US 11,446,299 B2 · Carbazole EHop-016 derivatives as anticancer and anti-migratory agents

Abstract

A series of novel EHop-016 derivatives is presented herein via designing and synthesizing compounds that mimics its more favorable “U-shaped” conformation that appears to be critical for inhibitory activity against Rac. Based on modeling studies on EHop-016, compounds with a more rigid structural conformation can mimic this “U-shaped” conformation and would improve the anti-migration activity against metastatic cells. Compounds are disclosed that inhibit RhoGTPases that are useful for inhibiting hyperprofilerative and neoplastic diseases, for instance compounds of formula Specifically, the compounds inhibit the GTPases Rac and Cdc42 that are overactive or overexpressed in signaling pathways in cancer and metastasis. Methods for treatment of cancer and hyperproliferative diseases are disclosed.

A compound of formula,

wherein
R1 is H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
each R2 is independently deuterium, halogen, —OH, —CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, —OR5, —C(O)OR5, —C(O)NR5R6, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)C1-C6 alkyl, —CO2H, —C(O)OC1-C6 alkyl, —C(O)NH2, —C(O)NH(C1-C6 alkyl), —C(O)N(C1-C6 alkyl)2, —SC1-C6 alkyl, —S(O)C1-C6 alkyl, —S(O)2C1-C6 alkyl, —S(O)NH(C1-C6 alkyl), —S(O)2NH(C1-C6 alkyl);
wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C6-C10 aryl is independently optionally substituted;
A is —O—, —S—, —N(R7)—, —N(R7)C(O)—, or —C(O)N(R7)—;
Y is —N—;
R3 is —NHR11, —NR11R12, —C(O)C1-C6 alkyl, —C(O)R11, or 3-to 7-membered heterocycloalkyl;
wherein each hydrogen atom in —C(O)C1-C6 alkyl or 3-to 7-membered heterocycloalkyl is optionally substituted by deuterium, halogen, —OH, oxo, —CN, —OC1-C6 alkyl, —NH2, —NH(C1-C6 alkyl), —NH(C6-C10 aryl), —NH(C6-C10 aryl)-N(C1-C6 alkyl)2, —NHC(O)C1-C6 alkyl, —N(C1-C6 alkyl)C(O)C1-C6 alkyl, —NHC(O)NH2, —NHC(O)NHC1-C6 alkyl, —N(C1-C6 alkyl)C(O)NH2, —N(C1-C6 alkyl)C(O)NHC1-C6 alkyl, —NHC(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, —NHC(O)OC1-C6 alkyl, —N(C1-C6 alkyl)C(O)OC1-C6 alkyl, —NHS(O)(C1-C6 alkyl), —NHS(O)2(C1-C6 alkyl), —N(C1-C6 alkyl)S(O)(C1-C6 alkyl), —N(C1-C6 alkyl)S(O)2(C1-C6 alkyl), —NHS(O)NH2, —NHS(O)2NH2, —N(C1-C6 alkyl)S(O)NH2, —N(C1-C6 alkyl)S(O)2NH2, —NHS(O)NH(C1-C6 alkyl), —NHS(O)2NH(C1-C6 alkyl), —NHS(O)N(C1-C6 alkyl)2, —NHS(O)2N(C1-C6 alkyl)2, —N(C1-C6 alkyl)S(O)NH(C1-C6 alkyl), —N(C1-C6 alkyl)S(O)2NH(C1-C6 alkyl), —N(C1-C6 alkyl)S(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)S(O)2N(C1-C6 alkyl)2, —CO2H, —C(O)C1-C6 alkyl, —C(O)OC1-C6 alkyl, —C(O)NH2, —C(O)NH(C1-C6 alkyl), —C(O)N(C1-C6 alkyl)2, —SC1-C6 alkyl, —S(O)C1-C6 alkyl, —S(O)2C1-C6 alkyl, —S(O)NH(C1-C6 alkyl), —S(O)2NH(C1-C6 alkyl), —S(O)N(C1-C6 alkyl)2, —S(O)2N(C1-C6 alkyl)2, —P(C1-C6 alkyl)2, —P(O)(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkyl-(3-to 7-membered heterocycloalkyl), —CF3, —CHF2, or —CH2F;
wherein each of R11 and R12 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 heteroalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6alkyl-(3- to 7-membered heterocycloalkyl), heteroaryl, —NHC1-C6alkyl, —N(C1-C6 alkyl)2, —S(O)2C1-C6 alkyl, —CF3, —CHF2, or —CH2F, wherein each hydrogen in C1-C6alkyl, C1-C6heteroalkyl, and C6-C10 aryl is optionally substituted by —O—C1-C6alkyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, 3- to 7-membered substituted heterocycloalkyl, —CH2CN, —N(C1-C6 alkyl)2, optionally substituted aryl, —C(O)NH-optionally substituted aryl, hydroxy, or mono- or bicyclic heteroaryl;
or R3 is —OR11, wherein R11 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 heteroalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6alkyl-(3-to 7-membered heterocycloalkyl), heteroaryl, —NHC1-C6 alkyl, —N(C1-C6 alkyl)2, —S(O)2C1-C6 alkyl, —CF3, —CHF2, or —CH2F, wherein each hydrogen in C1-C6 alkyl, C1-C6 heteroalkyl, and C6-C10 aryl is optionally substituted by C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, 3- to 7-membered substituted heterocycloalkyl, —CH2CN, —N(C1-C6 alkyl)2, optionally substituted aryl, —C(O)NH-optionally substituted aryl, hydroxy, or mono- or bicyclic heteroaryl
R8 is H, deuterium, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 heteroalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6alkyl-(3-to 7-membered heterocycloalkyl), mono- or bicyclic heteroaryl, —OC1-C6 alkyl, —NHC1-C6 alkyl, —N(C1-C6 alkyl)2, —S(O)2C1-C6 alkyl, —CF3, —CHF2, or —CH2F, wherein each hydrogen in C1-C6alkyl, C1-C6 heteroalkyl, 3- to 7-membered heterocycloalkyl, mono- or bicyclic heteroaryl, and C6-C10 aryl is optionally substituted by —O—C1-C6alkyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, 3- to 7-membered substituted heterocycloalkyl, —CH2CN, —N(C1-C6 alkyl)2, —OC1-C6 alkyl, optionally substituted aryl, —C(O)NH-optionally substituted aryl, hydroxy, or mono- or bicyclic heteroaryl;
R10 is H, deuterium, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl;
wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl is independently optionally substituted;
each R5, R6, and R7 is independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 heteroalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, C1-C6 alkyl-(3- to 7-membered heterocycloalkyl), heteroaryl, —OC1-C6 alkyl, —NHC1-C6 alkyl, —N(C1-C6 alkyl)2, —S(O)2C1-C6 alkyl, —CF3, —CHF2, or —CH2F, wherein each hydrogen in C1-C6alkyl, C1-C6 heteroalkyl, and C6-C10 aryl is optionally substituted by —O—C1-C6alkyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, 3- to 7-membered substituted heterocycloalkyl, —CH2CN, —N(C1-C6 alkyl)2, —OC1-C6 alkyl, optionally substituted aryl, —C(O)NH-optionally substituted aryl, hydroxy, or mono- or bicyclic heteroaryl;
and
a is 0, 1, 2, or 3;
or a salt thereof.

14 more elements

Carbazole EHop-016 derivatives as anticancer and anti-migratory agents

Life of this patent

Carbazole EHop-016 derivatives as anticancer and anti-migratory agents

Life of this patent

Abstract

Claims8