US 2024/0197888 A1Published application

Sos1 protein degraders, pharmaceutical compositions thereof, and their therapeutic applications

AssigneeBioTheryX, Inc.

InventorsAparajita Hoskote Chourasia, Paul E. Erdman, Leah M. Fung, Imelda Lam, Patrick Papa, Navin Rajapakse, Angela Schoolmeesters, Eduardo Torres

Life of this patent

Estimating the term…

Abstract

Provided herein are SOS1 protein degraders, for example, a compound of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a SOS1-mediated disorder, disease, or condition.

Claims124

Dependent claims

A compound of Formula (II):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
or
a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
wherein:
U, V, X, Y, and R1 are (i) or (ii):
(i) one of U, V, X, and Y is —C(R4)═ or —N(R4)—;
and the remaining three of U, V, X, and Y are each independently —C(R5)═ or —N═;
R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
and
R4 is -L-RB;
or
(ii) U is —C(R5a)═ or —N═;
V is —C(R5b)═ or —N═;
X is —C(R5c)═ or —N═;
Y is —C(R5d)═ or —N═;
and
R1 is -L-RB;
L is a linker;
RB is C2-6 fluoroalkyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
R3 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
each R5, R5a, R5b, R5d, and R5d is independently (i) hydrogen, deuterium, cyano, halo, nitro, or oxo;
(ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(O)SR1a, —C(NR1a)NR1bR1c, —C(S)R1a, —C(S)OR1a, —C(S)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(O)SR1a, —OC(NR1a)NR1bR1c, —OC(S)R1a, —OC(S)OR1a, —OC(S)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(O)SR1d, —NR1aC(NR1d)NR1bR1c1, —NR1aC(S)R1d, —NR1aC(S)OR1d, —NR1aC(S)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c or —S(O)2NR1bR1c;
R2a and R2b are each independently hydrogen, deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl;
R2c is C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl;
and
each R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
wherein each alkyl, heteroalkyl, fluoroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from:
(a) deuterium, cyano, halo, imino, nitro, and oxo;
(b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(O)SRa, —C(NRa)NRbRc, —C(S)Ra, —C(S)ORa, —C(S)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(O)SRa, —OC(NRa)NRbRc, —OC(S)Ra, —OC(S)ORa, —OC(S)NRbRc, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbRc, —OS(O)2NRbRc, —NRbRc, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbRc, —NRaC(O)SRd, —NRaC(NR1d)NRbRc, —NRaC(S)Rd, —NRaC(S)ORd, —NRaC(S)NRbRc, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbRc, and —S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium;
(ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
wherein each Qa is independently selected from:
(a) deuterium, cyano, halo, nitro, imino, and oxo;
(b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl;
and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, —C(S)Re, —C(S)ORe, —C(S)NRfRg, —ORe, —OC(O)Re, —OC(O)ORe, —OC(O)NRfRg, —OC(O)SRe, —OC(NRe)NRfRg, —OC(S)Re, —OC(S)ORe, —OC(S)NRfRg, —OS(O)Re, —OS(O)2Re, —OS(O)NRfRg, —OS(O)2NRfRg, —NRfRg, —NReC(O)Rh, —NReC(O)ORf, —NR C(O)NRfRg, —NReC(O)SRf, —NR C(NRh)NRfRg, —NReC(S)Rh, —NReC(S)ORf, —NReC(S)NRfRg, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRfRg, —NReS(O)2NRfRg, —SRe, —S(O)Re, —S(O)2Re, —S(O)NRfRg, and —S(O)2NRfRg;
wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium;
(ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.

37 more elements

A compound of:

(R)—N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methyl-7-((7-(piperidin-1-yl)heptyl)oxy)quinazolin-4-amine A1;
(R)-6-methoxy-2-methyl-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-((7-(piperidin-1-yl)heptyl)oxy)quinazolin-4-amine A2;
(S)-6-methoxy-2-methyl-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-((7-(piperidin-1-yl)heptyl)oxy)quinazolin-4-amine A3;
2-((3r,5r,7r)-adamantan-1-yl)-N-(2-(2-((6-methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)ethoxy)ethyl)-acetamide A4;
2-((3r,5r,7r)-adamantan-1-yl)-N-(2-(2-((6-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)ethoxy)ethyl)-acetamide A5;
2-((3r,5r,7r)-adamantan-1-yl)-N-(2-(2-((6-methoxy-2-methyl-4-(((S)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)ethoxy)-ethyl)acetamide A6;
2-(adamantan-2-yl)-N-(7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)acetamide A7;
(R)—N-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)-2-phenylacetamide A8;
(R)-2-(bicyclo[1.1.1]pentan-1-yl)-N-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)acetamide A9;
(R)-2-(bicyclo[2.1.1]hexan-1-yl)-N-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)acetamide A10;
(R)-2-(bicyclo[2.2.2]octan-1-yl)-N-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)acetamide A11;
2-(bicyclo[3.1.1]heptan-1-yl)-N-(7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)acetamide A12;
(R)-2-(bicyclo[2.2.1]heptan-1-yl)-N-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)acetamide A13;
2-(bicyclo[3.2.1]octan-1-yl)-N-(7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)acetamide A14;
(R)—N-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)-2-(9H-fluoren-9-yl)acetamide A15;
(R)—N-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)-3,3-diphenylpropanamide A16;
(R)—N-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)-3,3-dicyclohexylpropanamide A17;
(R)-2-([1,1′-biphenyl]-4-yl)-N-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)acetamide A18;
(R)—N-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)-2-(4-phenoxyphenyl)acetamide A19;
(R)—N-(7-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methyl-quinazolin-7-yl)oxy)heptyl)-2-(4-isobutylphenyl)propanamide A20;
7-((5-(4-(2-((3r,5r,7r)-adamantan-1-yl)ethyl)-1H-1,2,3-triazol-1-yl)pentyl)oxy)-N—((R)-1-(3-bromophenyl)ethyl)-6-methoxy-2-methylquinazolin-4-amine A21;
(R)—N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methyl-7-((7-(2,2,6,6-tetramethyl-piperidin-1-yl)heptyl)oxy)quinazolin-4-amine A22;
(R)—N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methyl-7-((7-(4-phenylpiperidin-1-yl)heptyl)oxy)quinazolin-4-amine A23;
(R)—N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methyl-7-((7-(4-(trifluoromethyl)-piperidin-1-yl)heptyl)oxy)quinazolin-4-amine A24;
(R)-1-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)piperidin-2-one A25;
(R)-1-(4-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methyl-quinazolin-7-yl)oxy)heptyl)piperazin-1-yl)ethan-1-one A26;
(R)—N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methyl-7-(8-(piperidin-1-yl)octyl)quinazolin-4-amine A27;
(R)—N4-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methyl-N7-(7-(piperidin-1-yl)heptyl)quinazoline-4,7-diamine A28;
(R)—N4-(1-(3-bromophenyl)ethyl)-6-methoxy-N7,2-dimethyl-N7-(7-(piperidin-1-yl)heptyl)quinazoline-4,7-diamine A29;
(R)-2-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)-1-(4-(2-(piperidin-1-yl)ethyl)piperazin-1-yl)ethan-1-one A30;
(R)-2-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)-1-(4-(3-(piperidin-1-yl)propyl)piperazin-1-yl)ethan-1-one A31;
(R)-2-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)-1-(4-(4-(piperidin-1-yl)butyl)piperazin-1-yl)ethan-1-one A32;
2-((3r,5r,7r)-adamantan-1-yl)-N-(2-(4-(2-((4-(((R)-1-(3-bromophenyl)ethyl)-amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)acetyl)piperazin-1-yl)ethyl)acetamide A33;
2-((3r,5r,7r)-adamantan-1-yl)-N-(3-(4-(2-((4-(((R)-1-(3-bromophenyl)ethyl)-amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)acetyl)piperazin-1-yl)propyl)acetamide A34;
2-((3r,5r,7r)-adamantan-1-yl)-N-(4-(4-(2-((4-(((R)-1-(3-bromophenyl)ethyl)-amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)acetyl)piperazin-1-yl)butyl)acetamide A35;
(R)-7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)-1-(piperidin-1-yl)heptan-1-one A36;
7-((7-((2-((3r,5r,7r)-adamantan-1-yl)ethyl)amino)heptyl)oxy)-N—((R)-1-(3-bromophenyl)ethyl)-6-methoxy-2-methylquinazolin-4-amine A37;
7-((7-((2-((3r,5r,7r)-adamantan-1-yl)ethyl)(methyl)amino)heptyl)oxy)-N—((R)-1-(3-bromophenyl)ethyl)-6-methoxy-2-methylquinazolin-4-amine A38;
7-((10-((3r,5r,7r)-adamantan-1-yl)decyl)oxy)-N—((R)-1-(3-bromophenyl)ethyl)-6-methoxy-2-methylquinazolin-4-amine A39;
7-((6-(4-(2-((3r,5r,7r)-adamantan-1-yl)ethyl)piperazin-1-yl)hexyl)oxy)-N—((R)-1-(3-bromophenyl)ethyl)-6-methoxy-2-methylquinazolin-4-amine A40;
(R)-1-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)heptyl)-2,4,6-triphenylpyridin-1-ium A41;
(R)—N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methyl-7-((7-(trityloxy)heptyl)-oxy)quinazolin-4-amine A42.
(R)—N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methyl-7-((7-(pyridin-4-yl)heptyl)-oxy)quinazolin-4-amine A43;
(R)—N-(1-(3-bromophenyl)ethyl)-7-((7-(3,3-difluoropiperidin-1-yl)heptyl)oxy)-6-methoxy-2-methylquinazolin-4-amine A44;
5-((6-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)pentyl 2-((3r,5r,7r)-adamantan-1-yl)acetate A45;
5-((6-methoxy-2-methyl-4-(((S)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)pentyl 2-((3r,5r,7r)-adamantan-1-yl)acetate A46;
2-(2-((6-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)-thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)ethoxy)ethyl 2-((3r,5r,7r)-adamantan-1-yl)acetate A47;
2-(2-((6-methoxy-2-methyl-4-(((S)-1-(4-(2-((methylamino)methyl)phenyl)-thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)ethoxy)ethyl 2-((3r,5r,7r)-adamantan-1-yl)acetate A48;
7-((6-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)heptyl 2-((3r,5r,7r)-adamantan-1-yl)acetate A49;
7-((6-methoxy-2-methyl-4-(((S)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)heptyl 2-((3r,5r,7r)-adamantan-1-yl)acetate A50;
2-((3r,5r,7r)-adamantan-1-yl)-N-(2-((6-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)ethyl)acetamide A51;
2-((3r,5r,7r)-adamantan-1-yl)-N-(2-((6-methoxy-2-methyl-4-(((S)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)ethyl)acetamide A52;
2-((3r,5r,7r)-adamantan-1-yl)-N-(7-((6-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)heptyl)acetamide A53;
2-((3r,5r,7r)-adamantan-1-yl)-N-(7-((6-methoxy-2-methyl-4-(((S)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)heptyl)acetamide A54;
(R)-7-(7-aminohept-5-yn-1-yl)-N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methylquinazolin-4-amine A55;
(R)-7-(8-aminooct-6-yn-1-yl)-N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methylquinazolin-4-amine A56;
(R)-7-(9-aminonon-7-yn-1-yl)-N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methylquinazolin-4-amine A57;
(R)-7-((7,7-dimethyloctyl)oxy)-6-methoxy-2-methyl-N-(1-(4-(2-((methylamino)-methyl)phenyl)thiophen-2-yl)ethyl)quinazolin-4-amine A58;
(S)-7-((7,7-dimethyloctyl)oxy)-6-methoxy-2-methyl-N-(1-(4-(2-((methylamino)-methyl)phenyl)thiophen-2-yl)ethyl)quinazolin-4-amine A59;
(R)-6-methoxy-2-methyl-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-((7-(4-phenylcyclohexyl)heptyl)oxy)quinazolin-4-amine A60;
(S)-6-methoxy-2-methyl-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-((7-(4-phenylcyclohexyl)heptyl)oxy)quinazolin-4-amine A61;
(R)-7-(3,3-dimethylbutoxy)-6-methoxy-2-methyl-N-(1-(4-(2-((methylamino)-methyl)phenyl)thiophen-2-yl)ethyl)quinazolin-4-amine A62;
(S)-7-(3,3-dimethylbutoxy)-6-methoxy-2-methyl-N-(1-(4-(2-((methylamino)-methyl)phenyl)thiophen-2-yl)ethyl)quinazolin-4-amine A63;
(R)-1-(4-(7-((6-methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)-thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)heptyl)piperazin-1-yl)ethan-1-one A64;
(S)-1-(4-(7-((6-methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)-thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)heptyl)piperazin-1-yl)ethan-1-one A65;
(R)-6-methoxy-2-methyl-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-((7-(4-(trifluoromethyl)piperidin-1-yl)heptyl)oxy)quinazolin-4-amine A66;
(R)-6-methoxy-2-methyl-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-((7-(4-(trifluoromethyl)piperidin-1-yl)heptyl)oxy)quinazolin-4-amine A67;
(R)-7-((6-methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)-1-(piperidin-1-yl)heptan-1-one A68;
(S)-7-((6-methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)oxy)-1-(piperidin-1-yl)heptan-1-one A69;
(R)—N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methyl-7-((7-((3,3,3-trifluoro-propyl)amino)heptyl)oxy)quinazolin-4-amine A70;
(R)-7-((7-(3,9-diazaspiro[5.5]undecan-3-yl)heptyl)oxy)-N-(1-(3-bromophenyl)-ethyl)-6-methoxy-2-methylquinazolin-4-amine A71;
tert-butyl (R)-9-(7-((4-((1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methyl-quinazolin-7-yl)oxy)heptyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate A72;
(R)—N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methyl-7-(4-(pyridin-4-yl)-butoxy)quinazolin-4-amine A73;
(R)—N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methyl-7-((7-(2,2,6,6-tetramethyl-piperidin-1-yl)heptyl)oxy)quinazolin-4-amine A74;
(R)—N-(1-(3-bromophenyl)ethyl)-6-methoxy-2-methyl-7-((7-morpholinoheptyl)-oxy)quinazolin-4-amine A75;
(R)-6-methoxy-2-methyl-7-((7-(piperidin-1-yl)heptyl)oxy)-N-(1-(3-(trifluoro-methyl)phenyl)ethyl)quinazolin-4-amine A76;
8-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)oxy)-N—((S)-2,6-dioxopiperidin-3-yl)octanamide A77;
(R)-7-methoxy-2-methyl-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6-((7-(piperidin-1-yl)heptyl)oxy)quinazolin-4-amine B1;
(R)—N-(1-(3-bromophenyl)ethyl)-7-methoxy-2-methyl-6-((7-(piperidin-1-yl)heptyl)oxy)quinazolin-4-amine B2;
(R)-2,2-difluoro-2-(3-(1-((7-methoxy-2-methyl-6-((7-(piperidin-1-yl)heptyl)oxy)quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol B3;
(R)—N-(1-(5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-((7-(piperidin-1-yl)heptyl)oxy)quinazolin-4-amine B4;
(R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-((7-(piperidin-1-yl)heptyl)oxy)quinazolin-4-amine B5;
(R)-6,7-dimethoxy-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-(8-(piperidin-1-yl)octyl)quinazolin-4-amine C1;
(R)—N-(1-(3-bromophenyl)ethyl)-6,7-dimethoxy-2-(8-(piperidin-1-yl)octyl)quinazolin-4-amine C2;
(R)-2-(3-(1-((6,7-dimethoxy-2-(8-(piperidin-1-yl)octyl)quinazolin-4-yl)amino)ethyl)phenyl)-2,2-difluoroethan-1-ol C3;
(R)-6,7-dimethoxy-2-(8-(piperidin-1-yl)octyl)-N-(1-(3-(trifluoromethyl)phenyl)-ethyl)quinazolin-4-amine C4;
(R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6,7-dimethoxy-2-(8-(piperidin-1-yl)octyl)quinazolin-4-amine C5;
or
(R)—N-(1-(3-bromophenyl)ethyl)-6,7-dimethoxy-2-methyl-8-(7-(piperidin-1-yl)heptyl)quinazolin-4-amine Dl;
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

88 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/550,960Filed 16 Mar 2022
Priority: 17 Mar 2021
Published: 20 Jun 2024
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

A61K 47/545
The modifying agent being an organic compound: heterocyclic compounds
C07D 239/94
With hetero atoms directly attached in position 4: nitrogen atoms
A61K 47/542
The modifying agent being an organic compound: carboxylic acids, e.g. a fatty acid or an amino acid
A61P 35/00
Antineoplastic agents

Family

Application63/162,500Us provisional application · filed 17 Mar 2021
Application63/216,536Us provisional application · filed 30 Jun 2021
US 2024/0197888 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula (II):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
or
a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
wherein:
U, V, X, Y, and R1 are (i) or (ii):
(i) one of U, V, X, and Y is —C(R4)═ or —N(R4)—;
and the remaining three of U, V, X, and Y are each independently —C(R5)═ or —N═;
R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
and
R4 is -L-RB;
or
(ii) U is —C(R5a)═ or —N═;
V is —C(R5b)═ or —N═;
X is —C(R5c)═ or —N═;
Y is —C(R5d)═ or —N═;
and
R1 is -L-RB;
L is a linker;
RB is C2-6 fluoroalkyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
R3 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
each R5, R5a, R5b, R5d, and R5d is independently (i) hydrogen, deuterium, cyano, halo, nitro, or oxo;
(ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(O)SR1a, —C(NR1a)NR1bR1c, —C(S)R1a, —C(S)OR1a, —C(S)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(O)SR1a, —OC(NR1a)NR1bR1c, —OC(S)R1a, —OC(S)OR1a, —OC(S)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(O)SR1d, —NR1aC(NR1d)NR1bR1c1, —NR1aC(S)R1d, —NR1aC(S)OR1d, —NR1aC(S)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c or —S(O)2NR1bR1c;
R2a and R2b are each independently hydrogen, deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl;
R2c is C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl;
and
each R1a, R1b, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
wherein each alkyl, heteroalkyl, fluoroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from:
(a) deuterium, cyano, halo, imino, nitro, and oxo;
(b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(O)SRa, —C(NRa)NRbRc, —C(S)Ra, —C(S)ORa, —C(S)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(O)SRa, —OC(NRa)NRbRc, —OC(S)Ra, —OC(S)ORa, —OC(S)NRbRc, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbRc, —OS(O)2NRbRc, —NRbRc, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbRc, —NRaC(O)SRd, —NRaC(NR1d)NRbRc, —NRaC(S)Rd, —NRaC(S)ORd, —NRaC(S)NRbRc, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbRc, and —S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium;
(ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
wherein each Qa is independently selected from:
(a) deuterium, cyano, halo, nitro, imino, and oxo;
(b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl;
and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, —C(S)Re, —C(S)ORe, —C(S)NRfRg, —ORe, —OC(O)Re, —OC(O)ORe, —OC(O)NRfRg, —OC(O)SRe, —OC(NRe)NRfRg, —OC(S)Re, —OC(S)ORe, —OC(S)NRfRg, —OS(O)Re, —OS(O)2Re, —OS(O)NRfRg, —OS(O)2NRfRg, —NRfRg, —NReC(O)Rh, —NReC(O)ORf, —NR C(O)NRfRg, —NReC(O)SRf, —NR C(NRh)NRfRg, —NReC(S)Rh, —NReC(S)ORf, —NReC(S)NRfRg, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRfRg, —NReS(O)2NRfRg, —SRe, —S(O)Re, —S(O)2Re, —S(O)NRfRg, and —S(O)2NRfRg;
wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium;
(ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.

37 more elements

Facts

Application

18/550,960Filed 16 Mar 2022

Priority

17 Mar 2021

Published

20 Jun 2024

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

A61K 47/545
The modifying agent being an organic compound: heterocyclic compounds
C07D 239/94
With hetero atoms directly attached in position 4: nitrogen atoms
A61K 47/542
The modifying agent being an organic compound: carboxylic acids, e.g. a fatty acid or an amino acid
A61P 35/00
Antineoplastic agents