IP Library › Patent Application 19451155

Patent Application

App. No. 19/451,155

QUINAZOLINONE DIONE COMPOUNDS AND USES THEREOF

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App. No.: 19/451,155

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Abstract

Provided are quinazolinone dione compounds for treating cardiac indications such as hypertrophic cardiomyopathy and diastolic dysfunction.

Claims (223)

1 . A method of treating a cardiovascular disease or a related condition, the method comprising administering to a subject in need thereof a compound or salt of Formula (IIIa):

or a salt thereof, wherein:

X 1 , X 2 , X 3 , and X 4 are each independently selected from C(R 1 ), N, and N + (—O − );

wherein no more than two of X 1 , X 2 , X 3 , and X 4 are N or N + (—O − );

each R 1 is independently selected from:

hydrogen;

halogen, —NO 2 , —CN, —OR 10a , —SR 10a , —N(R 10a ) 2 , —C(O)R 10a , —C(O)N(R 10a ) 2 , —N(R 10a )C(O)R 10a , —N(R 10a )C(O)N(R 10a ) 2 , —OC(O)N(R 10a ) 2 , —N(R 10a )C(O)OR 10a , —C(O)OR 10a , —OC(O)R 10a , —S(O)R 10a , and —S(O) 2 R 10a ;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10a , —SR 10a , —N(R 10a ) 2 , —C(O)R 10a , —C(O)N(R 10a ) 2 , —N(R 10a )C(O)R 10a , —C(O)OR 10a , —OC(O)R 10a , —N(R 10a )C(O)N(R 10a ) 2 , —OC(O)N(R 10a ) 2 , —N(R 10a )C(O)OR 10a , —S(O)R 10a , —S(O) 2 R 10a , —NO 2 , ═O, ═S, ═N(R 10a ), —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 9a ; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10a , —SR 10a , —N(R 10a ) 2 , —C(O)R 10a , —C(O)N(R 10a ) 2 , —N(R 10a )C(O)R 10a , —N(R 10a )C(O)N(R 10a ) 2 , —OC(O)N(R 10a ) 2 , —N(R 10a )C(O)OR 10a , —C(O)OR 10a , —OC(O)R 10a , —S(O)R 10a , —S(O) 2 R 10a , —NO 2 , ═O, ═S, ═N(R 10a ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 9a ;

R 2 is selected from:

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10b , —SR 10b , —N(R 10b ) 2 , —C(O)R 10b , —C(O)N(R 10b ) 2 , —N(R 10b )C(O)R 10b , —C(O)OR 10b , —OC(O)R 10b , —N(R 10b )C(O)N(R 10b ) 2 , —OC(O)N(R 10b ) 2 , —N(R 10b )C(O)OR 10b , —S(O)R 10b , —S(O) 2 R 10b , —NO 2 , ═O, ═S, —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R 9b ; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10b , —SR 10b , —N(R 10b ) 2 , —C(O)R 10b , —C(O)N(R 10b ) 2 , —N(R 10b )C(O)R 10b , —N(R 10b )C(O)N(R 10b ) 2 , —OC(O)N(R 10b ) 2 , —N(R 10b )C(O)OR 10b , —C(O)OR 10b , —OC(O)R 10b , —S(O)R 10b , —S(O) 2 R 10b , —NO 2 , ═O, ═S, ═N(R 10b ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 9b ;

R 5 and R 6 are each independently selected from:

hydrogen, halogen, —OR 10c , —SR 10c , —N(R 10c ) 2 , —NO 2 , and —CN;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, any of which is optionally substituted at each occurrence with one or more substituents independently selected from halogen, —OR 10c , —SR 10c , —N(R 10c ) 2 , —NO 2 , —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, —OR 10c , —SR 10c , —N(R 10c ) 2 , —NO 2 , and —CN; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10c , —SR 10c , —N(R 10c ) 2 , —NO 2 , and —CN; or

R 5 together with R 6 form a 3- to 10-membered heterocycle or C 3-10 carbocycle, wherein the 3- to 10-membered heterocycle or C 3-10 carbocycle is optionally substituted with one or more substituents independently selected from R 9c ;

R 7 is selected from:

hydrogen; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 10d , —SR 10d , —N(R 10d ) 2 , —NO 2 , and —CN;

R 8 is selected from:

hydrogen;

C 1 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 10e , —SR 10e , —N(R 10e ) 2 , —NO 2 , —CN, and 3- to 10-membered heterocycle, wherein each 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, —OR 10e , —SR 10e , —N(R 10e ) 2 , —NO 2 , and —CN; and

C 2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 10e , —SR 10e , —N(R 10e ) 2 , —NO 2 , —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, —OR 10e , —SR 10e , —N(R 10e ) 2 , —NO 2 , and —CN;

each R 9a is independently selected from:

halogen, —OH, —O(C 2-6 alkyl), —O(C 1-6 haloalkyl), —SR 10a , —N(R 10a ) 2 , —C(O)R 10a , —C(O)N(R 10a ) 2 , —N(R 10a )C(O)R 10a , —N(R 10a )C(O)N(R 10a ) 2 , —OC(O)N(R 10a ) 2 , —N(R 10a )C(O)OR 10a , —C(O)OR 10a , —OC(O)R 10a , —S(O)R 10a , —S(O) 2 R 10a , —NO 2 , ═O, ═S, ═N(R 10a ), and —CN; and

C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10a , —SR 10a , —N(R 10a ) 2 , —C(O)R 10a , —C(O)N(R 10a ) 2 , —N(R 10a )C(O)R 10a , —N(R 10a )C(O)N(R 10a ) 2 , —OC(O)N(R 10a ) 2 , —N(R 10a )C(O)OR 10a , —C(O)OR 10a , —OC(O)R 10a , —S(O)R 10a , —S(O) 2 R 10a , —NO 2 , ═O, ═S, ═N(R 10a ), and —CN;

each R 9b is independently selected from:

halogen, —OR 10b , —SR 10b , —N(R 10b ) 2 , —C(O)R 10b , —C(O)N(R 10b ) 2 , —N(R 10b )C(O)R 10b , —N(R 10b )C(O)N(R 10b ) 2 , —OC(O)N(R 10b ) 2 , —N(R 10b )C(O)OR 10b , —C(O)OR 10b , —OC(O)R 10b , —S(O)R 10b , —S(O) 2 R 10b , —NO 2 , ═O, ═S, ═N(R 10b ), and —CN; and

C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10b , —SR 10b , —N(R 10b ) 2 , —C(O)R 10b , —C(O)N(R 10b ) 2 , —N(R 10b )C(O)R 10b , —N(R 10b )C(O)N(R 10b ) 2 , —OC(O)N(R 10b ) 2 , —N(R 10b )C(O)OR 10b , —C(O)OR 10b , —OC(O)R 10b , —S(O)R 10b , —S(O) 2 R 10b , —NO 2 , ═O, ═S, ═N(R 10b ), and —CN;

each R 9c is independently selected from:

halogen, —OR 10c , —SR 10c , —N(R 10c ) 2 , —C(O)R 10c , —C(O)N(R 10c ) 2 , —N(R 10c )C(O)R 10c , —N(R 10c )C(O)N(R 10c ) 2 , —OC(O)N(R 10c ) 2 , —N(R 10c )C(O)OR 10c , —C(O)OR 10c , —OC(O)R 10c , —S(O)R 10c , —S(O) 2 R 10c , —NO 2 , ═O, ═S, ═N(R 10c ), and —CN; and

C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10c , —SR 10c , —N(R 10c ) 2 , —C(O)R 10c , —C(O)N(R 10c ) 2 , —N(R 10c )C(O)R 10c , —N(R 10c )C(O)N(R 10c ) 2 , —OC(O)N(R 10c ) 2 , —N(R 10c )C(O)OR 10c , —C(O)OR 10c , —OC(O)R 10c , —S(O)R 10c , —S(O) 2 R 10c , —NO 2 , ═O, ═S, ═N(R 10c ), and —CN;

each R 10a is independently selected from:

hydrogen;

C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 3-10 carbocycle, and 3- to 10-membered heterocycle; and

C 3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and C 1-6 haloalkyl;

each R 10b is independently selected from:

hydrogen;

each R 10c is independently selected from:

hydrogen;

each R 10d is independently selected from:

hydrogen;

each R 10e is independently selected from:

hydrogen;

wherein when R 5 or R 6 is isopropyl; then R 2 is selected from:

C 3-10 carbocycle, 3- to 4-membered heterocycle, and 6- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10b , —SR 10b , —N(R 10b ) 2 , —C(O)R 10b , —C(O)N(R 10b ) 2 , —N(R 10b )C(O)R 10b , —N(R 10b )C(O)N(R 10b ) 2 , —OC(O)N(R 10b ) 2 , —N(R 10b )C(O)OR 10b , —C(O)OR 10b , —OC(O)R 10b , —S(O)R 10b , —S(O) 2 R 10b , —NO 2 , ═O, ═S, ═N(R 10b ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 9b ; and

5-membered heterocycle, optionally substituted with one or more substituents independently selected from halogen, —OR 10b , —SR 10b , —N(R 10b ) 2 , —C(O)R 10b , —C(O)N(R 10b ) 2 , —N(R 10b )C(O)R 10b , —N(R 10b )C(O)N(R 10b ) 2 , —OC(O)N(R 10b ) 2 , —N(R 10b )C(O)OR 10b , —C(O)OR 10b , —OC(O)R 10b , —S(O)R 10b , —S(O) 2 R 10b , —NO 2 , ═O, ═S, ═N(R 10b ), —CN, C 2-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 2-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 9b .

2 . The method of claim 1 , wherein at least one of X 1 , X 2 , X 3 , and X 4 is N or N + (—O − ); and no more than two of X 1 , X 2 , X 3 , and X 4 are N or N+(—O − ).

3 . The method of claim 1 , wherein X 1 , X 2 , X 3 , and X 4 are each independently selected from C(R 1 ).

4 . The method of claim 3 , wherein no more than three of X 1 , X 2 , X 3 , and X 4 are C(H).

5 . The method of claim 1 , wherein each R 1 is independently selected from: hydrogen; halogen, —NO 2 , —CN, —OR 10a , —SR 10a , —N(R 10a ) 2 , —C(O)R 10a , and —C(O)N(R 10a ) 2 ; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, —OR 10a , —SR 10a , and —N(R 10a ) 2 ; and C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10a , —SR 10a , and —N(R 10a ) 2 .

6 . The method of claim 1 , wherein R 2 is selected from C 2 alkyl substituted with one or more substituents independently selected from 3- to 10-membered heterocycle, wherein 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from chloro, fluoro, —CN, —CH 3 , and —OH.

7 . The method of claim 1 , wherein R 2 is selected from

wherein:

Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from N, C(H), C(F), C(CN), C(CH 3 ), C(Cl), and C(OH);

at least one of Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 is N; and

Q 1 is a C 1-3 alkyl optionally substituted with one or more substituents selected from —OH and —F.

8 . The method of claim 1 , wherein R 5 and R 6 are —H.

9 . The method of claim 1 , wherein R 5 together with R 6 form a cyclopropyl.

10 . The method of claim 1 , wherein R 7 is —H, and R 8 is —H.

11 . The method of claim 1 , wherein:

X 1 , X 2 , X 3 , and X 4 are each independently selected from C(R 1 ), and N;

wherein no more than two of X 1 , X 2 , X 3 , and X 4 are N;

each R 1 is independently selected from:

hydrogen;

halogen, —NO 2 , —CN, —OH, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —SH, —S(C 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ;

C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, —NO 2 , —CN, —OH, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —SH, —S(C 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 , C 3-10 carbocycle and 3- to 10-membered heterocycle; and

R 2 is selected from:

C 1-6 alkyl, optionally substituted with one or more substituents independently selected from: halogen, —NO 2 , —CN, —OH, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —SH, —S(C 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ; and

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —NO 2 , —CN, —OH, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —SH, —S(C 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 , C 1-6 haloalkyl, and C 1-6 alkyl; and C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, —NO 2 , —CN, —OH, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —SH, —S(C 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ; and C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, —NO 2 , —CN, —OH, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —SH, —S(C 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ;

R 5 and R 6 are each independently selected from:

hydrogen, halogen, and —CN;

C 1-6 alkyl, optionally substituted at each occurrence with one or more substituents independently selected from halogen, —NO 2 , —CN, —OH, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —SH, —S(C 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ; and

R 5 together with R 6 form a 3- to 10-membered heterocycle or C 3-10 carbocycle, optionally substituted with one or more substituents independently selected from C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, —NO 2 , —CN, —OH, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —SH, —S(C 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ; and C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, —NO 2 , —CN, —OH, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), —SH, —S(C 1-6 alkyl), —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 , C 3-10 carbocycle and 3- to 10-membered heterocycle;

R 7 is selected from: hydrogen; and

R 8 is selected from: hydrogen.

12 . The method of claim 1 , wherein the compound or salt is selected from:

or a salt of any one thereof.

13 . The method of claim 1 , wherein the compound or salt is selected from:

or a salt of any one thereof.

14 . The method of claim 1 , wherein the compound or salt is selected from:

or a salt thereof.

15 . The method of claim 1 , wherein the cardiovascular disease or related condition comprises heart failure, a hypertrophy, or left ventricular stiffness.

16 . The method of claim 1 , wherein the cardiovascular disease or related condition is selected from: heart failure with preserved ejection fraction (HFpEF), heart failure with mid-ranged ejection fraction (HFmrEF), heart failure with reduced ejection fraction (HFrEF), cardiomyopathy, cardiac transplant allograft vasculopathy, valve disease, left ventricular (LV) hypertrophy, right ventricular (RV) hypertrophy, acute myocardial infarction, and acute revascularization.

17 . The method of claim 1 , wherein the patient exhibits arrhythmia, stroke, ischemia, angina, or myocarditis.

18 . The method of claim 1 , wherein the cardiovascular disease or related condition is selected from left ventricular (LV) hypertrophy.

19 . The method of claim 1 , wherein the cardiovascular disease or related condition is HFpEF.

20 . The method of claim 14 , wherein the cardiovascular disease or related condition is hypertrophic cardiomyopathy.

21 . The method of claim 19 , wherein the HFpEF comprises disorders of relaxation, disorders of chamber stiffness, or diabetic HFpEF.

22 . The method of claim 1 , wherein the cardiovascular disease or related condition is cardiomyopathy.

23 . The method of claim 1 , wherein the cardiovascular disease or related condition is hypertrophic cardiomyopathy.

24 . The method of claim 14 , wherein the cardiovascular disease or related condition is hypertrophic cardiomyopathy.

25 . The method of claim 1 , wherein the cardiovascular disease or related condition is obstructive hypertrophic cardiomyopathy.

26 . The method of claim 14 , wherein the cardiovascular disease or related condition is obstructive hypertrophic cardiomyopathy.

27 . The method of claim 1 , wherein the cardiovascular disease or related condition is non-obstructive hypertrophic cardiomyopathy.

28 . The method of claim 14 , wherein the cardiovascular disease or related condition is non-obstructive hypertrophic cardiomyopathy.

29 . The method of claim 1 , wherein the cardiovascular disease or the related condition comprises heart attack, heart infection, endocarditis, myocarditis, pericarditis, abnormal heart rhythms, aorta disease, Marfan syndrome, congenital heart disease, coronary artery disease, rhematic heart disease, peripheral vascular disease, heart valve disease, pericardial disease, deep vein thrombosis, or pulmonary embolism.

30 . A method of modulating myosin, the method comprising administering to a patient in need thereof a compound or salt of Formula (IIIa):

or a salt thereof, wherein:

X 1 , X 2 , X 3 , and X 4 are each independently selected from C(R 1 ), N, and N + (—O − );

wherein no more than two of X 1 , X 2 , X 3 , and X 4 are N or N + (—O − );

each R 1 is independently selected from:

hydrogen;

R 2 is selected from:

R 5 and R 6 are each independently selected from:

hydrogen, halogen, —OR 10c , —SR 10c , —N(R 10c ) 2 , —NO 2 , and —CN;

R 7 is selected from:

hydrogen; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 10d , —SR 10d , —N(R 10d ) 2 , —NO 2 , and —CN;

R 8 is selected from:

hydrogen;

C 1 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 10e , —SR 10e N(R 10e ) 2 , —NO 2 , —CN, and 3- to 10-membered heterocycle, wherein each 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, —OR 10e , —SR 10e N(R 10e ) 2 , —NO 2 , and —CN; and

each R 9a is independently selected from:

each R 9b is independently selected from:

each R 9c is independently selected from:

each R 10a is independently selected from:

hydrogen;

each R 10b is independently selected from:

hydrogen;

each R 10c is independently selected from:

hydrogen;

each R 10d is independently selected from:

hydrogen;

each R 10e is independently selected from:

hydrogen;

wherein when R 5 or R 6 is isopropyl; then R 2 is selected from:

31 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound or salt of Formula (IIIa):

or a salt thereof, wherein:

X 1 , X 2 , X 3 , and X 4 are each independently selected from C(R 1 ), N, and N + (—O − );

wherein no more than two of X 1 , X 2 , X 3 , and X 4 are N or N + (—O − );

each R 1 is independently selected from:

hydrogen;

R 2 is selected from:

R 5 and R 6 are each independently selected from:

hydrogen, halogen, —OR 10c , —SR 10c , —N(R 10c ) 2 , —NO 2 , and —CN;

C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10e , —SR 10c , —N(R 10c ) 2 , —NO 2 , and —CN; or

R 7 is selected from:

hydrogen; and

C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 10d , —SR 10d , —N(R 10d ) 2 , —NO 2 , and —CN;

R 8 is selected from:

hydrogen;

C 2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR 10e , —SR 10e N(R 10e ) 2 , —NO 2 , —CN, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C 3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, —OR 10c , —SR 10c , —N(R 10e ) 2 , —NO 2 , and —CN;

each R 9a is independently selected from:

each R 9b is independently selected from:

each R 9c is independently selected from:

each R 10a is independently selected from:

hydrogen;

each R 10b is independently selected from:

hydrogen;

each R 10c is independently selected from:

hydrogen;

each R 10a is independently selected from:

hydrogen;

each R 10c is independently selected from:

hydrogen;

wherein when R 5 or R 6 is isopropyl; then R 2 is selected from:

C 3-10 carbocycle, 3- to 4-membered heterocycle, and 6- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR 10 , —SR 10b , —N(R 10b ) 2 , —C(O)R 10b , —C(O)N(R 10b ) 2 , —N(R 10b )C(O)R 10b , —N(R 10b )C(O)N(R 10b ) 2 , —OC(O)N(R 10b ) 2 , —N(R 10b )C(O)OR 10b , —C(O)OR 10b , —OC(O)R 10b , —S(O)R 10b , —S(O) 2 R 10b , —NO 2 , ═O, ═S, ═N(R 10b ), —CN, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from R 9b ; and