EP-4735451-A1 - SUBSTITUTED CONDENSED TRICYCLIC AMINE COMPOUNDS AND USES THEREOF AS RAS INHIBITORS

Abstract

The present disclosure provides compounds of formula (Vc) and pharmaceutically acceptable salts thereof, and methods of using the same. The compounds and methods have a range of utilities as therapeutics, diagnostics, and research tools. In particular, the subject compositions and methods are useful for reducing signaling output of oncogenic protein.

Inventors

• WU, BAOGEN
• REN, PINGDA
• LI, LIANSHENG

Assignees

• Kumquat Biosciences Inc.

Dates

Publication Date

20260506

Application Date

20240628

Claims (1)

1. CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (Vc): or a pharmaceutically acceptable salt or solvate thereof, wherein: X is selected from C(R 6 ) and N; A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms; R 1 is selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, -C(O)OR 12 , -C(O)OC(O)R 12 , -C(O)O-(C1-6 alkyl)-OR 15 , -(C1-6 alkyl)-OR 15 , -C(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)2R 12 , -S(O)(NR 12 )R 12 , - S(O) 2 N(R 12 )(R 13 ), and -S(O)(NR 12 )N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ; R 2 , R 5 , and R 8 are each independently selected at each occurrence from hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 12 , -OR 15 , -O- (C 1-6 alkyl)-OR 15 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O) 2 R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , - S(O)2R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), and -OCH2C(O)OR 12 , wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ; R 3 is independently selected at each occurrence from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 12 , -OR 15 , -O-(C1-6 alkyl)-OR 15 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , -S(O) 2 R 12 , -S(O)(NR 12 )R 12 , - S(O) 2 N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), and -OCH 2 C(O)OR 12 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ; wherein two R 3 are optionally taken together with the atom or atoms to which they are attached to form C3-8 carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R 20 ; and further wherein two R 3 are optionally taken together to form =O, =NR 12 , or =C(R 14 ) 2 ; R 4 is selected from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 12 , -OR 15 , -O-(C 1-6 alkyl)-OR 15 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , - C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , -S(O)2R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ), - S(O)(NR 12 )N(R 12 )(R 13 ), and -OCH 2 C(O)OR 12 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ; or R 4 and R 5 , together with the atoms to which they are attached, form C 4-8 carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R 20 ; or R 3 and R 4 , together with the atoms to which they are attached, form 4- to 8-membered heterocycle optionally substituted with one, two, or three R 20 ; R 6 is selected from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 12 , -OR 15 , -O-(C1-6 alkyl)-OR 15 , -SR 12 , -SF5, -N(R 12 )(R 13 ), - C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -C(O)R 12 , -S(O)R 12 , - OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , -S(O) 2 R 12 , -S(O)(NR 12 )R 12 , - S(O) 2 N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), and -OCH 2 C(O)OR 12 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ; R 7 is selected from benzothiophenyl and thienopyridinyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from -OR 15 , -O-(C1-6 alkyl)-OR 15 , -NH(C1-6 alkyl)-OR 15 , - NHC(O)O-(C 1-6 alkyl)-OR 15 , (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-NH-, and R 20 ; m is 0, 1, 2, or 3; n is 1 or 2; R 12 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ; R 13 is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R 12 and R 13 attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R 20 ; R 14 is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two R 14 are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), C 3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R 20 ; R 15 is independently selected at each occurrence from (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, -C(O)OR 12 , -C(O)R 12 , -P(O)(Y-R 16 )(Z-R 17 ), and -CH 2 P(O)(Y-R 16 )(Z-R 17 ); Y and Z are independently selected at each occurrence from -O- and -N(R 12 )-; R 16 and R 17 are independently selected at each occurrence from hydrogen, C1-6 alkyl, and phenyl, wherein C1-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO 2 , -CN, C 3-12 carbocycle, 3- to 12-membered heterocycle, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O) 2 R 12 , -N(R 12 )S(O) 2 N(R 12 )(R 13 ), -S-S- R 12 , -S-C(O)R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -OC(O)OR 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), - N(R 12 )C(O)R 12 , -S(O)2R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), -P(O)(OR 12 )2, -P(O)(R 12 )2, -OP(O)(OR 12 ) 2 , =O, =S, and =NR 12 ; or R 16 and R 17 are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three R 20 ; R 20 is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -SF5, =N-OR 22 , =N-N(R 22 )(R 23 ), -P(O)(R 22 )(R 23 ), -ON=R 22 , -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), - N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), - C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -OS(O) 2 R 22 , -S(O) 2 R 22 , -S(O)(NR 22 )R 22 , -S(O) 2 N(R 22 )(R 23 )-, - S(O)(NR 22 )N(R 22 )(R 23 ), and -OCH 2 C(O)OR 22 ; wherein two R 20 attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C 3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -SF5, =N-OR 22 , =N- N(R 22 )(R 23 ), -P(O)(R 22 )(R 23 ), -ON=R 22 , -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), - N(R 22 )C(O)OR 22 , -N(R 22 )S(O) 2 R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), - N(R 22 )C(O)R 22 , -OS(O)2R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 ), and -S(O)(NR 22 )N(R 22 )(R 23 ); R 21 is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 are taken together with the carbon atom to which they are attached to form C 3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH; R 22 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle); and R 23 is independently selected at each occurrence from hydrogen and C1-6 alkyl; or R 22 and R 23 attached to the same nitrogen atom form 3- to 10 membered heterocycle. 2. A compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: X is selected from C(R 6 ) and N; A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms; R 1 is selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, -C(O)OR 12 , -C(O)OC(O)R 12 , -C(O)O-(C1-6 alkyl)-OR 15 , -(C1-6 alkyl)-OR 15 , -C(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)2R 12 , -S(O)(NR 12 )R 12 , - S(O) 2 N(R 12 )(R 13 ), and -S(O)(NR 12 )N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ; R 2 , R 3 , R 5 , R 6 , and R 8 are each independently selected at each occurrence from hydrogen, halogen, -CN, C 1- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 12 , -OR 15 , -O- (C 1-6 alkyl)-OR 15 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , - S(O)2R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), and -OCH2C(O)OR 12 , wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ; wherein two R 3 are optionally taken together with the atom or atoms to which they are attached to form C3-8 carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R 20 ; and further wherein two R 3 are optionally taken together to form =O, =NR 12 , or =C(R 14 )2; R 4 is selected from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 12 , -OR 15 , -O-(C1-6 alkyl)-OR 15 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , - C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , -S(O)2R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ), - S(O)(NR 12 )N(R 12 )(R 13 ), and -OCH 2 C(O)OR 12 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ; or R 4 and R 5 , together with the atoms to which they are attached, form C 4-8 carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R 20 ; or R 3 and R 4 , together with the atoms to which they are attached, form 4- to 8-membered heterocycle optionally substituted with one, two, or three R 20 ; R 7 is benzothiophenyl optionally substituted with one, two, three, or four substituents independently selected from -OR 15 , -O-(C 1-6 alkyl)-OR 15 , -NH(C 1-6 alkyl)-OR 15 , -NHC(O)O-(C 1-6 alkyl)-OR 15 , (5-methyl-2-oxo- 1,3-dioxol-4-yl)methyl-NH-, and R 20 ; m is 0, 1, 2, or 3; n is 1 or 2; R 12 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 ; R 13 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 12 and R 13 attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R 20 ; R 14 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 14 are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), C 3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R 20 ; R 15 is independently selected at each occurrence from (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, -C(O)OR 12 , -C(O)R 12 , -P(O)(Y-R 16 )(Z-R 17 ), and -CH2P(O)(Y-R 16 )(Z-R 17 ); Y and Z are independently selected at each occurrence from -O- and -N(R 12 )-; R 16 and R 17 are independently selected at each occurrence from hydrogen, C 1-6 alkyl, and phenyl, wherein C1-6 alkyl and phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, -NO2, -CN, C3-12 carbocycle, 3- to 12-membered heterocycle, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O) 2 R 12 , -N(R 12 )S(O) 2 N(R 12 )(R 13 ), -S-S- R 12 , -S-C(O)R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -OC(O)OR 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), - N(R 12 )C(O)R 12 , -S(O)2R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ), -S(O)(NR 12 )N(R 12 )(R 13 ), -P(O)(OR 12 )2, -P(O)(R 12 )2, -OP(O)(OR 12 )2, =O, =S, and =NR 12 ; or R 16 and R 17 are taken together with the atoms to which they are attached to form 3- to 12-membered heterocycle optionally substituted with one, two, or three R 20 ; R 20 is independently selected at each occurrence from halogen, oxo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 ) 2 , -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O) 2 R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -OS(O)2R 22 , -S(O)2R 22 , - S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 )-, -S(O)(NR 22 )N(R 22 )(R 23 ), and -OCH2C(O)OR 22 ; wherein two R 20 attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 ) 2 , -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O) 2 R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -OS(O)2R 22 , -S(O)2R 22 , - S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 ), and -S(O)(NR 22 )N(R 22 )(R 23 ); R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH; R 22 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkyl-(C 3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle); and R 23 is independently selected at each occurrence from hydrogen and C1-6 alkyl; or R 22 and R 23 attached to the same nitrogen atom form 3- to 10 membered heterocycle. 3. The compound, salt, or solvate of claim 1 or 2, wherein X is C(R 6 ). 4. The compound, salt, or solvate of claim 1 or 2, wherein X is N. 5. The compound, salt, or solvate of any one of claims 1 to 4, wherein A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. 6. The compound, salt, or solvate of any one of claims 1 to 4, wherein A is pyridinyl. 7. The compound, salt, or solvate of any one of claims 1 to 6, wherein R 1 is hydrogen. 8. The compound, salt, or solvate of any one of claims 1 to 7, wherein R 7 is benzo[b]thiophen-4-yl optionally substituted with one, two, three, or four R 20 . 9. The compound, salt, or solvate of any one of claims 1 to 8, wherein R 7 is substituted with fluorine, -CN, and -NH2. 10. The compound, salt, or solvate of any one of claims 1 to 9, wherein . 11. The compound, salt, or solvate of claim 1 or 2, having the structure of Formula (II-a): or a pharmaceutically acceptable salt or solvate thereof. 12. The compound, salt, or solvate of any one of claims 1 to 11, wherein R 3 is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R 20 . 13. The compound, salt, or solvate of any one of claims 1 to 11, wherein R 3 is independently selected at each occurrence from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, -OH, and -OCH3. 14. The compound, salt, or solvate of any one of claims 1 to 13, wherein m is 0 or 1. 15. The compound, salt, or solvate of any one of claims 1 to 11, wherein m is 0. 16. The compound, salt, or solvate of any one of claims 1 to 15, wherein R 6 and R 8 are independently selected from hydrogen, halogen, and C1-3 haloalkyl. 17. The compound, salt, or solvate of any one of claims 1 to 16, wherein R 6 is chlorine. 18. The compound, salt, or solvate of any one of claims 1 to 17, wherein R 8 is fluorine. 19. The compound, salt, or solvate of any one of claims 1 to 18, wherein n is 1. 20. The compound, salt, or solvate of any one of claims 1 to 19, wherein R 2 is -OR 12 . 21. The compound of claim 1, having the formula: ; or a pharmaceutically acceptable salt or solvate thereof, wherein: R 2 is -OR 12 ; R 4 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3- 12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3- 12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle) are optionally substituted with one, two, or three R 20 ; and R 5 is selected from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C 0-6 alkyl-(C 3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 12 , -OR 15 , -O-(C1-6 alkyl)-OR 15 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , -S(O) 2 R 12 , -S(O)(NR 12 )R 12 , -S(O) 2 N(R 12 )(R 13 ), - S(O)(NR 12 )N(R 12 )(R 13 ), and -OCH 2 C(O)OR 12 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R 20 . 22. The compound, salt, or solvate of any one of claims 1 to 21, wherein R 2 is selected from -O-CH 2 -(8- to 10- membered saturated heterocycle), -O-CH2-(cyclopropylene)-CH2-(5- to 8-membered saturated heterocycle), and -O- (C1-3 alkyl )-(5- to 8-membered non-aromatic heterocycle), wherein -O-CH2-(8- to 10-membered saturated heterocycle), -O-CH 2 -(cyclopropylene)-CH 2 -(5- to 8-membered saturated heterocycle), and -O-(C 1-3 alkyl )-(5- to 8- membered non-aromatic heterocycle) are optionally substituted with one or more substituents independently selected from =CF2, =CH2, =CHF, halogen, CN, -OCH3, -CHF2, C1-3 alkyl,-CH=N-OCH2CH3, =N-OCH2CH3, - S(O)(CH2CH3), -O-, =NOCH2CH3, =NOCH3, CH2P(O)(CH3)2, -CH2O(6-membered heteroaryl)-CF3, -CH2O(6- membered heteroaryl)-CHF 2 , -OCH 2 CH 2 CH 2 P(O)(CH 3 ) 2 , and -CH 2 N(C 1-3 alkyl) 2 . 23. The compound, salt, or solvate of any one of claims 1 to 21, wherein R 2 is -O(C 1-3 alkyl)(4- to 10- membered heterocycle) optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and =C(R 21 )2, wherein R 21 is independently selected at each occurrence from hydrogen, halogen, and C 1-3 alkyl. 24. The compound, salt, or solvate of any one of claims 1 to 21, wherein R 2 is selected from: 25. The compound, salt, or solvate of any one of claims 1 to 21, wherein R 2 is selected from: . 26. The compound, salt, or solvate of any one of claims 1 to 21, wherein R 2 is . 27. The compound, salt, or solvate of any one of any one of claims 1 to 26, wherein R 5 is selected from hydrogen, halogen, CN, cyclopropyl, C1-4 alkyl, -CF3, -C(O)CH3, -OCH3, -CH2NH2, -OCHF2, and -CH2N(C1-3 alkyl) 2 . 28. The compound, salt, or solvate of any one of any one of claims 1 to 26, wherein R 5 is selected from hydrogen and halogen. 29. The compound, salt, or solvate of any one of any one of claims 1 to 26, wherein R 5 is hydrogen. . The compound, salt, or solvate of any one of any one of claims 1 to 10, 12 to 20, and 22 to 26, wherein 31. The compound, salt, or solvate of any one of any one of claims 11 to 26, wherein . lt, or solvate of any one of any one of claims 1 to 10, 12 to 20, and 22 to 26, wherein . . The compound, salt, or solvate of any one of any one of claims 11 to 26, wherein . 34. The compound, salt, or solvate of any one of any one of claims 1 to 33, wherein R 4 is selected from C1-5 alkyl, C2-4 alkenyl, C2-3 alkynyl, -C1-2 alkyl-(C3-4 saturated carbocycle), and -C1-2 alkyl-(5- to 6-membered saturated heterocycle), -C 1-2 alkyl-(phenyl), and -C 1-2 alkyl-(5- to 6-membered heteroaryl), wherein C 1-5 alkyl, C 2-4 alkenyl, C 2- 3 alkynyl, -C 1-2 alkyl-(C 3-4 saturated carbocycle), and -C 1-2 alkyl-(5- to 6-membered saturated heterocycle), -C 1-2 alkyl-(phenyl), and -C1-2 alkyl-(5- to 6-membered heteroaryl) are optionally substituted with one or more substituents independently selected from halogen, -OH, -OCH3, -C(O)N(C1-3 alkyl)2, -N(C1-3 alkyl)2, -P(O)(CH3)2, - S(O)(CH 3 ), S(O) 2 CH 3 , and =N-OCH 2 CH 3 . 35. The compound, salt, or solvate of any one of any one of claims 1 to 33, wherein R 4 is selected from , 36. The compound, salt, or solvate of any one of any one of claims 1 to 33, wherein R 4 is C 1-3 alkyl optionally substituted with one, two, or three R 20 . 37. The compound, salt, or solvate of any one of any one of claims 1 to 33, wherein R 4 is CH3. 38. A compound selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof. 39. A pharmaceutical composition comprising a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. 40. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt or solvate thereof. 41. A method of treating cancer in a subject comprising a Ras mutant protein, the method comprising: inhibiting the Ras mutant protein of said subject by administering to said subject a compound of any one of claims 1 to 38, wherein the compound is characterized in that upon contacting the Ras mutant protein, said Ras mutant protein exhibits reduced Ras signaling output. 42. The method of claim 40 or 41, wherein the cancer is a solid tumor or a hematological cancer. 43. The method of any one of claims 40 to 42, wherein the cancer comprises a K-Ras G12C, G12D, G12S, or G12V mutant protein. 44. A method of modulating signaling output of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the signaling output of the Ras protein. 45. A method of inhibiting cell growth, comprising administering an effective amount of a compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells. 46. The method of any one of claims 40 to 45, comprising administering an additional agent. 47. The method of claim 46, wherein the additional agent comprises (1) an inhibitor of MEK; (2) an inhibitor of epidermal growth factor receptor (EGFR) and/or mutants thereof; (3) an immunotherapeutic agent; (4) a taxane; (5) an anti-metabolite; (6) an inhibitor of FGFR1 and/or FGFR2 and/or FGFR3 and/or mutants thereof; (7) a mitotic kinase inhibitor; (8) an anti-angiogenic drug; (9) a topoisomerase inhibitor; (10) a platinum-containing compound; (11) an inhibitor of c-MET and/or mutants thereof; (12) an inhibitor of BCR-ABL and/or mutants thereof; (13) an inhibitor of ErbB2 (Her2) and/or mutants thereof; (14) an inhibitor of AXL and/or mutants thereof; (15) an inhibitor of NTRK1 and/or mutants thereof; (16) an inhibitor of RET and/or mutants thereof; (17) an inhibitor of A-Raf and/or B-Raf and/or C-Raf and/or mutants thereof; (18) an inhibitor of ERK and/or mutants thereof; (19) an MDM2 inhibitor; (20) an inhibitor of mTOR; (21) an inhibitor of IGF1/2 and/or IGF1-R; (22) an inhibitor of CDK9; (23) an inhibitor of farnesyl transferase; (24) an inhibitor of SHIP pathway; (25) an inhibitor of SRC; (26) an inhibitor of JAK; (27) a PARP inhibitor, (28) a ROS1 inhibitor; (29) an inhibitor of SHP pathway; (30) an inhibitor of Src, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl or AKT; (31) an inhibitor of KRAS G12C; (32) an SHC inhibitor; (33) a GAB inhibitor; (34) a PI-3 kinase inhibitor; (35) a MARPK inhibitor; (36) a CDK4/6 inhibitor; (37) a MAPK inhibitor; (38) a SHP2 inhibitor; (39) a checkpoint immune blockade agent; (40) a SOS1 inhibitor; or (41) a SOS2 inhibitor. 48. The method of claim 46, wherein the additional agent comprises an inhibitor of SOS selected from RMC- 5845, BI-1701963, .

Description

SUBSTITUTED CONDENSED TRICYCLIC AMINE COMPOUNDS AND USES THEREOF AS RAS INHIBITORS CROSS-REFERENCE [001] This application claims the benefit of U.S. Provisional Application No. 63/511,279, filed June 30, 2023; U.S. Provisional Application No. 63/513,796, filed July 14, 2023; U.S. Provisional Application No. 63/582,484, filed September 13, 2023; U.S. Provisional Application No. 63/600,560, filed November 17, 2023; and U.S. Provisional Application No. 63/646,597, filed May 13, 2024, each incorporated herein by reference in its entirety. SEQUENCE LISTING [002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on June 20, 2024, is named 56690_771_601_SL.xml and is 14,003 bytes in size. BACKGROUND [003] Cancer (e.g., tumor, neoplasm, metastases) is the second leading cause of death worldwide estimated to be responsible for about 10 million deaths each year. Many types of cancers are marked with mutations in one or more proteins involved in various signaling pathways leading to unregulated growth of cancerous cells. In some cases, about 25 to 30 percent (%) of tumors are known to harbor Rat sarcoma (Ras) mutations. In particular, mutations in the Kirsten Ras oncogene (K-Ras) are one of the most frequent Ras mutations detected in human cancers, including lung adenocarcinomas (LUADs) and pancreatic ductal adenocarcinoma (PDAC). [004] Ras proteins have long been considered “undruggable,” due to, in part, high affinity to their substrate guanosine-5'-triphosphate (GTP) and/or their smooth surfaces without any obvious targeting region. The specific G12C Ras gene mutation has been identified as a druggable target to which a number of G12C specific inhibitors have been developed. However, such therapeutics are still of limited application, as the G12C mutation in Ras exhibits a much lower prevalence rate as compared to other known Ras mutations, such as G12D and G12V. Drug resistance and lack of durability impose further limitations to such therapeutics. SUMMARY [005] In view of the foregoing, there remains a considerable need for a new design of therapeutics and diagnostics that can specifically target Ras, including wildtype Ras, mutants and/or associated proteins of Ras to reduce Ras signaling output. Of particular interest are Ras inhibitors, including pan Ras inhibitors capable of inhibiting two or more Ras mutants and/or wildtype Ras, as well as mutant-selective inhibitors targeting mutant Ras proteins such as Ras G12D, G12C, G12S, G13D, and/or G12V, for the treatment of Ras-associated diseases (e.g., cancer). Such compositions and methods can be particularly useful for treating a variety of diseases including, but not limited to, cancers and neoplasia conditions. The present disclosure addresses these needs, and provides additional advantages applicable for diagnosis, prognosis, and/or treatment for a wide diversity of diseases. [006] In certain aspects, the present disclosure provides a compound of Formula (I): 1 or a pharmaceutically acceptable salt or solvate thereof, wherein: X is selected from C(R6) and N; A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms; R1 is selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, -C(O)OR12, -C(O)OC(O)R12, -C(O)O-(C1-6 alkyl)-OR15, -(C1-6 alkyl)-OR15, -C(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R12, -S(O)(NR12)R12, - S(O)2N(R12)(R13), and -S(O)(NR12)N(R12)(R13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20; R2, R3, R5, R6, and R8 are each independently selected at each occurrence from hydrogen, halogen, -CN, C1- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR12, -OR15, -O- (C1-6 alkyl)-OR15, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, - S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12