51 μmol		836.29 μmol	502.44 μmol	435.34 μmol
					40.0 μL
177	150.0 mg,	20 mL	69.27 mg,	142.04 mg,	38.68 mg,
	336.96 μmol		844.25 μmol	507.22 μmol	438.99 μmol
178	151.89 mg,	15 mL	70.04 mg,	143.51 mg,	29.1 mg,
	341.21 μmol		853.59 μmol	512.49 μmol	409.47 μmol
					30.0 μL
179	149.77 mg,	15 mL	69.01 mg,	141.51 mg,	35.15 mg,
	336.43 μmol		841.04 μmol	505.32 μmol	403.71 μmol
					40.0 μL

TABLE B 1-methyl-1H-

Example	181a	imidazole	TCFH	Amine
182	87.65 mg,	41.2 mg,	84.52 mg,	17.2 mg,
	200.82 μmol	501.8 μmol	301.23 μmol	301.23 μmol
				20.0 μL
183	7.91 mg,	3.72 mg,	7.63 mg,	1.63 mg,
	18.13 μmol	45.33 μmol	27.2 μmol	21.75 μmol
184	220.0 mg,	103.52 mg,	212.26 mg,	67.43 mg,
	504.05 μmol	1.26 mmol	756.52 μmol	756.52 μmol
185	89.9 mg,	42.28 mg,	86.68 mg,	35.0 mg,
	205.96 μmol	514.91 μmol	308.95 μmol	268.84 μmol,
				40.0 μL

TABLE C — Compounds and Analytical Data Amount Table note: *Amount and yield refer to the final total amount obtained and yield in the last step of the synthesis of the respective compound, respectively.

Example	Structure	Name	(Yield)*	Purity
152
N-((1r,3r)-3-(2- methoxyethoxy)cyclo- butyl)-5-methyl-2-(1- methyl-1H- imidazol-2- yl)-6-(pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin- 4-amine	3.0 mg (2.3%)	90%
153
N-((1s,3s)-3- methoxy- cyclobutyl)- 5-methyl- 2-(1-methyl- 1H-imidazol-2-yl)-6- (pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin- 4-amine	3.7 mg (3.1%)	96%
154
rac N-((1R,3R)-3- methoxy- cyclopentyl)- 5-methyl-2- (1-methyl- 1H-imidazol- 2-yl)-6- (pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin- 4-amine	2.6 mg (2.1%)	96%
155
rac N- ((1R,3S)-3- methoxy- cyclopentyl)- 5-methyl-2- (1-methyl- 1H-imidazol- 2-yl)-6- (pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin- 4-amine	22.0 mg (17.7%)	100%
156
5-Methyl-2- (1-methyl- 1H-imidazol- 2-yl)-6- (pyridin-3-yl)-N- (pyrimidin-4- yl)pyrrolo[2,1- f][1,2,4]triazin- 4-amine	14.0 mg (11.9%)	100%
157
N-(4- Methoxy- pyridin- 2-yl)-5- methyl-2-(1- methyl-1H- imidazol-2- yl)-6- (pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4- amine	17.0 mg (13.4%)	100%
158
N-(4- Methoxy- pyrimidin-2- yl)-5-methyl- 2-(1-methyl- 1H-imidazol- 2-yl)-6- (pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin- 4-amine	16.0 mg (12.6%)	100%
161
N-((1r,3r)-3-(2- Methoxy- ethoxy)cyclo- butyl)- 6-(2-methoxy- pyridin-4-yl)- 5-methyl-2- (1-methyl- 1H-imidazol-2- yl)pyrrolo[2,1- f][1,2,4]triazin- 4-amine	8.4 mg (3.2%)	100%
162
N-((1s,3s)-3- Methoxycyclobutyl)-6- (2-methoxypyridin-4- yl)-5-methyl-2-(1- methyl-1H-imidazol-2- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	9.2 mg (3.9%)	100%
163
rac N-((1R,3R)-3- Methoxycyclopentyl)- 6-(2-methoxypyridin-4- yl)-5-methyl-2-(1- methyl-1H-imidazol-2- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	23.0 mg (9.5%)	100%
164
rac N-((1R,3S)-3- Methoxycyclopentyl)- 6-(2-methoxypyridin-4- yl)-5-methyl-2-(1- methyl-1H-imidazol-2- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	4.7 mg (2.0%)	99%
167
N-(6- Methoxypyrimidin-4- yl)-2-(1-methyl-1H- imidazol-2-yl)-5- (pyridin-2-yl)-6- (pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	27.7 mg (21.4%)	100%
168
N-((1r,3r)-3- Methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5-(pyridin-2-yl)- 6-(pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	3.0 mg 2.4%	96%
170
N-(6- Methoxypyrimidin-4- yl)-2-(1-methyl-1H- imidazol-2-yl)-5,6- di(pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	Write up	100%
171
N-((1r,3r)-3- Methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5,6-di(pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	4.2 mg (3.4%)	93%
174
4-((4-Methoxypyridin- 2-yl)amino)-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3-yl)-N-(2,2,2- trifluoro- ethyl)pyrrolo[2,1- f][1,2,4]triazine-5- carboxamide	16.9 mg (9.6%)	100%
175
N-Cyclopropyl-4-((4- methoxypyridin-2- yl)amino)-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazine-5- carboxamide	23.6 mg (10.7%)	99%
176
N-(2-Methoxyethyl)-4- ((4-methoxypyridin-2- yl)amino)-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazine-5- carboxamide	13.7 mg (8.2%)	100%
177
N-(2- (Dimethylamino)ethyl)- 4-((4-methoxypyridin- 2-yl)amino)-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazine-5- carboxamide	14.1 mg (8.1%)	100%
178
(4-((4-Methoxypyridin- 2-yl)amino)-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-5- yl)(pyrrolidin-1- yl)methanone	16.0 mg (9.4%)	99%
179
(4-((4-Methoxypyridin- 2-yl)amino)-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-5- yl)(morpho- lino)methanone	24.0 mg (13.8%)	100%
182
rac N-Cyclopropyl-4- (((1S,3S)-3- methoxycyclo- pentyl)amino)-2- (1-methyl-1H- imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazine-5- carboxamide	10.4 mg (10.9%)	100%
183
rac 4-(((1S,3S)-3- Methoxycyclo- pentyl)amino)-N-(2- methoxyethyl)-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazine-5- carboxamide	4.2 mg (47.2%)	98%
184
rac 4-(((1S,3S)-3- methoxycyclo- pentyl)amino)-N-(3- methoxypropyl)-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazine-5- carboxamide	5.8 mg (2.3%)	100%
185
rac 4-(((1S,3S)-3- methoxycyclo- pentyl)amino)-2- (1-methyl-1H- imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(2- morpholino- ethyl)pyrrolo[2,1- f][1,2,4]triazine- 5-carboxamide	15.7 mg (13.9%)	100%
191
N-((1s,3s)-3- Methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5-phenyl-6- (pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	25.2 mg (20.1%)	99%
192
N-((1r,3r)-3- Methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5-phenyl-6- (pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	27.0 mg (21.6%)	99%
193
rac N-((1R,3S)-3- Methoxycyclopentyl)- 2-(1-methyl-1H- imidazol-2-yl)-5- phenyl-6-(pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	23.6 mg (18.5%)	100%
194
rac N-((1S,3S)-3- Methoxycyclopentyl)- 2-(1-methyl-1H- imidazol-2-yl)-5- phenyl-6-(pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	27.8 mg (21.8%)	100%
195
N-(2-Methoxyethyl)-2- (1-methyl-1H-imidazol- 2-yl)-5-phenyl-6- (pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	15.8 mg (13.6%)	99%
196
N-(4-Methoxypyridin- 2-yl)-2-(1-methyl-1H- imidazol-2-yl)-5- phenyl-6-(pyridin-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	24.1 mg (18.6%)	100%
197
rac N-((1R,2R)-2- methoxycyclopropyl)- 2-(1-methyl-1H- imidazol-2-yl)-5- phenyl-6-(pyridin-4- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	6.0 mg (5.0%)	100%
198
N-((1s,3s)-3- Methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5-phenyl-6- (pyridin-4- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	19.3 mg (15.7%)	98%
199
N-((1r,3r)-3- Methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5-phenyl-6- (pyridin-4- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	8.3 mg (6.7%)	95%
200
rac N-((1R,3S)-3- Methoxycyclopentyl)- 2-(1-methyl-1H- imidazol-2-yl)-5- phenyl-6-(pyridin-4- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	18.4 mg (14.4%)	98%
201
rac N-((1S,3S)-3- Methoxycyclopentyl)- 2-(1-methyl-1H- imidazol-2-yl)-5- phenyl-6-(pyridin-4- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	14.8 mg (11.6%)	98%
202
N-(2-Methoxyethyl)-2- (1-methyl-1H-imidazol- 2-yl)-5-phenyl-6- (pyridin-4- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	10.2 mg (8.8%)	95%
206
6-(4- (Aminomethyl)phenyl)- N-((1r,3r)-3- methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5- phenylpyrrolo[2,1- f][1,2,4]triazin-4-amine hydrochloride salt	8.3 mg (3.0%)	98%
207
6-(4-(2- Aminoethyl)phenyl)-N- ((1r,3r)-3- methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5- phenylpyrrolo[2,1- f][1,2,4]triazin-4-amine hydrochloride salt	41 mg (7.7%)	97%
208
6-(4-(2- Aminoethoxy)phenyl)- N-((1r,3r)-3- methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5- phenylpyrrolo[2,1- f][1,2,4]triazin-4-amine hydrochloride salt	41 mg (7.7%)	95%
209
6-(3-Methoxy-2- methylphenyl)-N- ((1r,3r)-3- methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5- phenylpyrrolo[2,1- f][1,2,4]triazin-4-amine	59.5 mg 96%	98%
210
6-(2,3- Dihydrobenzofuran-4- yl)-N-((1r,3r)-3- methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5- phenylpyrrolo[2,1- f][1,2,4]triazin-4-amine	26.8 mg 7.4%	95%
213
3-Methoxy-N-(2-(1- methyl-1H-imidazol-2- yl)-5,6- diphenylpyrrolo[2,1- f][1,2,4]triazin-4- yl)propane-1- sulfonamide	47 mg (36.2%)	100%
214
(1r,3r)-3-Methoxy-N- (2-(1-methyl-1H- imidazol-2-yl)-5,6- diphenylpyrrolo[2,1- f][1,2,4]triazin-4- yl)cyclobutane-1- sulfonamide	8.5 mg (14.8%)	98%
218
N-((1r,3r)-3- Methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-6-(4- methylpyridin-3-yl)-5- phenylpyrrolo[2,1- f][1,2,4]triazin-4-amine	5.0 mg (1.1%)	97%
219
6-(2,3- Dimethoxyphenyl)-N- ((1r,3r)-3- methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5- phenylpyrrolo[2,1- f][1,2,4]triazin-4-amine	80.7 mg (10.7%)	100%
220
4-((4-Methoxypyridin- 2-yl)oxy)-5-methyl-2- (1-methyl-1H-imidazol- 2-yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazine	8.4 mg (6.6%)	95%
221
N-(5-Methyl-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)- 2,3-dihydrofuro[3,2- c]pyridin-6-amine	3.9 mg (3.0%)	100%
222
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(4- morpholinopyridin-2- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	60 mg (39.6%)	100%
223
N-(4-Methoxypyridin- 2-yl)-N,5-dimethyl-2- (1-methyl-1H-imidazol- 2-yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	21.9 mg (15.9%)	96%
224
N-(5-Methoxypyridin- 2-yl)-5-methyl-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	21.9 mg (16.4%)	98%
225
N-(5-Methoxypyridin- 2-yl)-N,5-dimethyl-2- (1-methyl-1H-imidazol- 2-yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	3.5 mg (2.6%)	97%
226
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(5-methylpyridin- 2-yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	27.5 mg (21.4%)	100%
227
N5,N5-Dimethyl-N2-(5- methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4- yl)pyridine-2,5-diamine	39.0 mg (29.5%)	100%
228
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(5-(pyrrolidin-1- yl)pyridin-2- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	22.0 mg (15.0%)	100%
229
N-(5-Ethoxypyridin-2- yl)-5-methyl-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	63.5 mg (41.9%)	100%
230
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(5-(2,2,2- trifluoroethoxy)pyridin- 2-yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	13.9 mg (8.9%)	99%
231
N-(5- (Difluorometh- oxy)pyridin-2-yl)- 5-methyl-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	13.9 mg (9.6%)	100%
232
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(5-(trifluoro- methoxy)pyridin-2- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	31.0 mg (20.5%)	100%
233
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(5- (trifluoromethyl)pyridin- 2-yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	26.0 mg (17.8%)	100%
234
N-(5- (Difluoromethyl)pyridin- 2-yl)-5-methyl-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	6.5 mg (4.6%)	99%
235
N-(4-Methoxy-5- methylpyridin-2-yl)-5- methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	33.0 mg (23.9%)	100%
236
N-(5-Methoxy-4- methylpyridin-2-yl)-5- methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	32.1 mg (25.8%)	96%
237
N-(5-Fluoro-4- methoxypyridin-2-yl)- 5-methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	14.0 mg (10.0%)	100%
238
N-(5-Cyclopropyl-4- methoxypyridin-2-yl)- 5-methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	33.0 mg (22.6%)	100%
239
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-4-(5-methyl-2,3- dihydro-1H- pyrrolo[2,3-b]pyridin-1- yl)pyrrolo[2,1- f][1,2,4]triazine	19.0 mg (13.9%)	100%
240
2-(2-((5-Methyl-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4- yl)amino)pyridin-4- yl)propan-2-ol	42.0 mg (29.3%)	100%
241
2-(6-((5-Methyl-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4- yl)amino)pyridin-3- yl)propan-2-ol	23.2 mg (16.2%)	100%
242
N-(5-(1H-Imidazol-1- yl)pyridin-2-yl)-5- methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	47.0 mg (45.2%)	100%
243
5-Methyl-N-(5-(2- methyl-1H-imidazol-1- yl)pyridin-2-yl)-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	31.0 mg (22.5%)	100%
244
N-(4-Methoxy-5-(4- methyl-1H-imidazol-1- yl)pyridin-2-yl)-5- methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	16.0 mg (24.2%)	100%
245
N-(4-(1H-imidazol-1- yl)pyridin-2-yl)-5- methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	46.0 mg (31.7%)	100%
246
5-Methyl-N-(4-(2- methyl-1H-imidazol-1- yl)pyridin-2-yl)-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	23.0 mg (15.4%)	100%
247
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(5- morpholinopyridin-2- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	38.6 mg (26.8%)	100%
248
N-([2,4′-Bipyridin]-2′- yl)-5-methyl-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	43.0 mg (29.0%)	100%
249
N-([2,3′-Bipyridin]-6′- yl)-5-methyl-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	84.0 mg (28.2%)	100%
250
N-([3,4′-Bipyridin]-2′- yl)-5-methyl-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	50.0 mg (33.7%)	100%
251
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-4-(5- (trifluoromethyl)-2,3- dihydro-1H- pyrrolo[2,3-b]pyridin-1- yl)pyrrolo[2,1- f][1,2,4]triazine	18.0 mg (11.6%)	98%
252
N-(5-Methoxy-1H- pyrazol-3-yl)-5-methyl- 2-(1-methyl-1H- imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	11 mg (8.8%)	93%
253
N-(5-Methoxy-1- methyl-1H-pyrazol-3- yl)-5-methyl-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	42.0 mg (32.8%)	100%
254
N-(5- (Difluoromethoxy)-1- methyl-1H-pyrazol-3- yl)-5-methyl-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	11.1 mg (8.1%)	100%
255
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(5-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	41.0 mg (34.5%)	100%
256
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	23.0 mg (20.2%)	100%
257
N-(5-Cyclobutyl-1H- pyrazol-3-yl)-5-methyl- 2-(1-methyl-1H- imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	9.8 mg (7.5%)	100%
258
N-(5-(Difluoromethyl)- 1H-pyrazol-3-yl)-5- methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	3.1 mg (2.3%)	94%
259
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(5- (trifluoromethyl)-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	17.7 mg (13.1%)	96%
260
N-(5-Ethoxy-1H- pyrazol-3-yl)-5-methyl- 2-(1-methyl-1H- imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	13.0 mg (10.0%)	100%
261
5-Amino-2-(5-methyl- 2-(1-methyl-1H- imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-yl)- 1,2-dihydro-3H- pyrazol-3-one	7.7 mg 6.5%	100%
262
3-((5-Methyl-2-(1- methyl-1H-imidazol-2- yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4- yl)oxy)-1H-pyrazol-5- amine	13.9 mg (11.7%)	92%
263
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(5-phenyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	43 mg (31.2%)	100%
264
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(5-(pyridin-3-yl)- 1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	3.5 mg (2.5%)	100%
265
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(5-(pyridin-2-yl)- 1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	31 mg (22.5%)	100%
266
5-Methyl-2-(1-methyl- 1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)-N-(5-(pyridin-4-yl)- 1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	31 mg (22.5%)	100%
267
N-(4,5-Dimethyl-1H- pyrazol-3-yl)-5-methyl- 2-(1-methyl-1H- imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	10.6 mg (8.6%)	100%
268
N-(5-Isopropyl-1H- pyrazol-3-yl)-5-methyl- 2-(1-methyl-1H- imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	25 mg (19.7%)	95%
269
6-(3-Methoxy-2- methylphenyl)-N- ((1s,3s)-3- methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5- phenylpyrrolo[2,1- f][1,2,4]triazin-4-amine	77 mg, (22.1%)	100%
270
rac 6-(3-Methoxy-2- methylphenyl)-N- ((1R,3R)-3- methoxycyclopentyl)-2- (1-methyl-1H-imidazol- 2-yl)-5- phenylpyrrolo[2,1- f][1,2,4]triazin-4-amine	84 mg (23.6%)	100%
271
rac 6-(3-Methoxy-2- methylphenyl)-N- ((1R,3S)-3- methoxycyclopentyl)-2- (1-methyl-1H-imidazol- 2-yl)-5- phenylpyrrolo[2,1- f][1,2,4]triazin-4-amine	76.0 mg (21.2%)	100%
272
rac 6-(3-Methoxy-2- methylphenyl)-N- ((1R,2R)-2- methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5- phenylpyrrolo[2,1- f][1,2,4]triazin-4-amine	51.0 mg (14.7%)	100%
273
6-(2,6-Difluoro-3- methoxyphenyl)-N- ((1r,3r)-3- methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5- phenylpyrrolo[2,1- f][1,2,4]triazin-4-amine	60 mg (31.1%)	95%
274
6-(3-Methoxy-2- methylphenyl)-N- ((1r,3r)-3- methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-5-(pyridin-2- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	258.1 mg (53.3%)	95%
275
5-Cyclopropyl-N- ((1r,3r)-3- methoxycyclobutyl)-2- (1-methyl-1H-imidazol- 2-yl)-6-(1-methyl-1H- pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	17.1 mg (22.2%)	100%
276
5-Cyclopropyl-N-(4- methoxypyridin-2-yl)- 2-(1-methyl-1H- imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3- yl)pyrrolo[2,1- f][1,2,4]triazin-4-amine	35.4 mg (23.6%)	100%
	Example	Calc′d [M + 1]	Found [M + 1]	1 H NMR
	152	434.2	434.4
	153	390.2	390.4
	154	404.2	404.4
	155	404.2	404.2	500 MHz, DMSO-d 6 ) δ
				(ppm) 1.90 (m, 6H), 2.51
				(s, 3H), 3.12 (s, 3H), 3.97
				(s, 3H), 4.76 (m, 1H), 6.97
				(m, 2H), 7.27 (s, 1H), 7.47
				(dd, 1H), 7.88 (d, 1H), 7.96
				(s, 1H), 8.52 (d, 1H), 8.67
				(d, 1H).
	156	384.2	384.0
	157	413.2	413.2
	158	414.2	414.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 3.72 (s, 3H), 3.97 (m,
				6H), 6.42 (m, 1H), 7.00 (m,
				1H), 7.34 (m, 2H), 7.85 (m,
				2H), 8.30 (m, 1H), 8.47 (m,
				1H), 8.75 (m, 1H).
	161	464.2	464.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 2.31 (m, 4H), 2.57 (s,
				3H), 3.45 (m, 5H), 3.85 (s,
				3H), 3.91 (s, 3H), 4.15 (m,
				2H), 4.73 (m, 2H), 6.90 (m,
				1H), 6.97 (m, 1H), 7.12 (m,
				1H), 7.25 (m, 2H), 8.02 (m,
				1H), 8.15 (d, 1H).
	162	420.2	420.0	(500 MHz, CD 3 OD) δ (ppm)
				2.06 (m, 2H), 2.61 (s, 3H),
				2.80 (m, 2H), 3.27 (s, 3H),
				2.68 (m, 1H), 3.91 (s, 3H),
				4.08 (s, 3H), 4.53 (m, 1H),
				6.88 (m, 1H), 7.10 (m, 3H),
				7.80 (m, 1H), 8.12 (d, 1H).
	163	434.2	434.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 1.95 (m, 6H), 2.62 (m,
				3H), 3.21 (s, 3H), 3.95 (m,
				6H), 4.80 (m, 1H), 6.94 (m,
				2H), 7.35 (m, 3H), 8.21 (m,
				2H).
	164	434.2	434.2	(500 MHz, CD 3 OD) δ (ppm)
				1.98 (m, 6H), 2.53 (s, 3H),
				3.38 (s, 3H), 3.89 (s, 3H),
				3.99 (m, 1H), 4.02 (s, 3H),
				4.98 (m, 1H), 6.83 (m, 1H),
				7.10 (m, 3H), 7.71 (s, 1H),
				8.10 (d, 1H).
	167	477.1	477.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 3.88 (s, 3H), 4.01 (s,
				3H), 6.98 (m, 1H), 7.08 (d,
				1H), 7.38 (m, 3H), 7.73 (m,
				2H), 8.30 (m, 2H), 8.52 (m,
				3H), 8.79 (d, 1H), 14.37 (s,
				1H).
	168	453.2	453.2
	170	477.2	477.2
	171	453.2	453.2
	174	527.2	527.2
	175	485.2	485.2
	176	503.2	503.2
	177	516.2	516.2
	178	499.2	499.2
	179	515.2	515.2
	182	476.2	476.2
	183	494.2	494.2
	184	508.3	508.2
	185	549.3	549.2
	191	452.2	452.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 1.34 (m, 2H), 2.60 (m,
				2H), 3.04 (s, 3H), 3.68 (q,
				1H), 3.93 (s, 3H), 4.16 (q,
				1H), 5.33 (d, 1H), 6.97 (s,
				1H), 7.25 (m, 2H), 7.43 (m,
				2H), 7.55 (m, 4H), 8.25 (s,
				1H), 8.38 (m, 1H), 8.45 (m,
				1H).
	192	452.2	452.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 1.80 (m, 2H), 2.21 (m,
				2H), 3.05 (s, 3H), 3.78 (m,
				1H), 3.91 (s, 3H), 4.43 (m,
				1H), 5.41 (d, 1H), 6.97 (s,
				1H), 7.26 (m, 2H), 7.45 (m,
				2H), 7.55 (m, 4H), 8.26 (s,
				1H), 8.42 (m, 1H), 8.46 (d,
				1H).
	193	466.2	466.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 1.41 (m, 4H), 1.90 (m,
				2H), 2.82 (s, 3H), 3.69 (m,
				1H), 3.98 (s, 3H), 4.60 (m,
				1H), 5.62 (d, 1H), 6.96 (s,
				1H), 7.25 (m, 2H), 7.86 (m,
				2H), 7.49 (m, 4H), 8.21 (s,
				1H), 8.43 (m, 2H).
	194	466.2	466.2
	195	426.2	426.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 3.07 (s, 3H), 3.34 (t,
				2H), 3.55 (t, 2H), 3.96 (s,
				3H), 5.63 (m, 1H), 6.98 (s,
				1H), 7.25 (m, 2H), 7.39 (m,
				2H), 7.48 (m, 3H), 7.55 (d,
				1H), 8.21 (s, 1H), 8.35 (d,
				1H), 8.43 (s, 1H).
	196	475.2	475.2
	197	438.2	438.2	(500 MHz, CD 3 OD) δ (ppm)
				0.51 (m, 1H), 1.02 (m, 1H),
				3.00 (m, 3H), 3.30 (s, 3H),
				4.13 (s, 3H), 7.25 (m, 6H),
				7.51 (m, 3H), 8.30 (m, 3H).
	198	452.2	452.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 1.32 (m, 2H), 2.58 (m,
				2H), 3.02 (s, 3H), 3.54 (m,
				1H), 3.91 (s, 3H), 4.11 (m,
				1H), 5.30 (m, 1H), 6.97 (s,
				1H), 7.20 (m, 3H), 7.50 (m,
				5H), 8.36 (m, 3H).
	199	452.2	452.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 1.80 (m, 2H), 2.21 (m,
				2H), 3.06 (s, 3H), 3.78 (m,
				1H), 3.92 (s, 3H), 4.46 (m,
				1H), 5.41 (m, 1H), 6.92 (s,
				1H), 7.19 (m, 2H), 7.29 (s,
				1H), 7.49 (m, 2H), 7.58 (m,
				3H), 8.40 (m, 3H).
	200	466.2	466.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 1.60 (m, 6H), 2.89 (s,
				3H), 3.66 (m, 1H), 3.96 (s,
				3H), 4.60 (m, 1H), 5.60 (d,
				1H), 6.93 (s, 1H), 7.09 (m,
				2H), 7.22 (m, 1H), 3.38 (m,
				2H), 7.50 (m, 3H), 8.32 (m,
				3H).
	201	466.2	466.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 1.08 (m, 1H), 1.27 (m,
				1H), 1.52 (m, 2H), 1.91 (m,
				2H), 3.09 (s, 3H), 3.61 (m,
				1H), 3.97 (s, 3H), 4.36 (m,
				1H), 5.10 (d, 1H), 6.98 (s,
				1H), 7.20 (m, 3H), 7.50 (m,
				5H), 8.33 (m, 3H).
	202	426.2	426.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 3.03 (s, 3H), 3.31 (t,
				2H), 3.51 (t, 2H), 4.92 (s,
				3H), 5.60 (t, 1H), 6.94 (d,
				1H), 7.12 (m, 2H), 7.28 (s,
				1H), 7.40 (m, 2H), 7.52 (m,
				3H), 8.38 (m, 3H).
	206	480.2	480.2
	207	494.3	494.2
	208	496.2	494.2
	209	495.2	495.2
	210	493.2	493.2
	213	503.2	503.0
	214	515.2	515.0
	218	466.2	466.2
	219	511.2	511.4
	220	417.1	417.2
	221	428.2	428.0	(500 MHz, DMSO-d 6 ) δ
				(ppm) 2.88 (s, 3H), 3.20 (t,
				2H), 3.80 (s, 3H), 4.01 (s,
				3H), 4.61 (t, 2H), 6.51 (d,
				1H), 6.58 (d, 1H), 7.15 (d,
				1H), 7.46 (d, 1H), 7.69 (d,
				1H), 7.81 (s, 1H), 8.08 (d,
				1H), 14.91 (s, 1H).
	222	[M + 2]/2 =	[M + 2]/2 =
		236.1	236.2
	223	430.2	430.2
	224	416.2	416.2
	225	430.2	430.2
	226	400.2	400.2
	227	429.2	429.2
	228	455.2	4.6
	229	430.2	430.2
	230	484.1	484.0
	231	452.1	452.0
	232	470.1	470.0
	233	454.1	454.0
	234	436.1	436.0
	235	430.2	430.2
	236	430.2	430.2
	237	434.1	434.2
	238	456.2	456.2
	239	426.2	426.2
	240	444.2	444.4
	241	444.2	444.2
	242	452.2	452.2
	243	[M + 2]/2 =	[M + 2]/2 =
		233.6	233.6
	244	[M + 2]/2 =	[M + 2]/2 =
		248.6	248.6
	245	452.2	452.2
	246	[M + 2]/2 =	[M + 2]/2 =	(500 MHz, DMSO-d 6 ) δ
		233.6	233.6	(ppm) 2.32 (s, 3H), 2.86 (s,
				3H), 3.95 (m, 6H), 6.56 (d,
				1H), 6.98 (m, 1H), 7.34 (m,
				4H), 7.71 (m, 1H), 8.46 (m,
				3H), 14.61 (s, 1H).
	247	471.2	471.2
	248	463.2	463.0
	249	463.2	463.2
	250	463.2	463.0
	251	480.2	480.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 2.26 (s, 3H), 3.27 (t,
				2H), 3.35 (s, 3H), 3.95 (s,
				3H), 4.37 (t, 2H), 6.60 (s,
				1H), 7.01 (s, 1H), 7.34 (s,
				1H), 7.73 (d, 1H), 7.96 (d,
				1H), 8.30 (d, 1H), 8.36 (d,
				1H).
	252	405.1	405.2	(500 MHz, CD 3 OD) δ (ppm)
				2.74 (s, 3H), 3.85 (s, 3H),
				3.97 (s, 3H), 4.01 (s, 3H),
				5.75 (m, 1H), 6.48 (d, 1H),
				7.07 (d, 1H), 7.20 (d, 1H),
				7.70 (d, 1H), 7.96 (s, 1H),
				NH is not observed.
	253	419.2	419.2
	254	455.1	455.0
	255	389.2	389.0	(500 MHz, DMSO-d 6 ) δ
				(ppm) 2.19 (s, 3H), 2.74 (s,
				3H), 3.82 (s, 3H), 4.01 (s,
				3H), 5.88 (s, 1H), 6.49 (d,
				1H), 7.11 (s, 1H), 7.49 (d,
				1H), 7.68 (m, 2H), 12.48 (m,
				1H), 12.97 (m, 1H).
	256	375.2	375.0
	257	429.2	429.2
	258	425.1	425.2
	259	443.1	443.2
	260	419.2	419.2	(500 MHz, CD 3 OD) δ (ppm)
				1.31 (t, 3H), 2.71 (s, 3H),
				3.89 (s, 3H), 3.98 (s, 3H),
				4.11 (m, 2H), 5.77 (m, 1H),
				6.48 (d, 1H), 7.08 (d, 1H),
				7.21 (d, 1H), 7.61 (d, 1H),
				7.96 (m, 1H).
	261	391.1	391.0
	262	391.1	391.0
	263	451.2	451.0
	264	452.2	452.2
	265	452.2	452.0
	266	452.2	452.2
	267	403.2	403.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 1.89 (s, 3H), 2.10 (s,
				3H), 2.73 (s, 3H), 3.82 (s,
				3H), 3.99 (s, 3H), 6.49 (s,
				1H), 7.09 (s, 1H), 7.41 (d,
				1H), 7.63 (m, 2H), 12.32 (m,
				1H), 12.81 (m, 1H).
	268	417.2	417.2
	269	495.2	495.2
	270	509.3	509.2
	271	509.3	509.2
	272	495.2	495.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 1.09 (m, 1H), 1.43 (m,
				1H), 1.78 (s, 3H), 1.98 (m,
				2H), 3.09 (s, 3H), 3.40 (m,
				1H), 3.71 (s, 3H), 3.99 (s,
				3H), 4.41 (m, 1H), 5.81 (m,
				1H), 6.70 (d, 1H), 6.83 (m,
				1H), 7.02 (m, 2H), 7.52 (m,
				6H), 7.83 (s, 1H).
	273	517.2	517.2
	274	496.2	496.2	(500 MHz, DMSO-d 6 ) δ
				(ppm) 1.75 (s, 3H), 2.30 (m,
				4H), 3.12 (s, 3H), 3.72 (s,
				3H), 3.91 (s, 3H), 4.09 (m,
				1H), 4.60 (m, 1H), 6.82 (m,
				2H), 6.98 (m, 2H), 7.22 (m,
				3H), 7.58 (m, 1H), 7.76 (s,
				1H), 8.69 (s, 1H), 11.86 (d,
				1H).
	275	419.2	419.2
	276	442.2	442.2

TABLE 2 — Inhibition of Smad2/3, JNK, and MAPK p38 (at 10 μM), each in Panc-1 pancreatic cancer cell line % inh of Smad2/3 ND = not determined.

	phosphorylation	% inh of JNK	% inh of MAPK
Compound	in Panc-1	in Panc-1	p38 in Panc-1
1	ND	F*	H*
2	ND	F*	H*
3	ND	H*	H*
4	ND	G*	G*
5	ND	ND	ND
6	0	H*	E*
7	ND	H*	H*
8	0	E*	H*
9	0	F*	G*
10	A	E*	G*
11	0	G*	G*
12	0	E*	H*
13	0	H*	H*
14	0	F*	H*
15	0	F*	H*
16	0	F*	H*
17	ND	0	0
18	ND	F*	H*
19	ND	F*	H*
20	ND	H*	H*
21	ND	H*	H*
22	ND	H*	H*
23	0	H*	H*
24	B	H*	H*
25	0	H*	H*
26	C	H*	H*
27	D	H*	H*
28	0	H*	H*
29	D	H	H
30	D	F	F
31	D	H*	H*
32	D	H	H
33	D	G	H
34	ND	H	H
35	A	H*	H*
36	D	H*	H*
37	ND	ND	ND
38	0	ND	ND
39	ND	ND	ND
40	B	ND	ND
41	A*	ND	ND
42	0	H*	H*
43	D	H*	H*
44	D	H*	H*
45	0	H*	H*
46	0	H*	H
47	D	H*	F
48	B	ND	ND
49	B	ND	ND
50	B	ND	ND
51	D	H*	H*
52	D	0	F*
53	B	H*	H*
54	A	H*	H*
55	D	H*	H*
56	D*	H*	H*
57	A*	H*	E*
58	C	H*	G*
59	D	H*	H*
60	C	H*	H*
61	B	H*	H*
62	A*	H*	H*
63	D*	H*	H*
64	A	H*	H*
65	A*	H*	H*
66	A*	H*	H*
67	0	H*	H*
68	A*	ND	ND
69	A	H*	H*
70	0	H*	H*
71	0	H*	H*
72	0	H*	H*
73	B*	ND	ND
74	A*	ND	ND
75	A	ND	ND
76	B	ND	ND
77	C	ND	ND
78	A	ND	ND
79	B*	ND	ND
80	B*	ND	ND
81	A*	ND	ND
82	ND	ND	ND
83	B*	ND	ND
84	C*	ND	ND
85	D	ND	ND
86	B*	ND	ND
87	B*	ND	ND
88	C*	ND	ND
89	C*	ND	ND
90	C*	ND	ND
91	0	ND	ND
92	A*	ND	ND
93	A	H*	H*
94	B*	ND	ND
95	C*	ND	ND
96	D	ND	ND
97	D	ND	ND
98	D	ND	ND
99	D	ND	ND
100	C*	ND	ND
101	D*	ND	ND
102	A*	ND	ND
103	C*	ND	ND
104	D*	ND	ND
105	A	ND	ND
106	D*	ND	ND
107	A	ND	ND
108	D*	ND	ND
109	D*	ND	ND
110	A*	ND	ND
111	D*	ND	ND
112	D*	ND	ND
113	D*	ND	ND
114	D*	ND	ND
115	A	ND	ND
116	D	ND	ND
117	A	ND	ND
118	A*	ND	ND
119	B*	ND	ND
120	A*	ND	ND
121	A	ND	ND
122	C	ND	ND
123	B	ND	ND
124	A	ND	ND
125	B	ND	ND
126	A*	ND	ND
127	A	ND	ND
128	A	ND	ND
129	D*	ND	ND
130	C	ND	ND
131	0	ND	ND
132	A*	ND	ND
133	A	ND	ND
134	B	ND	ND
135	A*	ND	ND
136	A	ND	ND
137	C	ND	ND
138	A*	ND	ND
139	A*	ND	ND
140	A	ND	ND
141	D	ND	ND
142	C	ND	ND
143	A	ND	ND
144	D	ND	ND
145	B*	ND	ND
146	C	ND	ND
147	C	ND	ND
148	A	ND	ND
149	A	ND	ND
150	A	ND	ND
151	A	ND	ND
152	A	ND	ND
153	C	ND	ND
154	C	ND	ND
155	A	ND	ND
156	D	ND	ND
157	B*	ND	ND
158	B*	ND	ND
159	C	ND	ND
160	A*	ND	ND
161	B	ND	ND
162	A	ND	ND
163	B	ND	ND
164	A*	ND	ND
165	B*	ND	ND
166	C*	ND	ND
167	0	ND	ND
168	A*	ND	ND
169	C	ND	ND
170	A	ND	ND
171	B	ND	ND
172	A	ND	ND
173	D*	ND	ND
174	A*	ND	ND
175	B*	ND	ND
176	B	ND	ND
177	A	ND	ND
178	B*	ND	ND
179	C*	ND	ND
180	ND	ND	ND
181	A	ND	ND
182	A*	ND	ND
183	D*	ND	ND
184	B*	ND	ND
185	B*	ND	ND
186	D*	ND	ND
187	A*	ND	E*
188	B	ND	E
189	B	ND	ND
190	A	ND	E
191	A*	ND	E*
192	A*	ND	E*
193	A	ND	E
194	A	ND	E
195	A*	ND	E*
196	C	ND	F
197	C	ND	F
198	A	ND	E
199	B	ND	E
200	A	ND	E
201	A	ND	E
202	A	ND	E
203	D	ND	G
204	A	ND	E
205	D	ND	G
206	B	ND	E
207	D	ND	H
208	D	ND	G
209	D	ND	H
210	D	ND	G
211	D	ND	ND
212	C	ND	F
213	B	ND	F
214	D	ND	G
215	C	ND	F
216	C*	ND	ND
217	C	ND	F
218	B*	ND	F*
219	D	ND	ND
220	C	ND	F
221	A	ND	E
222	A*	ND	ND
223	B	ND	ND
224	0	ND	ND
225	0	ND	ND
226	D	ND	ND
227	C	ND	ND
228	0	ND	ND
229	A*	ND	ND
230	D	ND	ND
231	D	ND	ND
232	B	ND	ND
233	B	ND	ND
234	D	ND	ND
235	0	ND	ND
236	0	ND	ND
237	A	ND	ND
238	0	ND	ND
239	0	ND	ND
240	0	ND	ND
241	C*	ND	ND
242	A	ND	ND
243	A*	ND	ND
244	A*	ND	ND
245	B*	ND	ND
246	C*	ND	ND
247	C*	ND	ND
248	D*	ND	ND
249	0	ND	ND
250	C*	ND	ND
251	A*	ND	ND
252	B*	ND	ND
253	A*	ND	ND
254	B*	ND	ND
255	D*	ND	ND
256	D*	ND	ND
257	D*	ND	ND
258	A*	ND	ND
259	A	ND	ND
260	A*	ND	ND
261	B*	ND	ND
262	B*	ND	ND
263	C	ND	ND
264	A	ND	ND
265	A	ND	ND
266	D*	ND	ND
267	B	ND	ND
268	C	ND	ND
269	D	ND	ND
270	ND	ND	ND
271	ND	ND	ND
272	D	ND	ND
273	D	ND	ND
274	D	ND	ND
275	B	ND	ND
276	B	ND	ND
0 = 0% inhibition,
A = 1-25% inhibition,
B = 26-45% inhibition,
C = 46-75% inhibition,
D = 76-100% inhibition,
E = 1-30% inhibition,
F = 31-74% inhibition,
G = 75-99% inhibition,
H = 100% inhibition,
A* = 1-25% activation,
B* = 26-45% activation,
C* = 46-75% activation,
D* = 76-100% activation,
E* = 1-30% activation,
F* = 31-74% activation,
G* = 75-99% activation,
H* ≥ 100% activation,

TABLE 3 — % Inhibition at 10 μM of Erk1/2, Akt, IL-6, TNF-alpha and MiaPaca-2 proliferation ND = not determined.

	% inh of	% inh of
	Erk1/2	Akt
	phosphor-	phosphor-	Proliferation
	ylation	ylation	in MiaPaca-2:	IL-6:	TNFα:
Compound	in Panc-1	in Panc-1	IC50 (uM)	% inh.	% inh.
1	0	C*	I	H	E
2	B	C*	I	E	F
3	D	B	I	G	F
4	D	0	I	H	H
5	0	0	I	0	0
6	0	0	K	H	F
7	0	0	I	E	0
8	0	0	I	0	0
9	0	0	I	E	0
10	0	0	I	F	0
11	0	0	I	0	0
12	0	0	I	F	0
13	0	0	K	H	0
14	0	0	I	G	0
15	0	0	I	G	0
16	A	0	I	G	0
17	A	D	I	G	F
18	C	D*	I	F	E
19	0	D*	I	H	F
20	D	D	I	H	E
21	0	C*	I	E	0
22	0	A*	K	H	0
23	D	D	I	H	H
24	0	A*	I	F	F
25	0	D	I	E	E
26	D	C	J	G	E
27	0	A*	I	H	F
28	0	A*	I	F	E
29	D	D	J	H	H
30	D	D	J	H	H
31	D	D	I	H	H
32	D	D	K	H	H
33	D	D	J	H	H
34	D	D	J	H	E
35	0	0	I	F	0
36	C	0	I	G	E
37	0	0	I	0	0
38	0	0	I	F	E
39	0	0	I	0	0
40	0	0	I	H	F
41	0	A*	I	E	E
42	D	D	J	H	H
43	D	B	I	F	E
44	B	B	I	F	E
45	0	0	I	H	H
46	0	0	I	H	H
47	C	C*	I	0	E
48	A	D*	L	E	E
49	B*	D*	L	E	E
50	B*	D*	L	E	0
51	0	D*	I	G	F
52	0	B	I	0	E
53	D	A*	L	G	E
54	C	B*	L	F	E
55	A	A*	L	E	E
56	C	B*	K	F	E
57	A*	D*	L	E	0
58	D	A*	L	F	E
59	C	C*	K	F	E
60	A	D*	I	0	0
61	A*	C*	J	E	E
62	A	D*	L	F	E
63	A	D*	L	E	E
64	A	D*	L	E	0
65	A	D*	L	E	E
66	C	D*	I	E	E
67	D	D*	I	H	G
68	D*	D*	L	E	F
69	D*	D*	I	G	E
70	B*	C*	I	G	E
71	D*	D*	I	0	0
72	D*	D*	I	G	E
73	D*	D*	L	G	0
74	D*	D*	K	E	E
75	B	A*	I	E	E
76	0	D*	L	F	F
77	D*	D*	I	E	F
78	D*	D*	K	F	F
79	D*	D*	L	E	F
80	D*	D*	I	0	0
81	0	D*	K	H	G
82	A*	D*	L	H	F
83	D*	D*	K	F	E
84	D*	D*	L	F	0
85	C	D*	I	H	G
86	D*	D*	K	H	E
87	C*	D*	I	0	0
88	0	D*	I	E	E
89	D*	D*	L	H	F
90	D*	A*	I	0	E
91	D*	D*	L	E	E
92	A*	A*	I	G	E
93	D	D*	K	H	H
94	C*	D*	L	G	F
95	D*	D*	L	E	E
96	0	D*	K	G	0
97	D*	D*	L	E	0
98	D*	D*	L	E	0
99	D*	A*	I	H	H
100	C*	D*	L	G	0
101	A*	D*	K	G	0
102	A*	D*	L	H	F
103	A*	C*	I	0	0
104	D*	D*	L	H	0
105	A	C*	J	H	0
106	0	D*	L	G	0
107	D*	C*	L	F	E
108	A*	D*	J	G	0
109	B*	D*	J	G	0
110	B*	C*	L	E	E
111	A*	D*	K	H	G
112	A*	D*	L	F	0
113	D*	D*	L	H	F
114	B*	D*	L	H	G
115	C	D*	L	G	0
116	D*	D*	L	F	0
117	B	B	L	E	E
118	D*	D*	L	F	E
119	A*	D*	J	G	F
120	C*	B*	L	F	E
121	D*	B*	J	G	F
122	A*	C*	L	G	E
123	A*	B*	L	H	F
124	C*	C*	L	F	E
125	A	D*	K	G	E
126	D*	D*	L	F	0
127	D*	D*	L	G	0
128	D*	D*	L	F	F
129	D*	C*	L	G	E
130	B*	D*	I	0	E
131	A*	A	I	0	E
132	0	A	I	0	0
133	A	B	I	0	E
134	B	A	I	E	E
135	D*	D*	L	F	E
136	D*	D*	L	F	E
137	B*	D*	L	E	E
138	D*	D*	L	G	0
139	D*	D*	L	G	E
140	D*	D*	L	G	0
141	B	A	L	F	0
142	C	A	L	F	0
143	D*	D*	L	H	G
144	A	B*	L	F	E
145	C*	D*	L	G	E
146	D*	D*	K	0	E
147	A*	A*	I	0	E
148	C*	A	I	E	E
149	D*	D*	J	H	H
150	A	B*	I	E	0
151	D*	C*	I	0	0
152	B*	B*	I	E	0
153	A	B	I	0	0
154	C*	B*	I	F	0
155	A*	A	I	F	0
156	D*	D*	L	E	0
157	C*	D*	L	E	0
158	A	D*	L	E	0
159	A	B	I	E	0
160	A*	B*	I	H	F
161	A	A*	I	H	G
162	A	B	I	F	F
163	A*	A*	I	H	E
164	A*	A*	I	H	E
165	C*	D*	L	G	E
166	B*	D*	I	H	H
167	A	B*	I	0	0
168	0	0	I	E	F
169	B*	C*	L	E	0
170	A*	C*	L	G	0
171	B	B	I	0	0
172	0	B*	I	E	0
173	C	C*	J	H	0
174	D*	D*	K	E	0
175	D*	D*	K	H	0
176	D*	D*	J	H	0
177	D*	A*	I	H	0
178	D*	D*	I	G	0
179	D*	D*	I	G	0
180	ND	ND	ND	G	F
181	A	B*	I	G	E
182	A*	B*	I	F	E
183	D*	A	I	F	F
184	A*	A*	I	F	F
185	B	A	I	F	F
186	A*	A*	I	E	E
187	A	C*	I	G	E
188	A	A*	I	G	0
189	A*	B	I	0	E
190	D*	D*	I	G	E
191	D*	D*	I	G	E
192	D*	D*	I	H	F
193	D*	D*	I	H	F
194	D*	D*	I	H	G
195	B*	D*	I	G	0
196	D*	D*	L	H	H
197	D*	A*	I	G	F
198	D*	C	I	F	F
199	D*	A	I	H	E
200	D*	B	I	E	E
201	D*	B	I	H	G
202	D*	B	I	G	E
203	D	D	J	H	H
204	D*	C*	I	H	F
205	D*	C*	I	ND	ND
206	B	C	I	H	E
207	D*	C*	I	H	H
208	C*	D*	I	H	F
209	D	D	K	H	H
210	D	D	J	H	H
211	A*	A	I	G	0
212	B*	A*	I	E	0
213	D*	D*	J	F	0
214	A*	A*	I	E	0
215	A*	B*	I	E	F
216	C*	A*	I	G	F
217	D*	D*	L	H	F
218	D*	D*	I	E	E
219	D	D	J	H	H
220	A	A	I	F	E
221	A*	D*	L	F	0
222	A*	D*	L	G	0
223	A	B	I	0	E
224	C*	D*	L	G	E
225	B	A*	I	0	0
226	A*	D*	L	G	F
227	C*	D*	L	G	G
228	A*	D*	L	F	E
229	A	D*	K	B	0
230	D*	D*	L	G	E
231	D*	D*	L	E	0
232	B*	D*	L	F	E
233	D*	D*	L	F	E
234	D*	D*	L	E	E
235	B*	D*	L	C	0
236	D*	B*	K	0	0
237	0	D*	L	0	0
238	A	D*	L	H	G
239	C*	D*	L	G	E
240	A*	D*	L	G	0
241	D*	D*	I	F	E
242	0	D*	I	F	0
243	C*	D*	L	0	0
244	0	D*	L	0	0
245	0	D*	L	F	0
246	0	D*	K	F	0
247	D*	D*	J	H	G
248	C*	D*	L	H	F
249	D*	D*	L	H	E
250	C*	D*	L	H	G
251	B	A	I	ND	ND
252	A*	D*	L	E	0
253	C*	D*	J	F	0
254	D*	D*	I	F	0
255	A	D*	L	G	E
256	C	D*	I	G	0
257	C*	D*	K	H	F
258	A*	A	I	0	0
259	A*	D*	I	G	0
260	A*	C*	I	H	F
261	B	B	I	G	E
262	A	B	I	E	0
263	A	D*	L	H	G
264	B*	D*	K	H	F
265	A*	D*	L	H	F
266	D	D*	L	F	0
267	D*	D*	L	G	E
268	D*	D*	L	H	F
269	D	C	J	H	H
270	D	D	K	H	H
271	D	D	K	H	H
272	D	D	I	H	H
273	D	D	I	H	H
274	D	D	K	H	H
275	0	D*	I	0	0
276	D*	D*	K	G	0
0 = 0% inhibition,
A = 1-25% inhibition,
B = 26-49% inhibition,
C = 50-84% inhibition,
D = 85-100% inhibition,
A* = 1-25% activation,
B* = 26-49% activation,
C* = 46-84% activation,
D* = 85-100% activation,
E = 1-24% inhibition,
F = 25-49% inhibition,
G = 50-74% inhibition,
H = 75-100% inhibition,
E* = 1-24% activation,
F* = 25-49% activation,
G* = 50-74% activation,
H* = 75-100% activation
I = >1 uM IC 50 ,
J = 0.51-1 uM IC 50 ,
K = 0.15-0.5 uM IC 50 ,
L = <0.15 uM IC 50 ,

TABLE 4A — Proliferation assay IC50 data

		KRas	Compound	Compound
Cell Line	Tumor Type	mutation	6 IC 50 (uM)	58 IC 50 (uM)
BxPC3	pancreatic	WT	L	ND
MiaPaca2	pancreatic	G12C	L	L
Panc1	pancreatic	G12D	L	L
SU86.86	pancreatic	G12D	K	ND
HPAF-II	pancreatic	G12D	L	L
CF-PAC1	pancreatic	G12V	L	ND
NCI-H1975	NSCLC	WT	J	ND
NCI-H358	NSCLC	G12C	L	L
A549	NSCLC	G12S	J	L
NCI-H441	NSCLC	G12S	J	ND
NCI-H1299	NSCLC	Q61H	L	ND
		(N-Ras)
HT29	colon	WT	L	ND
GP2d	colon	G12D	K	L
SW-620	colon	G12V	K	L
LS-123	colon	G12S	L	ND
A375	melanoma	WT	L	L
HCC-1806	Breast (TNBC)	WT	J	ND
BT-549	Breast (TNBC)	WT	L	L
BT-20	Breast (TNBC)	WT	L	L
I = >1 uM IC 50 ,
J = 0.51-1 uM IC 50 ,
K = 0.15-0.5 uM IC 50 ,
L = <0.15 uM IC 50 ,
ND = not determined

TABLE 4B — Proliferation assay IC50 data

	MiaPaca-	NCI-	A375	GP2d		MM.1R
	2	H358	IC50	IC50	BT549	IC50
	IC50	IC50	(nM)	(nM)	IC50	(nM)
Com-	(nM)	(nM)	Mela-	Colo-	(nM)	Multiple
pound	Pancreatic	NSCLC	noma	rectal	TNBC	Myloma
6	N	N	M	M	M	O
58	O	N	O	N	O	P
84	O	O	O	O	O	P
91	N	O	O	ND	O	ND
100	O	M	M	N	N	P
102	O	O	O	N	O	P
104	O	M	M	N	N	P
124	O	O	O	O	O	P
221	O	N	M	M	M	P
222	O	N	M	M	N	P
235	O	M	M	M	N	P
238	O	M	M	M	N	P
252	N	O	M	O	N	P
255	O	O	N	O	O	P
267	O	O	O	O	N	P
M = >50 nM IC 50 ,
N = 10-50 nM IC 50 ,
O = 1-10 nM IC 50 ,
P = <1 nM IC 50 ,
ND = not determined

TABLE 5 — % Inhibition at 20 μM of K-Ras mutant and wild-type protein

		KRas		KRas		KRas		KRas
	KRas	wild	KRas	G12D	KRas	G12C	KRas	Q61H
	wild	type +	G12D	mutant +	G12C	mutant +	Q61H	mutant +
	type:	SOS:	mutant:	SOS:	mutant:	SOS:	mutant:	SOS:
Compound	% inh.	% inh.	% inh.	% inh.	% inh.	% inh.	% inh.	% inh.
1	0	A	A	0	0	0	0	0
2	0	0	0	0	0	0	0	0
3	0	0	0	0	0	0	0	0
4	A	A	A	0	0	0	0	0
5	0	0	0	0	0	0	0	0
6	D	C	D	C	C	C	C	C
7	A	0	A	0	0	A	B	A
8	A	0	0	A	0	A	0	0
9	0	0	0	0	B	0	A	0
10	A	0	A	0	B	0	A	0
11	0	0	A	0	B	0	A	0
12	0	0	A	0	B	0	0	0
13	A	0	A	0	A	0	0	0
14	0	A	A	0	B	0	0	0
15	A	A	A	0	0	0	A	A
16	0	A	A	0	B	0	A	0
17	C	C	C	C	C	C	C	C
18	B	A	A	0	0	0	0	A
19	A	A	B	A	0	A	0	B
20	A	A	A	0	A	0	0	0
21	A	A	B	0	0	0	0	A
22	B	A	B	B	B	A	B	A
23	0	A	A	0	A	0	A	0
24	0	0	0	0	0	0	0	0
25	A	A	A	A	A	A	A	A
26	A	0	0	A	0	A	A	A
27	A	A	0	0	0	0	A	0
28	A	A	A	A	A	A	A	A
29	A	0	0	A	0	A	0	0
30	A	0	0	A	A	0	0	0
31	A	0	A	B	A	0	0	A
32	A	0	0	0	0	0	A	A
33	A	0	A	0	A	0	A	0
34	0	A	0	0	0	A	0	0
35	A	A	0	0	A	0	A	A
36	0	A	A	A	A	0	A	A
37	B	B	B	B	C	C	0	0
38	0	0	0	0	0	0	0	0
39	A	A	A	A	B	A	A	0
40	0	0	0	0	0	0	0	A
41	A	0	0	A	0	0	0	0
42	0	0	0	0	0	0	B	B
43	0	0	A	0	0	0	B	B
44	0	B	B	C	0	B	D	D
45	B	B	B	A	B	A	D	D
46	A	A	B	A	B	A	D	D
47	0	0	A	A	0	0	A	A
48	C	B	C	C	C	A	D	D
49	B	0	C	B	A	0	D	D
50	C	B	C	C	A	A	D	D
51	D	C	D	C	C	C	ND	ND
52	0	A	A	A	0	A	ND	ND
53	C	C	C	C	C	C	D	D
54	C	C	D	C	D	C	D	D
55	D	C	D	C	B	C	D	D
56	B	0	B	B	C	A	C	D
57	D	D	D	D	D	D	D	D
58	D	D	D	D	D	C	C	D
59	C	C	D	C	C	B	D	D
60	A	A	A	A	A	0	B	C
61	D	D	D	D	D	D	D	D
62	A	0	B	A	A	0	A	A
63	D	D	D	D	D	C	D	D
64	D	D	D	D	D	C	D	D
65	C	B	C	C	C	A	C	C
66	D	D	D	D	D	C	D	D
67	C	C	C	C	C	B	C	C
68	D	D	D	D	D	D	D	D
69	A	0	A	A	A	0	A	0
70	A	0	A	A	A	0	A	0
71	0	A	A	A	0	A	0	0
72	C	C	D	D	C	C	C	D
73	C	B	C	B	B	B	C	C
74	0	0	A	0	0	0	0	0
75	A	A	B	A	A	A	A	B
76	B	0	C	0	ND	ND	ND	ND
77	C	C	D	B	ND	ND	ND	ND
78	D	D	D	D	ND	ND	ND	ND
79	C	B	D	C	ND	ND	ND	ND
80	A	A	A	0	ND	ND	ND	ND
81	C	B	D	C	ND	ND	ND	ND
82	C	0	C	B	ND	ND	ND	ND
83	D	C	D	D	ND	ND	ND	ND
84	D	C	C	D	ND	ND	ND	ND
85	0	0	0	A	ND	ND	ND	ND
86	B	0	A	C	ND	ND	ND	ND
87	0	0	A	A	ND	ND	ND	ND
88	0	0	A	A	ND	ND	ND	ND
89	D	D	D	D	ND	ND	ND	ND
90	B	0	0	A	ND	ND	ND	ND
91	D	C	D	D	ND	ND	ND	ND
92	0	0	A	A	0	0	0	A
93	D	D	D	D	D	C	C	D
94	C	B	C	B	B	B	B	C
95	C	B	C	C	B	B	C	C
96	D	D	D	D	ND	ND	ND	ND
97	D	D	D	D	ND	ND	ND	ND
98	C	A	C	C	ND	ND	ND	ND
99	C	B	B	B	B	B	ND	ND
100	D	D	D	D	ND	ND	ND	ND
101	D	B	D	C	ND	ND	ND	ND
102	D	D	D	D	ND	ND	ND	ND
103	B	A	B	B	ND	ND	ND	ND
104	D	D	D	D	ND	ND	ND	ND
105	C	D	D	D	ND	ND	ND	ND
106	A	0	B	A	ND	ND	ND	ND
107	C	D	C	C	ND	ND	ND	ND
108	D	C	D	C	ND	ND	ND	ND
109	D	C	D	C	ND	ND	ND	ND
110	B	C	C	B	ND	ND	ND	ND
111	C	A	B	B	ND	ND	ND	ND
112	A	0	A	A	ND	ND	ND	ND
113	C	D	D	D	ND	ND	ND	ND
114	D	D	D	D	ND	ND	ND	ND
115	D	C	C	C	ND	ND	ND	ND
116	C	D	C	C	ND	ND	ND	ND
117	A	A	A	A	ND	ND	ND	ND
118	D	D	D	D	ND	ND	ND	ND
119	C	A	C	B	ND	ND	ND	ND
120	A	C	B	A	ND	ND	ND	ND
121	D	C	D	D	ND	ND	ND	ND
122	D	D	D	D	ND	ND	ND	ND
123	D	D	D	D	ND	ND	ND	ND
124	D	C	C	C	ND	ND	ND	ND
125	C	B	C	C	ND	ND	ND	ND
126	A	A	B	B	ND	ND	ND	ND
127	D	D	D	D	ND	ND	ND	ND
128	D	D	D	D	ND	ND	ND	ND
129	B	B	B	B	ND	ND	ND	ND
130	A	0	B	A	ND	ND	ND	ND
131	B	0	A	0	ND	ND	ND	ND
132	B	0	B	A	ND	ND	ND	ND
133	A	0	B	0	ND	ND	ND	ND
134	0	0	A	A	ND	ND	ND	ND
135	D	D	D	D	ND	ND	ND	ND
136	C	D	D	D	ND	ND	ND	ND
137	C	B	C	B	ND	ND	ND	ND
138	C	D	D	D	ND	ND	ND	ND
139	D	D	D	D	ND	ND	ND	ND
140	C	C	C	D	ND	ND	ND	ND
141	C	B	D	D	ND	ND	ND	ND
142	D	D	D	D	ND	ND	ND	ND
143	D	D	D	D	ND	ND	ND	ND
144	C	D	D	D	ND	ND	ND	ND
145	D	D	D	D	ND	ND	ND	ND
146	D	D	D	D	ND	ND	ND	ND
147	C	A	0	0	ND	ND	ND	ND
148	B	A	0	0	ND	ND	ND	ND
149	D	D	D	D	ND	ND	ND	ND
150	D	D	D	D	ND	ND	ND	ND
151	C	C	B	D	ND	ND	ND	ND
152	C	B	C	C	ND	ND	ND	ND
153	B	B	C	C	ND	ND	ND	ND
154	B	B	D	D	ND	ND	ND	ND
155	A	A	A	A	ND	ND	ND	ND
156	D	D	D	D	ND	ND	ND	ND
157	D	D	D	D	ND	ND	ND	ND
158	D	D	D	D	ND	ND	ND	ND
159	A	0	0	0	ND	ND	ND	ND
160	0	0	0	A	ND	ND	ND	ND
161	A	0	A	0	ND	ND	ND	ND
162	A	0	0	0	ND	ND	ND	ND
163	0	0	0	0	ND	ND	ND	ND
164	A	A	A	0	ND	ND	ND	ND
165	D	D	D	D	ND	ND	ND	ND
166	C	D	D	D	ND	ND	ND	ND
167	A	A	B	A	ND	ND	ND	ND
168	A	A	B	A	ND	ND	ND	ND
169	D	D	D	D	ND	ND	ND	ND
170	D	D	D	D	ND	ND	ND	ND
171	A	B	A	A	ND	ND	ND	ND
172	B	B	B	B	ND	ND	ND	ND
173	C	D	B	C	ND	ND	ND	ND
174	B	B	B	B	ND	ND	ND	ND
175	D	D	C	D	ND	ND	ND	ND
176	D	D	D	D	ND	ND	ND	ND
177	D	D	C	D	ND	ND	ND	ND
178	D	D	D	D	ND	ND	ND	ND
179	D	D	D	D	ND	ND	ND	ND
180	A	A	A	A	ND	ND	ND	ND
181	A	A	A	0	ND	ND	ND	ND
182	A	A	A	0	ND	ND	ND	ND
183	0	A	A	A	ND	ND	ND	ND
184	A	A	B	0	ND	ND	ND	ND
185	A	0	A	0	ND	ND	ND	ND
186	D	D	D	D	ND	ND	ND	ND
187	D	D	D	D	ND	ND	ND	ND
188	D	D	D	D	ND	ND	ND	ND
189	0	0	A	A	ND	ND	ND	ND
190	A	B	B	B	ND	ND	ND	ND
191	A	B	B	B	ND	ND	ND	ND
192	B	B	B	B	ND	ND	ND	ND
193	A	A	A	A	ND	ND	ND	ND
194	A	0	A	A	ND	ND	ND	ND
195	A	0	A	A	ND	ND	ND	ND
196	D	D	D	D	ND	ND	ND	ND
197	0	A	A	A	ND	ND	ND	ND
198	A	B	B	B	ND	ND	ND	ND
199	A	B	B	B	ND	ND	ND	ND
200	B	B	B	B	ND	ND	ND	ND
201	A	B	B	B	ND	ND	ND	ND
202	B	C	C	C	ND	ND	ND	ND
203	0	0	0	0	ND	ND	ND	ND
204	A	A	A	A	ND	ND	ND	ND
205	A	A	A	A	ND	ND	ND	ND
206	A	A	A	A	ND	ND	ND	ND
207	B	B	B	A	ND	ND	ND	ND
208	B	C	B	C	ND	ND	ND	ND
209	A	0	A	A	ND	ND	ND	ND
210	A	0	A	A	ND	ND	ND	ND
211	C	D	C	C	C	D	ND	ND
212	C	D	C	D	ND	ND	ND	ND
213	D	D	D	D	ND	ND	ND	ND
214	C	C	C	C	ND	ND	ND	ND
215	D	D	D	D	ND	ND	ND	ND
216	D	D	D	D	ND	ND	ND	ND
217	C	B	C	B	ND	ND	ND	ND
218	A	A	A	A	ND	ND	ND	ND
219	A	0	A	0	ND	ND	ND	ND
220	B	A	B	A	ND	ND	ND	ND
221	D	D	D	D	ND	ND	ND	ND
222	D	D	D	D	ND	ND	ND	ND
223	B	0	B	A	ND	ND	ND	ND
224	D	D	D	D	ND	ND	ND	ND
225	A	A	B	A	ND	ND	ND	ND
226	D	D	D	D	ND	ND	ND	ND
227	D	D	D	D	ND	ND	ND	ND
228	C	C	D	C	ND	ND	ND	ND
229	C	D	D	D	ND	ND	ND	ND
230	D	D	D	D	ND	ND	ND	ND
231	B	B	C	C	ND	ND	ND	ND
232	D	D	D	D	ND	ND	ND	ND
233	D	D	D	D	ND	ND	ND	ND
234	C	D	D	D	ND	ND	ND	ND
235	C	B	C	C	ND	ND	ND	ND
236	B	B	C	B	ND	ND	ND	ND
237	D	D	D	D	ND	ND	ND	ND
238	D	D	D	D	ND	ND	ND	ND
239	D	D	D	D	ND	ND	ND	ND
240	D	D	D	D	ND	ND	ND	ND
241	D	D	D	D	ND	ND	ND	ND
242	A	0	B	A	ND	ND	ND	ND
243	D	D	D	D	ND	ND	ND	ND
244	C	D	D	D	ND	ND	ND	ND
245	A	B	C	C	ND	ND	ND	ND
246	D	D	D	D	ND	ND	ND	ND
247	D	D	D	D	ND	ND	ND	ND
248	D	D	D	D	ND	ND	ND	ND
249	C	C	C	C	ND	ND	ND	ND
250	D	D	D	D	ND	ND	ND	ND
251	B	A	C	B	ND	ND	ND	ND
252	C	D	D	D	ND	ND	ND	ND
253	D	D	C	D	ND	ND	ND	ND
254	D	D	D	D	ND	ND	ND	ND
255	ND	D	D	D	ND	ND	ND	ND
256	A	D	D	D	ND	ND	ND	ND
257	C	D	D	D	ND	ND	ND	ND
258	A	0	0	0	ND	ND	ND	ND
259	C	D	C	D	ND	ND	ND	ND
260	D	D	C	C	ND	ND	ND	ND
261	C	C	D	C	ND	ND	ND	ND
262	B	C	D	D	ND	ND	ND	ND
263	C	D	D	D	ND	ND	ND	ND
264	C	D	C	D	ND	ND	ND	ND
265	ND	D	C	D	ND	ND	ND	ND
266	D	C	D	D	ND	ND	ND	ND
267	D	D	D	D	ND	ND	ND	ND
268	C	D	C	D	ND	ND	ND	ND
269	C	A	B	B	ND	ND	ND	ND
270	B	A	B	B	ND	ND	ND	ND
271	B	A	B	B	ND	ND	ND	ND
272	0	0	C	A	ND	ND	ND	ND
273	0	A	B	A	ND	ND	ND	ND
274	0	0	B	A	ND	ND	ND	ND
275	A	0	A	A	ND	ND	ND	ND
276	D	D	D	D	ND	ND	ND	ND
0 = 0% inhibition,
A = 1-25% inhibition,
B = 26-49% inhibition,
C = 50-75% inhibition,
D = 76-100% inhibition,
ND = not determined

TABLE 6 — % Inhibition at 20 μM of Rac-1, Rho-A, Cdc42, and Rheb protein ND = not determined.

	Rac-1:	Rho-A:	Cdc42:	Rheb:
Compound	% inh.	% inh..	% inh.	% inh.
1	A	0	ND	ND
2	0	0	ND	ND
3	A	0	ND	ND
4	A	A	ND	ND
5	B	B	ND	ND
6	C	D	C	D
7	0	0	ND	ND
8	0	0	ND	ND
9	0	0	ND	ND
10	A	0	ND	ND
11	0	0	ND	ND
12	0	0	ND	ND
13	0	0	ND	ND
14	0	0	ND	ND
15	0	A	ND	ND
16	0	0	ND	ND
17	C	D	ND	ND
18	0	A	ND	ND
19	0	A	ND	ND
20	0	A	ND	ND
21	0	A	ND	ND
22	B	C	ND	ND
23	A	A	ND	ND
24	0	0	ND	ND
25	A	A	ND	ND
26	0	A	ND	ND
27	A	A	ND	ND
28	B	A	ND	ND
29	0	A	ND	ND
30	0	A	ND	ND
31	A	A	ND	ND
32	0	A	A	B
33	0	A	ND	ND
34	B	A	A	B
35	0	A	ND	ND
36	0	A	ND	ND
37	0	0	ND	ND
38	0	A	ND	ND
39	0	0	ND	ND
40	A	A	ND	ND
41	0	0	ND	ND
42	0	A	A	A
43	A	A	A	B
44	B	A	B	B
45	C	C	B	C
46	C	B	C	C
47	0	A	A	A
48	C	D	C	C
49	B	B	A	B
50	B	C	B	B
51	D	D	C	C
52	0	0	A	0
53	D	D	C	D
54	D	D	C	D
55	D	D	C	D
56	C	C	B	C
57	D	D	D	D
58	D	D	D	D
59	D	D	C	C
60	A	A	A	B
61	D	D	D	D
62	C	B	A	0
63	D	D	D	C
64	D	D	D	C
65	D	D	B	0
66	D	D	D	C
67	C	D	B	C
68	D	D	D	D
69	A	A	0	A
70	A	A	A	A
71	A	A	A	A
72	D	D	C	C
73	C	D	C	C
74	A	B	0	0
75	B	C	A	A
76	C	ND	ND	ND
77	D	ND	ND	ND
78	D	ND	ND	ND
79	D	ND	ND	ND
80	A	ND	ND	ND
81	D	ND	ND	ND
82	B	ND	ND	ND
83	D	ND	ND	ND
84	D	ND	ND	ND
85	0	ND	ND	ND
86	C	ND	ND	ND
87	0	ND	ND	ND
88	A	ND	ND	ND
89	D	ND	ND	ND
90	D	ND	ND	ND
91	D	ND	ND	ND
92	A	A	A	0
93	D	D	D	D
94	C	D	B	B
95	D	D	C	C
96	D	ND	ND	ND
97	D	ND	ND	ND
98	C	ND	ND	ND
99	C	ND	ND	ND
100	D	ND	ND	ND
101	D	ND	ND	ND
102	D	ND	ND	ND
103	A	ND	ND	ND
104	D	ND	ND	ND
105	D	ND	ND	ND
106	B	ND	ND	ND
107	D	ND	ND	ND
108	D	ND	ND	ND
109	D	ND	ND	ND
110	C	ND	ND	ND
111	B	ND	ND	ND
112	0	ND	ND	ND
113	D	ND	ND	ND
114	D	ND	ND	ND
115	A	ND	ND	ND
116	C	ND	ND	ND
117	A	ND	ND	ND
118	D	ND	ND	ND
119	B	ND	ND	ND
120	B	ND	ND	ND
121	D	ND	ND	ND
122	D	ND	ND	ND
123	D	ND	ND	ND
124	D	ND	ND	ND
125	C	ND	ND	ND
126	B	ND	ND	ND
127	D	ND	ND	ND
128	D	ND	ND	ND
129	B	ND	ND	ND
130	0	ND	ND	ND
131	0	ND	ND	ND
132	A	ND	ND	ND
133	A	ND	ND	ND
134	A	ND	ND	ND
135	D	ND	ND	ND
136	D	ND	ND	ND
137	C	ND	ND	ND
138	C	ND	ND	ND
139	D	ND	ND	ND
140	D	ND	ND	ND
141	D	ND	ND	ND
142	D	ND	ND	ND
143	D	ND	ND	ND
144	D	ND	ND	ND
145	D	ND	ND	ND
146	D	ND	ND	ND
147	0	ND	ND	ND
148	0	ND	ND	ND
149	D	ND	ND	ND
150	C	ND	ND	ND
151	C	ND	ND	ND
152	C	ND	ND	ND
153	C	ND	ND	ND
154	C	ND	ND	ND
155	A	ND	ND	ND
156	D	ND	ND	ND
157	D	ND	ND	ND
158	D	ND	ND	ND
159	0	ND	ND	ND
160	A	ND	ND	ND
161	A	ND	ND	ND
162	0	ND	ND	ND
163	0	ND	ND	ND
164	A	ND	ND	ND
165	C	ND	ND	ND
166	D	ND	ND	ND
167	A	ND	ND	ND
168	A	ND	ND	ND
169	D	ND	ND	ND
170	D	ND	ND	ND
171	A	ND	ND	ND
172	B	ND	ND	ND
173	C	ND	ND	ND
174	C	ND	ND	ND
175	B	ND	ND	ND
176	D	ND	ND	ND
177	D	ND	ND	ND
178	D	ND	ND	ND
179	D	ND	ND	ND
180	A	ND	ND	ND
181	A	ND	ND	ND
182	A	ND	ND	ND
183	A	ND	ND	ND
184	A	ND	ND	ND
185	0	ND	ND	ND
186	D	ND	ND	ND
187	D	ND	ND	ND
188	D	ND	ND	ND
189	A	ND	ND	ND
190	B	ND	ND	ND
191	A	ND	ND	ND
192	A	ND	ND	ND
193	A	ND	ND	ND
194	A	ND	ND	ND
195	A	ND	ND	ND
196	D	ND	ND	ND
197	A	ND	ND	ND
198	B	ND	ND	ND
199	B	ND	ND	ND
200	B	ND	ND	ND
201	B	ND	ND	ND
202	B	ND	ND	ND
203	A	ND	ND	ND
204	A	ND	ND	ND
205	A	ND	ND	ND
206	A	ND	ND	ND
207	A	ND	ND	ND
208	B	ND	ND	ND
209	B	ND	ND	ND
210	A	ND	ND	ND
211	C	ND	ND	ND
212	C	ND	ND	ND
213	C	ND	ND	ND
214	C	ND	ND	ND
215	D	ND	ND	ND
216	D	ND	ND	ND
217	C	ND	ND	ND
218	A	ND	ND	ND
219	A	ND	ND	ND
220	B	ND	ND	ND
221	D	ND	ND	ND
222	D	ND	ND	ND
223	B	ND	ND	ND
224	D	ND	ND	ND
225	A	ND	ND	ND
226	D	ND	ND	ND
227	D	ND	ND	ND
228	D	ND	ND	ND
229	D	ND	ND	ND
230	D	ND	ND	ND
231	D	ND	ND	ND
232	D	ND	ND	ND
233	D	ND	ND	ND
234	D	ND	ND	ND
235	C	ND	ND	ND
236	C	ND	ND	ND
237	D	ND	ND	ND
238	D	ND	ND	ND
239	D	ND	ND	ND
240	D	ND	ND	ND
241	D	ND	ND	ND
242	A	ND	ND	ND
243	D	ND	ND	ND
244	D	ND	ND	ND
245	C	ND	ND	ND
246	D	ND	ND	ND
247	D	ND	ND	ND
248	D	ND	ND	ND
249	D	ND	ND	ND
250	D	ND	ND	ND
251	B	ND	ND	ND
252	D	ND	ND	ND
253	D	ND	ND	ND
254	D	ND	ND	ND
255	D	ND	ND	ND
256	D	ND	ND	ND
257	C	ND	ND	ND
258	0	ND	ND	ND
259	D	ND	ND	ND
260	C	ND	ND	ND
261	D	ND	ND	ND
262	C	ND	ND	ND
263	D	ND	ND	ND
264	D	ND	ND	ND
265	D	ND	ND	ND
266	D	ND	ND	ND
267	D	ND	ND	ND
268	D	ND	ND	ND
269	B	ND	ND	ND
270	B	ND	ND	ND
271	B	ND	ND	ND
272	A	ND	ND	ND
273	A	ND	ND	ND
274	0	ND	ND	ND
275	A	ND	ND	ND
276	D	ND	ND	ND
0 = 0% inhibition,
A = 1-25% inhibition,
B = 26-49% inhibition,
C = 50-75% inhibition,
D = 76-100% inhibition,

TABLE 7 — Apoptosis-related caspase activation and increased Puma expression after 48 hours Increased

		Caspase	Caspase	Caspase	PUMA
Compound	Cell Line	3	6	9	expression
6	Panc-1	yes	yes	ND	ND
6	MiaPaca2	yes	yes	yes	yes
6	A549	yes	yes	yes	yes
6	A375	yes	yes	yes	ND
6	BT-549	yes	yes	yes	yes
58	MiaPaca2	yes	yes	yes	yes
58	A549	yes	yes	yes	yes
58	BT-549	yes	yes	yes	yes
84	MiaPaca2	yes	yes	yes	yes
91	MiaPaca2	yes	yes	yes	yes
91	BT-549	yes	yes	yes	yes
91	A549	yes	yes	yes	yes
102	MiaPaca2	yes	yes	yes	yes
102	A375	yes	yes	yes	ND
102	NCI-H1975	yes	yes	yes	ND
102	A549	yes	yes	yes	yes
102	IM.9	yes	yes	yes	ND
102	MM.1R	yes	yes	yes	ND
124	MiaPaca2	yes	yes	yes	yes
124	A375	yes	yes	yes	ND
124	BT-549	yes	yes	yes	ND
124	HCC1806	yes	yes	yes	yes
124	NCI-H358	yes	yes	yes	yes

TABLE 8 — Kinetic Solubility in pH 7.4 Buffer + 2% DMSO C denotes >30 μM.

Example Number	Solubility (μM)
6	A
50	A
53	B
54	A
55	B
57	B
58	B
59	A
62	A
63	A
84	B
91	C
100	B
102	C
104	A
116	B
118	C
124	B
137	B
141	B
142	B
143	A
144	A
145	B
157	A
158	B
221	B
222	B
224	A
226	A
227	A
235	A
238	A
248	A
250	A
252	A
255	C
260	A
265	A
267	B
268	A
A denotes <10 μM,
B denotes 10-30 μM,

TABLE 9 — Mouse Liver Microsome Metabolic Stability Assay B denotes >10 min.

Example Number	t½ (min)
6	B
102	B
104	B
124	B
126	B
127	A
128	B
129	B
137	B
141	B
142	B
143	A
144	B
145	B
156	B
157	B
158	A
222	A
224	B
226	B
227	B
235	B
238	B
248	B
250	A
252	A
255	B
260	A
265	B
267	B
268	A
A denotes <10 min,

R 3A is —CH 3 , unsubstituted phenyl, isopropyl, cyclopropyl, R 4A hydrogen, unsubstituted phenyl,

R 5A is hydrogen;	R 6A is methyl, —CH 2 CH 2 NH 2 , or
R 7A is methyl; and	m is 0 or 1.

R 3A is —CH 3 , unsubstituted phenyl, (4-methoxy)-phenyl, or isopropyl;	R 4A is
R 5A is hydrogen;	R 6A is methyl; and	m is 0.

R 3A is —CH 3 or substituted phenyl;	R 4A is
R 5A is hydrogen;	R 6A is methyl; and	m is 0.

R 3A is —CH 3 or unsubstituted phenyl;	R 4A hydrogen, unsubstituted phenyl,
R 5A is hydrogen;	R 6A is methyl; and	m 0.

R 3A is —CH 3 or unsubstituted phenyl;	R 4A is
R 5A is hydrogen;	R 7A is methyl; and	m is 0.

R 3A is —CH 3 or unsubstituted phenyl;	R 4A is
R 5A is hydrogen;	R 7A is methyl; and	m is 0.

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3 codes

IPC · International Patent Classification

Section A — Human necessities

A61P35/00
A61K31/53

Section C — Chemistry; metallurgy

C07D487/04

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