	US 12,234,212 B2
	Peptide conjugates of microtubule-targeting agents as therapeutics
Daniel Richard Marshall, New Haven, CT (US); Johanna Marie Csengery, New Fairfield, CT (US); Robert John Maguire, New Haven, CT (US); and Robert A. Volkmann, Mystic, CT (US)
Assigned to Cybrexa 3, Inc., New Haven, CT (US)
Filed by Cybrexa 3, Inc., New Haven, CT (US)
Filed on Jan. 11, 2023, as Appl. No. 18/152,987.
Application 18/152,987 is a division of application No. 16/924,445, filed on Jul. 9, 2020, granted, now 11,555,019.
Claims priority of provisional application 63/041,324, filed on Jun. 19, 2020.
Claims priority of provisional application 62/872,638, filed on Jul. 10, 2019.
Prior Publication US 2024/0067616 A1, Feb. 29, 2024
Int. Cl. C07D 265/12 (2006.01); A61K 47/64 (2017.01)

CPC C07D 265/12 (2013.01) [A61K 47/64 (2017.08)]

22 Claims

1. A method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I):

R²-L-R¹ (I)

or a pharmaceutically acceptable salt thereof, wherein:

R¹is a peptide capable of selectively delivering R²L-across a cell membrane having an acidic or hypoxic mantle;

R²is selected from the group consisting of:

L is the following group:

wherein

R³, R⁴, R⁵, and R⁶are each independently selected from H, C_1-4alkyl, C_1-4alkenyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, and NR^c1C(O)NR^c1R^d1, wherein said C_1-4alkyl, C_1-4alkenyl, C_6-10aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^e1C(O)OR^a1, and NR^c1C(O)NR^c1R^d1;

or R³and R⁴together with the carbon atom to which they are attached form a C_3-14cycloalkyl group or 4-14 membered heterocycloalkyl group, each optionally substituted with 1,2, or 3 substituents independently selected from C_1-4alkyl, halo, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^e1C(O)R^b1, NR^c1C(O)OR^a1, and NR^c1C(O)NR^c1R^d1;

or R³and R⁵together with the carbon atoms to which they are attached form a C_3-14cycloalkyl group or 4-14 membered heterocycloalkyl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C_1-4alkyl, halo, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1NR^e1C(O)R^b1, NR^c1C(O)OR^a1, and NR^c1C(O)NR^c1R^d1;

or R⁴and R⁶together with the carbon atoms to which they are attached form a C_3-14cycloalkyl group or 4-14 membered heterocycloalkyl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C_1-4alkyl, halo, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^e1C(O)R^b1, NR^c1C(O)OR^a1, and NR^c1C(O)NR^c1R^d1;

or R⁵and R⁶together with the carbon atom to which they are attached form a C_3-14cycloalkyl group or 4-14 membered heterocycloalkyl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C_1-4alkyl, halo, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1NR^e1C(O)R^b1, NR^c1C(O)OR^a1, and NR^c1C(O)NR^c1R^d1;

A is H or C_1-4alkyl; and

R^a1, R^b1, R^c1, and R^d1are each independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, OH, CN, NO₂, and CO₂CH₃; wherein said C_1-6alkyl and C_2-6alkenyl are each optionally substituted with OH, CN, NO₂, or CO₂CH.