IP Library › Granted Patent US 12,419,962

Granted Patent B2

US 12,419,962 · App. 18/184,077 · Granted Sep 23, 2025

Quinazolines, pharmaceutical compositions, and therapeutic applications

Inventors: Paul E. Erdman (San Diego, CA); Leah M. Fung (San Diego, CA); Patrick Papa (Carlsbad, CA); Brandon W. Whitefield (San Diego, CA)

Assignee: BioTheryX, Inc.

A61K47/55 A61K47/545 A61P1/00 A61P35/00 C07D401/12 C07D401/14 C07D417/14 C07D471/04

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Quick Facts

Patent No.: US 12,419,962
App. No.: 18/184,077
Granted: Sep 23, 2025
Kind: B2

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Abstract

Provided herein are quinazolines, e.g., 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 an SOS1-mediated disorder, disease, or condition.

Claims (153)

1. A compound of Formula (I):

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, or hydrate thereof; wherein:

R 1 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;

R 3 , R 4a , R 4b , and R 4c are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(NR 1a ) NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 14 , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ,

R 2a and R 2b are each independently hydrogen, deuterium, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;

R 2c is C 3-10 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;

R E is a moiety having the structure of Formula (EC-I), (EC-XV), (EC-XXVIII), or (EC-XXXV):

wherein:

each A E is independently a bond, —O—, —N(R 1b )—, —S—, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, C 2-6 heteroalkenylene, C 2-6 alkynylene, C 2-6 heteroalkynylene, C 3-10 cycloalkylene, C 6-14 arylene, C 7-15 aralkylene, heteroarylene, heterocyclylene, C 1-6 heteroalkylene-C 6-14 arylene, C 1-6 heteroalkylene-heterocyclylene, or C 2-6 alkynylene-heterocyclylene;

each X E is independently C(R E1 ) or N;

Y E is a bond, C 1-6 alkylene, —O—, —S—, —S(O)—, —S(O 2 )—, or —N(R E7 )—;

Z is —CH 2 — or —C(O)—;

one of Z 1 , Z 2 , Z 3 , and Z 4 is —C═ and the remaining three of Z 1 , Z 2 , Z 3 , and Z 4 are each independently —C(R E5 )═; or Z 1 is a bond; one of Z 2 , Z 3 , and Z 4 is —C═, and the remaining two of Z 2 , Z 3 , and Z 4 are each independently —C(R E5 )═ or —S—;

each R E1 is independently hydrogen, deuterium, halo, or C 1-6 alkyl;

each R E2 is independently hydrogen or C 1-6 alkyl;

R E3 is hydrogen, deuterium, halo, or C 1-6 alkyl;

each R E4 is independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a ) NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(NR 1a ) NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(NR 1d ) NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;

each R E5 is independently hydrogen or R E4 ;

R E6 is (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a ) NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(NR 1a ) NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 14 , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(NR 1d ) NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;

R E7 is hydrogen or C 1-6 alkyl;

each m is independently an integer of 0, 1, or 2; and

each n is independently an integer of 0, 1, 2, or 3;

L is a linker having the structure of —Z L —(R L —Z L ) z —, wherein:

each R L is independently C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, C 3-10 cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene;

each Z L is independently a bond, —C(O)—, —C(O)O—, —C(O)NR 1b , —C(O)S—, —C(NR 1a ) NR 1b —, —C(S)—, —C(S)O—, —C(S)NR 1b —, —O—, —OC(O)O—, —OC(O)NR 1b —, —OC(O)S—, —OC(NR 1a ) NR 1b —, —OC(S)—, —OC(S)O—, —OC(S)NR 1b —, —OS(O)—, —OS(O) 2 —, —OS(O)NR 1b —, —OS(O) 2 NR 1b —, —NR 1b —, —NR 1a C(O)NR 1b —, —NR 1a C(O)S—, —NR 1a C(NR 1d ) NR 1b —, —NR 1a C(S)NR 1b —, —NR 1a S(O)NR 1b —, —NR 1a S(O) 2 NR 1b —, —S—, —S(O)—, —S(O) 2 —, —S(O)NR 1b —, or —S(O) 2 NR 1b —; and

z is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;

with the proviso that the compound is not any one of 3-(4-(1-(7-(4-(((R)-1-(3-bromo-phenyl)ethyl)amino)-6,7-dimethoxy-2-methyl-quinazolin-8-yl) heptyl)-piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione; 3-(4-(1-(7-(6,7-dimethoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)-phenyl)thiophen-2-yl)ethyl)amino) quinazolin-8-yl) heptyl)-piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione; and 3-(4-(1-(7-(6,7-dimethoxy-2-methyl-4-(((S)-1-(4-(2-((methylamino)methyl)-phenyl)thiophen-2-yl)ethyl)amino)-quinazolin-8-yl) heptyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione;

wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more substituents Q a , and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(O)SR a , —C(NR a ) NR b R c , —C(S)R a , —C(S)OR a , —C(S)NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(O)SR a , —OC(NR a ) NR b R c , —OC(S)R a , —OC(S)OR a , —OC(S)NR b R c , —OP(O)(OR b ) OR c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(O)SR d , —NR a C(NR d ) NR b R c , —NR a C(S)R 4 , —NR a C(S)OR d , —NR a C(S)NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d is independently (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; or (iii) Rb and Re together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q a ;

wherein each Q a is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , —C(O)OR e , —C(O)NR f R g , —C(O)SR e , —C(NR e ) NR f R g , —C(S)R e , —C(S)OR e , —C(S)NR f R g , —OR e , —OC(O)R e , —OC(O)OR e , —OC(O)NR f R g , —OC(O)SR e , —OC(NR e ) NR f R g , —OC(S)R e , —OC(S)OR e , —OC(S)NR f R g , —OP(O)(OR f )OR g , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR f R g , —OS(O) 2 NR f R g , —NR f R g , —NR e C(O)R h , —NR e C(O)OR f , —NR e C(O)NR f R g , —NR e C(O)SR f , —NR e C(NR h ) NR f R g , —NR e C(S)R h , —NR e C(S)OR f , —NR e C(S)NR f R g , —NR e S(O)R h , —NR e S(O) 2 R h , —NR e S(O)NR f R g , —NR e S(O) 2 NR f R g , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR f R g , and —S(O) 2 NR f R g ; wherein each R e , R f , R g , and R h is independently (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and R g together with the N atom to which they are attached form heterocyclyl.

2. The compound of claim 1 , wherein R 2c is C 6-14 aryl or heteroaryl, each of which is optionally substituted with one, two, or three substituents Q.

3. The compound of claim 2 , wherein R 2c is 3-cyano-phenyl, 3-bromo-phenyl, 3-methylphenyl, 3-difluoromethylphenyl, 3-trifluoromethylphenyl, 3-(1,1-difluoroethyl)phenyl, 3-(1-cyano-1-fluoromethyl)phenyl, 3-(1-cyano-1,1-difluoromethyl)-phenyl, 3-(1,1-difluoro-2-hydroxyethyl)phenyl, 3-(2-aminomethylphenyl)phenyl, 3-cyano-5-fluorophenyl, 3-cyano-2-methylphenyl, 3-cyano-5-methylphenyl, 3-cyano-2-trifluoromethyl-phenyl, 3-cyano-5-hydroxyphenyl, 3-cyano-2-methoxyphenyl, 2,3-difluorophenyl, 2,4-difluoro-phenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-3-difluoromethylphenyl, 2-chloro-3-methylphenyl, 3-chloro-2-methylphenyl, 3-difluoromethyl-2-fluorophenyl, 3-difluoro-methyl-2-methylphenyl, 2-fluoro-3-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl, 2-fluoro-3-methylphenyl, 3-fluoro-2-methylphenyl, 3-fluoro-4-methylphenyl, 4-fluoro-2-methylphenyl, 2-fluoro-3-difluoromethylphenyl, 2-fluoro-3-trifluoromethylphenyl, 3-fluoro-5-trifluoromethyl-phenyl, 2-fluoro-methyl-3-difluoromethylphenyl, 2,3-di (difluoromethyl)phenyl, 2-methyl-3-trifluoromethylphenyl, 2-ethyl-3-difluoromethylphenyl, 2-methyl-3-methylaminomethylphenyl, 2-methyl-3-methylsulfonylphenyl, 3-methyl-5-trifluoromethylphenyl, 3-hydroxy-5-trifluoro-methylphenyl, 3-amino-5-trifluoromethylphenyl, 3-amino-4-fluoro-5-trifluoromethylphenyl, 5-amino-2-fluoro-3-trifluoromethylphenyl, 5-amino-2-methyl-3-trifluoromethylphenyl, 3-cyano-2,5-difluorophenyl, 3-cyano-5-fluoro-2-methylphenyl, 5-fluoro-2-methyl-3-trifluoromethyl-phenyl, 1,1-difluoro-2,3-dihydroinden-4-yl, naphth-1-yl, 5-(2-aminomethylphenyl) thien-2-yl, 5-(2-(2-aminoethyl)-phenyl) thien-2-yl, 4-(2-methylaminomethylphenyl) thien-2-yl, 4-(2-dimethyl-aminomethyl-phenyl) thien-2-yl, 5-(2-methylaminomethylphenyl) thien-2-yl, 5-(3-fluoro-2-methylaminomethylphenyl) thien-2-yl, 5-(2-dimethylaminomethylphenyl) thien-2-yl, 2-methyl-pyridin-3-yl, 4-amino-6-difluoromethylpyridin-2-yl, 4-amino-6-trifluoromethylpyridin-2-yl, or 3,3-difluoro-2,3-dihydrobenzofuran-7-yl.

4. The compound of claim 1 , having the structure 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, or hydrate thereof; wherein:

R 5a , R 5b , R 5c , R 5d , and R 5e are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a ) NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(NR 1a ) NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 14 , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(NR 1d ) NR 1b R 1c , —NR 1a C(S)R 14 , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a s (O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c , or

R 5a and R 5b or R 5b and R 5c together with the carbon atoms to which they are attached form C 5-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

5. The compound of claim 4 , having the structure of Formula (XI):

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, or hydrate thereof.

6. The compound of claim 4 , having the structure of Formula (XII):

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, or hydrate thereof.

7. The compound of claim 4 , wherein the compound is a compound of Formula (XIII):

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, or hydrate thereof.

8. The compound of claim 4 , wherein the compound is a compound of Formula (XIV):

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, or hydrate thereof.

9. The compound of claim 4 , having the structure of Formula (XV):

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, or hydrate thereof.

10. The compound of claim 4 , having the structure of Formula (XVI):

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, or hydrate thereof.

11. The compound of claim 1 , wherein R E is a moiety having the structure of Formula (EC-I):

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;

wherein:

A E is a bond, —O—, —N(R 1b )—, —S—, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, C 2-6 heteroalkenylene, C 2-6 alkynylene, C 2-6 heteroalkynylene, C 3-10 cycloalkylene, C 6-14 arylene, C 7-15 aralkylene, heteroarylene, heterocyclylene, C 1-6 heteroalkylene-C 6-14 arylene, C 1-6 heteroalkylene-heterocyclylene, or C 2-6 alkynylene-heterocyclylene;

Z is —CH 2 — or —C(O)—;

one of Z 1 , Z 2 , Z 3 , and Z 4 is —C═ and the remaining three of Z 1 , Z 2 , Z 3 , and Z 4 are each independently —C(R E5 )═; or Z 1 is a bond; one of Z 2 , Z 3 , and Z 4 is —C—, and the remaining two of Z 2 , Z 3 , and Z 4 are each independently —C(R E5 )═ or —S—;

m is an integer of 0, 1, or 2;

R E1 is hydrogen, deuterium, halo, or C 1-6 alkyl;

R E2 is hydrogen or C 1-6 alkyl;

each R E5 is independently hydrogen or R E4 ,

wherein each alkyl, heteroalkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q.

12. The compound of claim 1 , wherein R E is a moiety having the structure of Formula (EC-XV):

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;

wherein:

one of Z 1 , Z 2 , Z 3 , and Z 4 is —C═ and the remaining three of Z 1 , Z 2 , Z 3 , and Z 4 are each independently —C(R E5 )—; or Z 1 is a bond; one of Z 2 , Z 3 , and Z 4 is —C—, and the remaining two of Z 2 , Z 3 , and Z 4 are each independently —C(R E5 )═ or —S—;

m is an integer of 0, 1, or 2;

R E1 is hydrogen, deuterium, halo, or C 1-6 alkyl;

R E2 is hydrogen or C 1-6 alkyl;

R E3 is hydrogen, deuterium, halo, or C 1-6 alkyl;

each R E4 is independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a ) NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(NR 1a ) NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 14 , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(NR 1d ) NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a s (O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; and

each R E5 is independently hydrogen or R E4 ,

13. The compound of claim 1 , wherein R E is a moiety having the structure of:

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;

wherein:

X E is C(R E1 ) or N;

R E1 is hydrogen, deuterium, halo, or C 1-6 alkyl;

R E2 is hydrogen or C 1-6 alkyl;

each R E4 is independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a ) NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(NR 1a ) NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 14 , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(NR 1d ) NR 1b R 1c , —NR 1a C(S)R 14 , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 14 , —NR 1a s (O) 2 R 14 , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;

R E6 is (i) hydrogen; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a ) NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(NR 1a ) NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(NR 1d ) NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a s (O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;

m is an integer of 0, 1, or 2; and

n is an integer of 0, 1, 2, or 3;

14. The compound of claim 1 , wherein R E is a moiety having the structure of:

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;

wherein:

X E is C(R E1 ) or N;

Y E is a bond, C 1-6 alkylene, —O—, —S—, —S(O)—, —S(O 2 )—, or —N(R E7 )—;

R E1 is hydrogen, deuterium, halo, or C 1-6 alkyl;

R E2 is hydrogen or C 1-6 alkyl;

each R E4 is independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a ) NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(NR 1a ) NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(NR 1d ) NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a s (O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;

R E7 is hydrogen or C 1-6 alkyl;

m is an integer of 0, 1, or 2; and

n is an integer of 0, 1, 2, 3, or 4;

15. A pharmaceutical composition comprising the compound of claim 1 , 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, or hydrate thereof, and a pharmaceutically acceptable excipient.

16. The compound of claim 1 , wherein R E is a moiety having the structure of:

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.

17. The compound of claim 1 , wherein R E is a moiety having the structure of:

or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

18. The compound of claim 1 , wherein R E is a moiety having the structure of:

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.

19. The compound of claim 1 , wherein R E is a moiety having the structure of:

or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

20. The compound of claim 1 , wherein R E is a moiety having the structure of:

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.

21. The compound of claim 1 , wherein R E is a moiety having the structure of:

or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

22. The compound of claim 1 , wherein L is:

23. A compound of:

3-(4-(1-(6-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) hexyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A101;

3-(5-(4-(7-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) heptyl) piperazin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A102;

3-(4-(1-(6-(4-(((S)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) hexyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A103;

3-(4-(1-(7-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) heptyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A104;

3-(4-(1-(8-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) octyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A105;

3-(4-(1-(10-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) decyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A106;

3-(4-(1-(12-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) dodecyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A107;

3-(4-(1-(12-(4-(((S)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) dodecyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A108;

3-(5-(4-(7-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) heptyl) piperazin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A109;

3-(4-(1-(10-(4-(((S)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) decyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A110;

3-(4-(1-(8-(4-(((S)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) octyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A111;

3-(4-((4-(((7-(6,7-dimethoxy-2-methyl-4-(((S)-1-(4-(2-((methylamino)methyl)-phenyl)thiophen-2-yl)ethyl)amino) quinazolin-8-yl) heptyl)amino) methyl)benzyl)oxy)-1-oxoisoindolin-2-yl) piperidine-2,6-dione A112;

3-(4-((4-(((7-(6,7-dimethoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)-phenyl)thiophen-2-yl)ethyl)amino) quinazolin-8-yl) heptyl)amino) methyl)benzyl)oxy)-1-oxoisoindolin-2-yl) piperidine-2,6-dione A113;

3-(5-(1-(7-(4-(((S)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) heptyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A114;

3-(6-(1-(7-(6,7-dimethoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)-phenyl)thiophen-2-yl)ethyl)amino) quinazolin-8-yl) heptyl) piperidin-4-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione A115;

3-(6-(1-(7-(6,7-dimethoxy-2-methyl-4-(((S)-1-(4-(2-((methylamino)methyl)-phenyl)thiophen-2-yl)ethyl)amino) quinazolin-8-yl) heptyl) piperidin-4-yl)-1-oxoisoindolin-2-yl) piperidine-2,6-dione A116;

3-(4-(1-(7-(4-(((S)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) heptyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A117;

3-(4-((4-(((7-(4-(((R)-1-(3-bromophenyl)ethyl)amino)-6,7-dimethoxy-2-methyl-quinazolin-8-yl) heptyl)amino) methyl)benzyl)oxy)-1-oxoisoindolin-2-yl) piperidine-2,6-dione A118;

3-(5-(1-(5-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) pentyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A119;

3-(5-(1-(6-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) hexyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)-piperidine-2,6-dione A120;

3-(5-(1-((1-(3-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) propyl) piperidin-4-yl)methyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione A121;

3-(5-(1′-(4-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl)butyl)-[1,4′-bipiperidin]-4-yl)-6-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione A122;

3-(5-(1-(2-(4-(2-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl)ethyl) piperazin-1-yl)ethyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione A123;

3-(7-(2-(4-(4-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl)butyl) piperazin-1-yl)-2-oxoethoxy)-1-methyl-1H-indazol-3-yl) piperidine-2,6-dione A201;

3-(6-(2-(4-(4-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl)butyl) piperazin-1-yl)-2-oxoethoxy)-1-methyl-1H-indazol-3-yl) piperidine-2,6-dione A202;

3-(7-(2-(4-(6-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) hexyl) piperazin-1-yl)-2-oxoethoxy)-1-methyl-1/-indazol-3-yl) piperidine-2,6-dione A203;

3-(6-(2-(4-(6-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) hexyl) piperazin-1-yl)-2-oxoethoxy)-1-methyl-1/-indazol-3-yl) piperidine-2,6-dione A204;

3-(7-(2-(4-(8-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) octyl) piperazin-1-yl)-2-oxoethoxy)-1-methyl-1H-indazol-3-yl) piperidine-2,6-dione A205;

3-(6-(2-(4-(8-(4-(((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) amino)-6,7-dimethoxy-2-methylquinazolin-8-yl) octyl) piperazin-1-yl)-2-oxoethoxy)-1-methyl-1H-indazol-3-yl) piperidine-2,6-dione A206;

3-(4-(1-(7-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy) quinazolin-7-yl)oxy) heptyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione B101; or

3-(5-(1-(11-((4-(((R)-1-(3-bromophenyl)ethyl)amino)-6-methoxy-2-methyl-quinazolin-7-yl)oxy) undecanoyl) piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl) piperidine-2,6-dione B102;

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, or hydrate thereof.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 28, 2024

From: ERDMAN, PAUL E.; FUNG, LEAH M.; PAPA, PATRICK; WHITEFIELD, BRANDON

To: BIOTHERYX, INC.

Reel/Frame 066586/0983 →

Continuity (2)

Provisional Application 63269462 · Mar 16, 2022

Related Publication 20230293702A1 · Sep 21, 2023

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