CD73 inhibitors

This application is a U.S. National Stage of International Application PCT/US2018/059004, filed Nov. 2, 2018, which claims the benefit of U.S. Provisional Application Ser. No. 62/581,574, filed Nov. 3, 2017, and U.S. Provisional Application Ser. No. 62/664,841, filed Apr. 30, 2018 each of which are hereby incorporated by reference in their entirety.

A need exists in the art for an effective treatment of cancer, infections, and neurodegenerative diseases.

Provided herein are compounds of Formulas (I), (II), (IIa), (IIb), (III), and (IV) or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as CD73 inhibitors. Furthermore, the subject compounds and compositions are useful for the treatment of cancers, infections, and neurodegenerative diseases.

Provided herein are compounds having the structure of Formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

A is —O— or —CH 2 —; Q 1 is CW and Q 2 is N; or Q 1 is N and Q 2 is N; W is hydrogen, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 , —OR 60 , —SR 61 , or —C 62 R 63 R 64 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 60 is hydrogen, —C(═O)R 15e , —C(═O)OR 16e , —C(═O)NR 16e R 17e , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m ;

R 61 is hydrogen, —C(═O)R 15f , —C(═O)OR 16f , —C(═O)NR 16f R 17f , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m ;

R 62 , R 63 , and R 64 are each independently hydrogen, halogen, —CN, —OH, —OR 15g , —SH, —SR 15g , —S(═O)R 15g , —NO 2 , —NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 15g , —C(═O)R 15g , —OC(═O)R 15g , —C(═O)OR 16g , —OC(═O)OR 17g , —C(═O)NR 16g R 17g , —OC(═O)NR 16g R 17g , —NR 16g C(═O)NR 16g R 17g , —NR 16g C(═O)R 15g , —NR 16g C(═O)OR 16g , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o ; R 3 is halogen, —CN, —OH, —OR 15b , —SR 18b , —NR 16b R 17b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16d C(═O)R 15c , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, —OH, —OR 15d , —NR 16c S(═O) 2 R 15d , —NR 16d C(═O)R 15d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30e ; X 1 is a bond; Y 1 is —S(═O) 2 —; Y 2 is —(CR 45 R 46 ) v2 —; R 45 and R 46 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v2 is 1-3; R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30g ; R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 17a , R 17b , R 17e , R 17f , and R 17g are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30h . or R 16a and R 17a or R 16b and R 17b or R 16e and R 17e or R 16f and R 17f or R 16g and R 17g are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 18b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30i ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , (CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30g , R 30h , R 30i , R 30j , R 30k , R 30l , R 30m , R 30n , and R 30o are independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —CN, —OH, —OR b , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

Also provided herein are compounds having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Q 3 and Q 4 are independently N or CW 1 ; provided that at least one of Q 3 or Q 4 is N; W 1 is hydrogen, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; A is —O— or —CH 2 —; Z is —NR 1 R 2 , —OR 60 , —SR 61 , or —CR 62 R 63 R 64 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ;

or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 60 is hydrogen, —C(═O)R 15e , —C(═O)OR 16e , —C(═O)NR 16e R 17e , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m .

R 61 is hydrogen, —C(═O)R 15f , —C(═O)OR 16f , —C(═O)NR 16f R 17f , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n ;

R 62 , R 63 , and R 64 are each independently hydrogen, halogen, —CN, —OH, —OR 15g , —SH, —SR 15g , —S(═O)R 15g , —NO 2 , —NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —OC(═O)R 15g , —C(═O)OR 16g , —OC(═O)OR 16g , —C(═O)NR 16g R 17g , —OC(═O)NR 16g R 17g , —NR 16g C(═O)NR 16g R 17g , —NR 16g C(═O)R 15g , —NR 16g C(═O)OR 16g , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o ; R 3 is halogen, —CN, —OH, —OR 15b , —SR 18b , —NR 16b R 17b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, —OH, —OR 15d , —NR 16d S(═O) 2 R 15d , —NR 16d C(═O)R 15d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X 1 is bond, —C(═O)—, —S(═O) 2 —, —O—, or —CR 40 R 41 —; Y 1 is —C(═O)—, —(CR 42 R 43 ) v1 —, —S(═O) 2 —, —NR 44 —, —S—, or —O—; Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—; R 40 , R 41 , R 42 , R 43 , R 45 , and R 46 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30p ; R 44 and R 47 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; v1 and v2 are each independently 1-3; R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30g ; R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 17a , R 17b , R 17e , R 17f , and R 17g are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30h . or R 16a and R 17a or R 16b and R 17b or R 16e and R 17e or R 16f and R 17f or R 16g and R 17g are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 18b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30i ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , (CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30j , R 30k , R 30l , R 30m , R 30n , R 30o , and R 30p are independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

Also disclosed herein are methods of inhibiting CD73 comprising contacting CD73 with a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

Also disclosed herein are methods of treating cancer in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof or administering to the subject a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

Also disclosed herein are methods of treating an infection in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof or administering to the subject a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

Also disclosed herein are methods of treating a neurodegenerative disease in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof or administering to the subject a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.

CD73 is a glycosylphosphatidylinositol (GPI) anchored cell surface protein that catalyzes the hydrolysis of AMP to adenosine, and works in concert with CD39, which converts ATP into AMP. The resulting adenosine functions as a signaling molecule that activates the P1 receptors expressed on the cell surface in many different tissues. Four G protein-coupled P1 or adenosine receptors have been cloned and designated as A1, A2A, A2B, and A3. Adenosine impacts a wide range of physiological processes including neural function, vascular perfusion, and immune responses. In doing so, this metabolite regulates CNS, cardiovascular, and immune system functions, to name a few.

Increasing evidence suggests that interactions between tumor cells and their microenvironment are essential for tumorigenesis. The purinergic signaling pathway in which CD73 plays a critical role, has emerged as an important player in cancer progression. It has become clear in recent years that adenosine is one of the most important immunosuppressive regulatory molecules in the tumor microenvironment, and contributes to immune escape and tumor progression.

CD73 is a key protein molecule in cancer development. CD73 has been found to be overexpressed in many cancer cell lines and tumor types including, for example, breast cancer, colorectal cancer, ovarian cancer, gastric cancer, gallbladder cancer, and cancers associated with poor prognosis.

The expression of CD73 in tumors is regulated by a variety of mechanisms. CD73 expression is negatively regulated by estrogen receptor (ER) in breast cancer. Thus, CD73 is highly expressed in ER negative breast cancer patients. The hypoxia-inducible factor-1α (HIF-1α) has also been shown to regulate CD73 transcription. Additionally, inflammatory factors such as IFN-γ affect CD73 levels. CD73 expression is also epigenetically regulated by CpG island methylation in cell lines and clinical tumor samples.

In addition to being a prognostic biomarker in cancer patients, overexpression of CD73 has also been found to be functionally linked to therapy resistance. Elevated levels of CD73 were initially linked to resistance to a variety of chemotherapeutic agents including vincristine and doxorubicin.

CD73 has also been shown to be involved in immunotherapy resistance. This ectonucleotidase participates in the process of tumor immune escape by inhibiting the activation, clonal expansion, and homing of tumor-specific T cells (in particular, T helper and cytotoxic T cells); impairing tumor cell killing by cytolytic effector T lymphocytes; driving, via pericellular generation of adenosine, the suppressive capabilities of Treg and Th17 cells; enhancing the conversion of type 1 macrophages into tumor-promoting type 2 macrophages; and promoting the accumulation of MDSCs.

Small molecular inhibitors and monoclonal antibodies targeting CD73 have shown anti-tumor activity in a variety of immune-competent but not in immune-deficient mouse tumor models. Overall, these studies suggest that anti-CD73 therapy activity is dependent on its ability to elicit immune responses in vivo.

Antibodies which block PD-1, PD-L1, and CTLA-4 have shown impressive objective response in cancer patients. Recent data demonstrates that anti-CD73 mAb significantly enhances the activity of both anti-CTLA-4 and anti-PD-1 mAbs in several mouse tumor models. In addition to checkpoint blockade, CD73-mediated production of adenosine could contribute to resistance to additional immunotherapy modalities including CAR-T cells and cancer vaccines.

Interfering with CD73 activity represents a strategy to re-sensitize tumors to therapy. Based on the link between CD73 and therapy resistance, combining anti-CD73 treatment with chemotherapy or immunotherapy is an effective approach to enhance their activity in cancer patients with high CD73 levels. In some instances, CD73 expression serves as a biomarker to identify patients that could benefit from anti-CD73 combination therapy.

In some instances, the CD39/CD73 couple turns ATP-driven pro-inflammatory cell activity toward an adenosine-mediated anti-inflammatory state. A number of studies have shown changes in the activity of the CD39/CD73 axis during infections induced by a variety of microorganisms. An increase in CD73 expression has also been observed in the brain of mice infected with Toxoplasma gondii , which promotes the parasite life cycle through the production of adenosine. Thus, the pharmacological blockade of CD73 is a promising therapeutic approach to treat human toxoplasmosis.

Enhanced expression and activity of CD39 and CD73 have been observed in endothelial cells infected with cytomegalovirus (CMV). The increase in local adenosine production, associated with the upregulation of ecto-nucleotidases, generates an immunosuppressive and antithrombotic microenvironment, which facilitates viral entry into target cells.

In some instances, inhibitors of CD73, by driving a decrease on adenosine production, have applications as antiviral agents. The elevated expression/activity of CD39 and CD73 on lymphocytes of individuals infected with human immunodeficiency virus (HIV) indicates a role for ecto-nucleotidases in the immune dysfunction associated with this disease. In fact, an increased proportion of Tregs expressing CD39, as well as a positive correlation between CD39 expression on Tregs and disease progression has been observed in different cohorts of HIV-infected patients. It has also been shown that HIV-positive patients had a higher number of CD39+ Treg, and that their Teff exhibited an increased sensitivity in vitro to the suppressive effect of adenosine, which was related to the elevated expression of immunosuppressive A2A receptors.

In the central nervous system, adenosine plays a critical role in controlling a multitude of neural functions. Through the activation of P1 receptors, adenosine is involved in diverse physiological and pathological processes such as regulation of sleep, general arousal state and activity, local neuronal excitability, and coupling of the cerebral blood flow to the energy demand. In some instances, manipulation of adenosine production via CD73 inhibitors is useful for treating neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease, and psychiatric disorders such as schizophrenia and autism.

As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

“Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms, wherein a sp3-hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C 1 -C 6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C 1 -C 10 alkyl, a C 1 -C 9 alkyl, a C 1 -C 8 alkyl, a C 1 -C 7 alkyl, a C 1 -C 6 alkyl, a C 1 -C 5 alkyl, a C 1 -C 4 alkyl, a C 1 -C 3 alkyl, a C 1 -C 2 alkyl, or a C 1 alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the alkyl is optionally substituted with halogen.

“Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp2-hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (—CH═CH 2 ), 1-propenyl (—CH 2 CH═CH 2 ), isopropenyl [—C(CH 3 )═CH 2 ], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C 2 -C 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C 2 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, an alkenyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

“Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C 2 -C 6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C 2 -C 10 alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, an alkynyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

“Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, an alkylene is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the alkylene is optionally substituted with halogen.

“Alkoxy” refers to a radical of the formula —OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, an alkoxy is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

“Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the aryl is optionally substituted with halogen.

“Cycloalkyl” refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 cycloalkyl), from three to ten carbon atoms (C 3 -C 10 cycloalkyl), from three to eight carbon atoms (C 3 -C 8 cycloalkyl), from three to six carbon atoms (C 3 -C 6 cycloalkyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl), or three to four carbon atoms (C 3 -C 4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

“Heterocycloalkyl” refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

“Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., —NH—, —N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

“Heteroaryl” refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

“Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more —OH e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, dihydroxymethyl, dihydroxyethyl, dihydroxypropyl, dihydroxybutyl, dihydroxypentyl, and the like.

The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., —CH 2 CH 3 ), fully substituted (e.g., —CF 2 CF 3 ), mono-substituted (e.g., —CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., —CH 2 CHF 2 , —CH 2 CF 3 , —CF 2 CH 3 , —CFHCHF 2 , etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

The terms “inhibit,” “block,” “suppress,” and grammatical variants thereof are used interchangeably herein and refer to any statistically significant decrease in biological activity, including full blocking of the activity. In some embodiments, “inhibition” refers to a decrease of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 100% in biological activity. Accordingly, when the terms “inhibition” or “suppression” are applied to describe, e.g., an effect on the enzymatic activity of CD73, the term refers to the ability of a compound disclosed herein to statistically significantly decrease the 5′-nucleotidase activity of CD73 (catabolizing the hydrolysis of adenosine monophosphate, AMP, to adenosine), relative to the CD73-mediated 5′-nucleotidase activity in an untreated (control) cell. In some instances, the cell which expresses CD73 is a naturally occurring cell or cell line (e.g., a cancer cell) or is recombinantly produced by introducing a nucleic acid encoding CD73 into a host cell. In some aspects, compounds disclosed herein statistically significantly decrease the 5′-nucleotidase activity of a soluble form of CD73 in a biological fluid. In one aspect, the compound disclosed herein inhibit CD73-mediated 5′-nucleotidase activity by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or about 100%, as determined, for example, by the methods described in the Examples and/or methods known in the art.

As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

Compounds

Described herein are compounds that are CD73 inhibitors. These compounds, and compositions comprising these compounds, are useful for the treatment of cancer, infections, and neurodegenerative diseases.

In some embodiments provided herein is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), or alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 , —OR 60 , —SR 61 , or —CR 62 R 63 R 64 ; R 1 and R 2 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 60 is hydrogen, —C(═O)R 15e , —C(═O)OR 16e , —C(═O)NR 16e R 17e , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m ; R 61 is hydrogen, —C(═O)R 15f , —C(═O)OR 16f , —C(═O)NR 16f R 17f , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n ; R 62 , R 63 , and R 64 are each independently hydrogen, halogen, —CN, —OH, —OR 15g , —SH, —SR 15g , —S(═O)R 15g , —NO 2 , —NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —OC(═O)R 15g , —C(═O)OR 16g , —OC(═O)OR 16g , —C(═O)NR 16g R 17g , —OC(═O)NR 16g R 17g , —NR 16g C(═O)NR 16g R 17g , —NR 16g C(═O)R 15g , —NR 16g C(═O)OR 16g , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), or alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o ; R 3 is halogen, —CN, —OH, —OR 15b , —SR 18b , —NR 16b R 17b , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), or alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, —OH, —OR 15d , —NR 16d S(═O) 2 R 15a , —NR 16d C(═O)R 15d , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 8 is hydrogen, halogen, —OH, —OR a , —NR c R d , alkyl, or haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, alkyl, or haloalkyl; X is —O— or —NR 11 —; Y is —(CR 13 R 14 ) v — or —NR 12 —; R 11 and R 12 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 13 and R 14 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , alkyl, or haloalkyl; v is 1-3; R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g are each independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30g ; R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 17a , R 17b , R 17e , R 17f , and R 17g are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30h ; or R 16a and R 17a or R 16b and R 17b or R 16e and R 17e or R 16f and R 17f or R 16g and R 17g are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, alkyl, or haloalkyl; R 18b is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), or alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30i ; R 20 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30j ; R 21 and R 22 are each independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , alkyl, or haloalkyl; each R 25 is independently hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl; each R 26 is independently alkyl, alkenyl, alkynyl, or heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30j , R 30k , R 30l , R 30m , R 30n , and R 30o is independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), or alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, or cycloalkyl optionally substituted with one, two, or three halogen, alkyl, or haloalkyl; each R a is independently alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, alkyl, or haloalkyl; each R b is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, alkyl, or haloalkyl; and R c and R d are each independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, alkyl, or haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, alkyl, or haloalkyl.

In some embodiments provided herein is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 , —OR 60 , —SR 61 , or —CR 62 R 63 R 64 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 60 is hydrogen, —C(═O)R 15e , —C(═O)OR 16e , —C(═O)NR 16e R 17e , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m .

R 61 is hydrogen, —C(═O)R 15f , —C(═O)OR 16f , —C(═O)NR 16f R 17f , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n .

R 62 , R 63 , and R 64 are each independently hydrogen, halogen, —CN, —OH, —OR 15g , —SH, —SR 15g , —S(═O)R 15g , —NO 2 NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —OC(═O)R 15g , —C(═O)OR 16g , —OC(═O)OR 16g , —C(═O)NR 16g R 17g , —OC(═O)NR 16g R 17g , —NR 16g C(═O)NR 16g R 17g , —NR 16g C(═O)R 15g , —NR 16g C(═O)OR 16g , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o ; R 3 is halogen, —CN, —OH, —OR 15g , —SR 18b , —NR 16b R 17b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogenogen, halogen, —OH, —OR 15d , —NR 15d S(═O) 2 R 15d , —NR 16d C(═O)R 15d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X is —O— or —NR 11 —; Y is —(CR 13 R 14 ) v — or —NR 12 ; R 11 and R 12 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 13 and R 14 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v is 1-3; R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , and R 15g are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30g ; R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 17a , R 17b , R 17e , R 17f , and R 17g are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30h ; or R 16a and R 17a or R 16b and R 17b or R 16e and R 17e or R 16f and R 17f or R 16g and R 17g are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 18b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30i ; R 20 is hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30j ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30j , R 30k , R 30l , R 30m , R 30n and R 30o is independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)W, —OC(═O)W, —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, when X is —O—, Y is not —CH 2 —, —CCl 2 —, —CF 2 —, or —C(CH 3 ) 2 —. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 1 —. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 11 — and R 11 is hydrogen or alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, v is 2 or 3. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —NR 12 —.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30a ; R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X is —O— or —NR 11 —; Y is —(CR 13 R 14 ) v — or —NR 12 ; R 11 and R 12 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 13 and R 14 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v is 1-3; R 15c is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30g ; R 16c is hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30h ; R 18b is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30i ; R 20 is hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30j ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30j , R 30k , and R 30l is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; and R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; provided that, when X is —O—, Y is not —CH 2 —, —CCl 2 —, —CF 2 —, or —C(CH 3 ) 2 —.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is hydrogen; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen; R 4 and R 7 are each independently hydrogen, halogen, —OH, or —OR 15c ; R 5 and R 6 are each hydrogen; R 8 is hydrogen; R 9 and R 10 are each hydrogen; X is —O— or —NR 11 —; Y is —(CR 13 R 14 ) v — or —NR 12 —; R 11 and R 12 are each independently hydrogen or C 1 -C 6 alkyl; R 13 and R 14 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; v is 1 or 2; R 15c is C 1 -C 6 alkyl; R 20 is hydrogen, C 1 -C 20 alkyl, —(CR 23 R 24 ) w OC(═O)OR 25 , or aryl optionally substituted with one, two, or three R 30j ; R 21 and R 22 are each hydrogen, C 1 -C 20 alkyl, —(CR 23 R 24 ) w OC(═O)OR 25 , or aryl optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen; each R 25 is independently hydrogen or C 1 -C 6 alkyl; each w is independently 1 or 2; each R 30a , R 30b , R 30j , R 30k , and R 30l is independently halogen, —OH, —OR a , —NR c R d , —C(═O)OR b , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl; each R b is independently hydrogen or C 1 -C 6 alkyl; and R c and R d are each independently hydrogen or C 1 -C 6 alkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen or C 1 -C 6 alkyl; provided that, when X is —O—, Y is not —CH 2 —, —CCl 2 —, —CF 2 —, or —C(CH 3 ) 2 —.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X is —NR 11 —; Y is —(CR 13 R 14 ) v — or —NR 12 ; R 11 and R 12 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 13 and R 14 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v is 1-3; R 15c is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30g ; R 16c is hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30h ; R 18b is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30i ; R 20 is hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30j ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30j , R 30k , and R 30l is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; and R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is hydrogen; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen; R 4 and R 7 are each independently hydrogen, halogen, —OH, or —OR 15c ; R 5 and R 6 are each hydrogen; R 8 is hydrogen; R 9 and R 10 are each hydrogen; X is —NR 11 —; Y is —(CR 13 R 14 ) v - or —NR 12 —; R 11 and R 12 are each independently hydrogen or C 1 -C 6 alkyl; R 13 and R 14 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; v is 1 or 2; R 15c is C 1 -C 6 alkyl; R 20 is hydrogen, C 1 -C 20 alkyl, —(CR 23 R 24 ) w OC(═O)OR 25 , or aryl optionally substituted with one, two, or three R 30j ; R 21 and R 22 are each hydrogen, C 1 -C 2 alkyl, —(CR 23 R 24 ) w OC(═O)OR 25 , or aryl optionally substituted with one, two, or three R 30k or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen; each R 25 is independently hydrogen or C 1 -C 6 alkyl; each w is independently 1 or 2; each R 30a , R 30b , R 30j , R 30k , and R 30l is independently halogen, —OH, —OR a , —NR c R d , —C(═O)OR b , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl; each R b is independently hydrogen or C 1 -C 6 alkyl; and R c and R d are each independently hydrogen or C 1 -C 6 alkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 3d ; R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X is —O— or —NR 11 —; Y is —(CR 13 R 14 ) v — or —NR 12 ; R 11 and R 12 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 13 and R 14 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v is 2 or 3; R 15c is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30g ; R 16c is hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30h ; R 18b is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30i ; R 20 is hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30j ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30j , R 30k , and R 30l is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; and R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is hydrogen; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen; R 4 and R 7 are each independently hydrogen, halogen, —OH, or —OR 15c ; R 5 and R 6 are each hydrogen; R 8 is hydrogen; R 9 and R 10 are each hydrogen; X is —O— or —NR 11 —; Y is —(CR 13 R 14 ) v — or —NR 12 ; R 11 and R 12 are each independently hydrogen or C 1 -C 6 alkyl; R 13 and R 14 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; v is 2; R 15c is C 1 -C 6 alkyl; R 20 is hydrogen, C 1 -C 20 alkyl, —(CR 23 R 24 ) w OC(═O)OR 25 , or aryl optionally substituted with one, two, or three R 30j ; R 21 and R 22 are each hydrogen, C 1 -C 20 alkyl, —(CR 23 R 24 ) w OC(═O)OR 25 , or aryl optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen; each R 25 is independently hydrogen or C 1 -C 6 alkyl; each w is independently 1 or 2; each R 30a , R 30b , R 30j , R 30k , and R 30f is independently halogen, —OH, —OR a , —NR c R d , —C(═O)OR b , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl; each R b is independently hydrogen or C 1 -C 6 alkyl; and R c and R d are each independently hydrogen or C 1 -C 6 alkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X is —O— or —NR 11 —; Y is —NR 12 —; R 11 and R 12 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 15c is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30g ; R 16c is hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30h ; R 18b is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30i ; R 20 is hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30j ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30j , R 30k , and R 30l is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O) w C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; and R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is hydrogen; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen; R 4 and R 7 are each independently hydrogen, halogen, —OH, or —OR 15c ; R 5 and R 6 are each hydrogen; R is hydrogen; R 9 and R 10 are each hydrogen; X is —O— or —NR 11 —; Y is —NR 12 —; R 11 and R 12 are each independently hydrogen or C 1 -C 6 alkyl; R 15c is C 1 -C 6 alkyl; R 20 is hydrogen, C 1 -C 20 alkyl, —(CR 23 R 24 ) w OC(═O)OR 25 , or aryl optionally substituted with one, two, or three R 30j ; R 21 and R 22 are each hydrogen, C 1 -C 20 alkyl, —(CR 23 R 24 ) w OC(═O)OR 25 , or aryl optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen; each R 25 is independently hydrogen or C 1 -C 6 alkyl; each w is independently 1 or 2; each R 30a , R 30b , R 30j , R 30k and R 30l is independently halogen, —OH, —OR a , —NR c R d , —C(═O)OR b , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl; each R is independently hydrogen or C 1 -C 6 alkyl; and R c and R d are each independently hydrogen or C 1 -C 6 alkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen or C 1 -C 6 alkyl.

For any and all of the embodiments of Formula (I), substituents are selected from among a subset of the listed alternatives.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen, halogen, —OH, —OMe, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen, halogen, —OH, —NH 2 , or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 9 and R 10 are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 9 and R 10 are each hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 1 is N; and Q 2 is CW. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 1 is CW; and Q 2 is N. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 1 is N; and Q 2 is N. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 1 is CW; and Q 2 is CW.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl, is independently optionally substituted with one, two, or three R 30 . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl, is independently optionally substituted with one, two, or three R 30 ; and each R 30 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each W is independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each W is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, A is —O—. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, A is —CH 2 —.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —O—. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 11 —. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 1 —; and R 11 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 11 —; and R 11 is hydrogen or methyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —NR 12 —. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —NR 12 —; and R 12 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —NR 12 —; and R 12 is hydrogen or methyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —NR 12 —; and R 12 is hydrogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —NR 12 —; and R 12 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 13 R 14 ) v —. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v is 1 or 2. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 13 R 14 ) v —; R 3 and R 14 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v is 2 or 3. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v is 1. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v is 2. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each hydrogen; and v is 1 or 2. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each hydrogen; and v is 2 or 3. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each hydrogen; and v is 1. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each hydrogen; and v is 2. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each halogen or C 1 -C 6 alkyl; and v is 1 or 2. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each halogen or C 1 -C 6 alkyl; and v is 2 or 3. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each halogen or C 1 -C 6 alkyl; and v is 1. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each halogen or C 1 -C 6 alkyl; and v is 2.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —O— and Y is —NR 12 —. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —O—; Y is —NR 12 —; and R 12 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —O—; Y is —NR 12 —; and R 12 is hydrogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —O—; Y is —NR 12 —; and R 12 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 11 — and Y is —(CR 13 R 14 ) v —. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 11 —; Y is —(CR 13 R 14 ) v —; R 11 is hydrogen or C 1 -C 6 alkyl; R 13 and R 14 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v is 1 or 2. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 11 —; Y is —(CR 13 R 14 ) v —; R 11 is hydrogen; R 13 and R 14 are each hydrogen; and v is 1. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 11 —; Y is —(CR 13 R 14 ) v —; R 11 is C 1 -C 6 alkyl; R 13 and R 14 are each hydrogen; and v is 1.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 11 — and Y is —NR 12 —. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 11 —; Y is —NR 12 —; R 11 is hydrogen or C 1 -C 6 alkyl; and R 1 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 11 —; Y is —NR 12 —; R 11 is hydrogen; and R 1 is hydrogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 11 —; Y is —NR 12 —; R 11 is C 1 -C 6 alkyl; and R 12 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 11 —; Y is —NR 12 —; R 11 is hydrogen; and R 12 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —NR 11 —; Y is —NR 12 —; R 11 is C 1 -C 6 alkyl; and R 12 is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —O—; Y is —(CR 13 R 14 ) v —. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —O—; Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v is 2 or 3. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —O—; Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each hydrogen; and v is 2. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —O—; Y is —(CR 13 R 14 ) v —; R 13 and R 14 are each hydrogen; and v is 3.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one, two, or three R 30e . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one, two, or three R 30e ; and each R 30e is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5 and R 6 are each hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d ; and each R 30d is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , or —NR 16c C(═O)R 15c . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , or —NR 16c C(═O)R 15c ; R 15c are each independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; and R 16c are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , or —NR 16c C(═O)R 15c ; R 15c are each independently C 1 -C 6 alkyl; and R 16c are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, or —OH. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently halogen or —OH. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each —OH.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is —NR 1 R 2 .

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; R 15a is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen; and R 16a and R 17a are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; R 15a is C 1 -C 6 alkyl; and R 16a and R 17a are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15a is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen; and R 16a and R 17a are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15a is C 1 -C 6 alkyl; and R 16a and R 17a are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15a is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15a is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16a and R 17a are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16a and R 17a are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a .

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 3a ; and each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; and each R 30a is independently halogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; and each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; and each R 30a is independently halogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen or C 1 -C 6 alkyl; and R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen; and R 2 is hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen or C 1 -C 6 alkyl; and R 2 is hydrogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R 2 is hydrogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen; and R 2 is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen or C 1 -C 6 alkyl; and R 2 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R 2 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen; and R 2 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen or C 1 -C 6 alkyl; and R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen; and R 2 is hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen or C 1 -C 6 alkyl; and R 2 is hydrogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R 2 is hydrogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen; and R 2 is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen or C 1 -C 6 alkyl; and R 2 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 3a ; each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R 2 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen; and R 2 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; each R 30b is independently aryl optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; and R 30b is aryl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one R 30b ; and R 30b is aryl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine or a pyrrolidine optionally substituted with one, two, or three R 30b . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine or a pyrrolidine optionally substituted with one, two, or three R 30b ; each R 30b is independently aryl optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine or a pyrrolidine optionally substituted with one, two, or three R 30b ; and R 30b is aryl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine or a pyrrolidine optionally substituted with one R 30b ; and R 30b is aryl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine optionally substituted with one, two, or three R 30b . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine optionally substituted with one, two, or three R 30b ; each R 30b is independently aryl optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine optionally substituted with one, two, or three R 30b ; and R 30b is aryl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine optionally substituted with one R 30b ; and R 30b is aryl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a pyrrolidine optionally substituted with one, two, or three R 30b . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a pyrrolidine optionally substituted with one, two, or three R 30b ; each R 30b is independently aryl optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a pyrrolidine optionally substituted with one, two, or three R 30b ; and R 30b is aryl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a pyrrolidine optionally substituted with one R 30b ; and R 30b is aryl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is —OR 0 .

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is hydrogen, —C(═O)R 15e , —C(═O)OR 16e , —C(═O)NR 16e R 17e , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is —C(═O)R 15e , —C(═O)OR 16e , —C(═O)NR 16e R 17e , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m .

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is cycloalkyl or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30m In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is cycloalkyl optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30m .

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15e is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen; and R 16e and R 17e are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15e is C 1 -C 6 alkyl; and R 16e and R 17e are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5e is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15e is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16e and R 17e are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16e and R 17e are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is —SR 61 .

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is hydrogen, —C(═O)R 5f , —C(═O)OR 16 f, —C(═O)NR 16f R 17f , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is —C(═O)R 15f , —C(═O)OR 16f , —C(═O)NR 16f R 17f , C L-C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 3n . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is cycloalkyl optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30n .

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15f is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen; and R 16f and R 17f are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15f is C 1 -C 6 alkyl; and R 16f and R 17f are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15f is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15f is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16f and R 17f are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16f and R 17f are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is —CR 62 R 63 R 64 ;

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen, halogen, —CN, —OH, —OR 15g , —NR 16g R 17g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen, halogen, —CN, —OH, —OR 15g , —NR 16g R 17g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30o ; R 15g is C 1 -C 6 alkyl; and R 16g and R 17g are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen, halogen, or —OH. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen or halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen, halogen, —CN, —OH, —OR 15g , —NR 16g R 17g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen, halogen, —CN, —OH, —OR 15g , —NR 16g R 17g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30o ; R 15g is C 1 -C 6 alkyl; and R 16g and R 17g are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen, halogen, or —OH. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen or halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g , —SR 15g , —S(═O)R 15g , —NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g , —SR 15g , —S(═O)R 15g , —NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g , —NR 16g R 17g , —C(═O)R 15g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g , —NR 16g R 17g is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g or —NR 16g R 17g . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is aryl, or heteroaryl; wherein each aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o .

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15g is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen; and R 16g and R 17g are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15g is C 1 -C 6 alkyl; and R 16g and R 17g are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15g is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15g is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16g and R 17g are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16g and R 17g are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , —NR 16b R 17b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; and R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl). In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl); and each R 30c is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl); and each R 30c is independently halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl); and each R 30c is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 17b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; and R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl). In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl); and each R 30c is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl); and each R 30c is independently halogen. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl); and each R 30c is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is —NH 2 . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each independently hydrogen, aryl, or —(CR 23 R 24 ) w OC(═O)OR 25 .

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each hydrogen.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each —(CR 23 R 24 ) w OC(═O)OR 25 . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R and R 22 are each —(CR 23 R 24 ) w OC(═O)OR 25 ; w is 1 or 2; each R 23 and R 24 are independently hydrogen, halogen, or C 1 -C 6 alkyl; and each R 25 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each —(CR 23 R 24 ) w OC(═O)OR 25 ; w is 1; R 23 and R 24 are hydrogen; and each R 25 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each —(CR 23 R 24 ) w OC(═O)OR 25 ; w is 1; R 23 and R 24 are hydrogen; and each R 25 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l . In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; and each R 30l is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; and each R 30l is independently halogen.

Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

In some embodiments provided herein is a compound having the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), or alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 , —OR 60 , —SR 61 , or —CR 62 R 63 R 64 ; R 1 and R 2 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 60 is hydrogen, —C(═O)R 15e , —C(═O)OR 16e , —C(═O)NR 16e R 17e , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m ; R 61 is hydrogen, —C(═O)R 15f , —C(═O)OR 16f , —C(═O)NR 16f R 17f , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n ; R 62 , R 63 , and R 64 are each independently hydrogen, halogen, —CN, —OH, —OR 15g , —SH, —SR 15g , —S(═O)R 15g , —NO 2 , —NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —OC(═O)R 15g , —C(═O)OR 16g , —OC(═O)OR 16g , —C(═O)NR 16g R 17g , —OC(═O)NR 16g R 17g , —NR 16g C(═O)NR 16g R 17g , —NR 16g C(═O)R 15g , —NR 16g C(═O)OR 16g , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), or alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o ; R 3 is halogen, —CN, —OH, OR 15b , SR 18b , —NR 16b R 17b , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), or alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, —OH, —OR 15d , —NR 16d S(═O) 2 R 15d , —NR 16d C(═O)R 15d , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —OR a , —NR c R d , alkyl, or haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, alkyl, or haloalkyl; X 1 is bond, —C(═O)—, —S(═O) 2 —, or —CR 40 R 41 —; Y 1 is —(CR 42 R 43 ) v1 —, —S(═O) 2 —, —NR 44 —, or —O—; Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—; Y 3 is —(CR 45 R 49 ) v3 —, —NR 50 —, or —O—; Y 4 is —O—, —NH—, or —N(CH 3 )—; R 40 , R 41 , R 42 , R 43 , R 45 , R 46 , R 48 , and R 49 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , alkyl, or haloalkyl; R 44 , R 47 , and R 50 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; v1, v2, and v3 are each independently 1-3; R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g are each independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30g ; R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 17a , R 17b , R 17e , R 17f , and R 17g are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30h ; or R 16a and R 17a or R 16b and R 17b or R 16e and R 17e or R 16f and R 17f or R 16g and R 17g are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, alkyl, or haloalkyl; R 18b is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30i ; R 21 and R 22 are each independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , alkyl, or haloalkyl; each R 25 is independently hydrogen, alkyl, alkenyl, alkynyl, or heteroalkyl; each R 26 is independently alkyl, alkenyl, alkynyl, or heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30e , R 30f , R 30g , R 30h , R 30i , R 30k , R 30l , R 30m , R 30n , and R 30o are independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR), alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyl(aryl), alkyl(heteroaryl), alkyl(cycloalkyl), or alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, or cycloalkyl optionally substituted with one, two, or three halogen, alkyl, or haloalkyl; each R a is independently alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, alkyl, or haloalkyl; each R b is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, alkyl, or haloalkyl; R c and R d are each independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, alkyl, or haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, alkyl, or haloalkyl; n is 0 or 1; and m is 0 or 1.

In some embodiments provided herein is a compound having the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 3 ; Z is —NR 1 R 2 , —OR 60 , —SR 61 , or —CR 62 R 63 R 64 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 60 is hydrogen, —C(═O)R 15e , —C(═O)OR 16e , —C(═O)NR 16e R 17e , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m .

R 61 is hydrogen, —C(═O)R 15f , —C(═O)OR 16f R 17f , —C(═O)NR 16f R 17f , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n ;

R 62 , R 63 , and R 64 are each independently hydrogen, halogen, —CN, —OH, —OR 15g , —SH, —SR 15g , —S(═O)R 15g , —NO 2 , —NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —OC(═O)R 15g , —C(═O)OR 16g , —OC(═O)OR 16g , —C(═O)NR 16g R 17g , —OC(═O)NR 16g R 17g , —NR 16g C(═O)NR 16g R 17g , —NR 16g C(═O)R 15g , —NR 16g C(═O)OR 16g , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o ; R 3 is halogen, —CN, —OH, OR 15b , SR 18b , —NR 16b R 17b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, —OH, —OR 15d , —NR 16d S(═O) 2 R 15d , —NR 16d C(═O)R 15d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X 1 is bond, —C(═O)—, —S(═O) 2 —, or —CR 40 R 41 —; Y 1 is —(CR 42 R 43 ) v1 —, —S(═O) 2 —, —NR 44 —, or —O—; Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—; Y 3 is —(CR 48 R 49 ) v3 —, —NR 50 —, or —O—; Y 4 is —O—, —NH—, or —N(CH 3 )—; R 40 , R 41 , R 42 , R 43 , R 45 , R 46 , R 48 , and R 49 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 44 , R 47 , and R 50 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; v1, v2, and v3 are each independently 1-3; R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30g ; R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 17a , R 17b , R 17e , R 17f , and R 17g are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30h ; or R 16a and R 17a or R 16b and R 17b or R 16e and R 17e or R 16f and R 17f or R 16g and R 17g are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 18b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30i ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30k , R 30l , R 30m , R 30n , and R 30o are independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; n is 0 or 1; and m is 0 or 1.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, at least one of n or m is 1. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 1. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, n is 1 and m is 0. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, m is 1. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, m is 1 and n is 0.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X 1 is bond, —C(═O)—, —S(═O) 2 —, or —CR 40 R 41 ; Y 1 is —(CR 42 R 43 ) v1 —, —S(═O) 2 —, —NR 44 —, or —O—; Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—; Y 3 is —(CR 48 R 49 ) v3 — or —NR 50 —, or —O—; Y 4 is —O— or —NH—; R 44 , R 47 , and R 50 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 40 , R 41 , R 42 , R 43 , R 45 , R 46 , R 48 , and R 49 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v1, v2, and v3 are each independently 1-3; R 15c is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30g ; R 16c is hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30h ; R 18b is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30i ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30k , and R 30l is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; n is 0 or 1; and m is 0 or 1; provided that at least one of n or m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is hydrogen; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen; R 4 and R 7 are each independently hydrogen, halogen, —OH, or —OR 15c ; R 5 and R 6 are each hydrogen; R 8 is hydrogen; R 9 and R 10 are each hydrogen; X 1 is bond, —C(═O)—, —S(═O) 2 —, or —CR 40 R 41 —; Y 1 is —(CR 42 R 43 ) v1 —, —S(═O) 2 —, —NR 44 —, or —O—; Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—; Y 3 is —(CR 48 R 49 ) v3 — or —NR 50 —; Y 4 is —O—; R 44 , R 47 , and R 50 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 40 , R 41 , R 42 , R 43 , R 45 , R 46 , R 48 and R 49 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v1, v2, and v3 are each independently 1 or 2; R 15c is C 1 -C 6 alkyl; R 21 and R 22 are each hydrogen, C 1 -C 20 alkyl, —(CR 23 R 24 ) w OC(═O)OR 25 , or aryl optionally substituted with one, two, or three R 30k or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen; each R 25 is independently hydrogen or C 1 -C 6 alkyl; each w is independently 1 or 2; each R 30a , R 30b , R 30f , R 30k and R 30l is independently halogen, —OH, —OR a , —NR c R d , —C(═O)OR b , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl; each R b is independently hydrogen or C 1 -C 6 alkyl; R c and R d are each independently hydrogen or C 1 -C 6 alkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen or C 1 -C 6 alkyl n is 0 or 1; and m is 0 or 1; provided that at least one of n or m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—; Y 3 is —(CR 48 R 49 ) v3 — or —NR 50 —, or —O—; Y 4 is —O— or —NH—; R 47 and R 50 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 45 , R 46 , R 48 and R 49 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v2 and v3 are each independently 1-3; R 15c is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30g ; R 16 is hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30h ; R 18b is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30i ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30k , and R 30l is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; n is 1; and m is 0.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is hydrogen; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen; R 4 and R 7 are each independently hydrogen, halogen, —OH, or —OR 15c ; R 5 and R 6 are each hydrogen; R 8 is hydrogen; R 9 and R 10 are each hydrogen; Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—; Y 3 is —(CR 48 R 49 ) v3 — or —NR 50 —; Y 4 is —O—; R 47 and R 50 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 45 , R 46 , R 48 and R 49 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v2 and v3 are each independently 1 or 2; R 15c is C 1 -C 6 alkyl; R 21 and R 22 are each hydrogen, C 1 -C 20 alkyl, —(CR 23 R 24 ) w OC(═O)OR 25 , or aryl optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen; each R 25 is independently hydrogen or C 1 -C 6 alkyl; each w is independently 1 or 2; each R 30a , R 30b , R 30f , R 30k , and R 30l is independently halogen, —OH, —OR a , —NR c R d , —C(═O)OR b , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl; each R b is independently hydrogen or C 1 -C 6 alkyl; R c and R d are each independently hydrogen or C 1 -C 6 alkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen or C 1 -C 6 alkyl n is 1; and m is 0.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15 , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X 1 is bond, —C(═O)—, —S(═O) 2 —, or —CR 40 R 41 —; Y 1 is —(CR 42 R 43 ) v1 —, —S(═O) 2 —, —NR 44 —, or —O—; Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—; Y 4 is —O— or —NH—; R 44 and R 47 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 40 , R 41 , R 42 , R 43 , R 45 , and R 46 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v1 and v2 are each independently 1-3; R 15c is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30g ; R 16c is hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30h ; R 18b is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30i ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30k , and R 30l is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; n is 0; and m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 and Q 2 are independently N or CW; each W is hydrogen; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen; R 4 and R 7 are each independently hydrogen, halogen, —OH, or —OR 15c ; R 5 and R 6 are each hydrogen; R 8 is hydrogen; R 9 and R 10 are each hydrogen; X 1 is bond, —C(═O)—, —S(═O) 2 —, or —CR 40 R 41 —; Y 1 is —(CR 42 R 43 ) v1 —, —S(═O) 2 —, —NR 44 —, or —O—; Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—; Y 4 is —O—; R 44 and R 47 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 40 , R 41 , R 42 , R 43 , R 45 , and R 46 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v1 and v2 are each independently 1 or 2; R 15c is C 1 -C 6 alkyl; R 21 and R 22 are each hydrogen, C 1 -C 20 alkyl, —(CR 23 R 24 ) w OC(═O)OR 25 , or aryl optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen; each R 25 is independently hydrogen or C 1 -C 6 alkyl; each w is independently 1 or 2; each R 30a , R 30b , R 30f , R 30k and R 30l is independently halogen, —OH, —OR a , —NR c R d , —C(═O)OR b , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl; each R b is independently hydrogen or C 1 -C 6 alkyl; R c and R d are each independently hydrogen or C 1 -C 6 alkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen or C 1 -C 6 alkyl n is 0; and m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 is N or CW; Q 2 is N; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X 1 is bond; Y 1 is —O—; Y 2 is —(CR 45 R 46 ) v2 —; Y 4 is —O— or —NH—; R 45 and R 46 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v2 is 1-3; R 15c is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30g ; R 16c is hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30h ; R 18b is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30i ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30g , R 30h , R 30i , R 30k , and R 30l is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; n is 0 or 1; and m is 0 or 1; provided that at least one of n or m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q is N or CW; Q 2 is N; each W is hydrogen; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen; R 4 and R 7 are each independently hydrogen, halogen, —OH, or —OR 15c ; R 5 and R 6 are each hydrogen; R 8 is hydrogen; R 9 and R 10 are each hydrogen; X 1 is bond; Y 1 is —O—; Y 2 is —(CR 45 R 46 ) v2 —; Y 4 is —O—; R 45 and R 46 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v2 is 1 or 2; R 15c is C 1 -C 6 alkyl; R 21 and R 22 are each hydrogen, C 1 -C 20 alkyl, —(CR 23 R 24 ) w OC(═O)OR 25 , or aryl optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen; each R 25 is independently hydrogen or C 1 -C 6 alkyl; each w is independently 1 or 2; each R 30a , R 30b , R 30k , and R 30l is independently halogen, —OH, —OR a , —NR c R d , —C(═O)OR b , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl; each R b is independently hydrogen or C 1 -C 6 alkyl; R c and R d are each independently hydrogen or C 1 -C 6 alkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen or C 1 -C 6 alkyl n is 0 or 1; and m is 0 or 1; provided that at least one of n or m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 is N or CW; Q 2 is N; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X 1 is bond, —C(═O)—, —S(═O) 2 —, or —CR 40 R 41 —; Y 1 is —(CR 42 R 43 ) v1 —, —S(═O) 2 —, —NR 44 —, or —O—; Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—; Y 4 is —O— or —NH—; R 44 and R 47 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 40 , R 41 , R 42 , R 43 , R 45 , and R 46 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v1 and v2 are each independently 1-3; R 15c is C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 16c is hydrogen or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30h ; R 18b is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30i ;

R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30k , and R 30l is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; n is 0; and m is 1.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q is N or CW; Q 2 is N; each W is hydrogen; Z is —NR 1 R 2 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 3 is halogen; R 4 and R 7 are each independently hydrogen, halogen, —OH, or —OR 15c ; R 5 and R 6 are each hydrogen; R 8 is hydrogen; R 9 and R 10 are each hydrogen; X 1 is bond, —C(═O)—, —S(═O) 2 —, or —CR 40 R 41 —; Y 1 is —(CR 42 R 43 ) v1 —, —S(═O) 2 —, —NR 44 —, or —O—; Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—; Y 4 is —O—; R 44 and R 47 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; R 40 , R 41 , R 42 , R 43 , R 45 , and R 46 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v1 and v2 are each independently 1 or 2; R 15c is C 1 -C 6 alkyl; R 21 and R 22 are each hydrogen, C 1 -C 20 alkyl, —(CR 23 R 24 ) w OC(═O)OR 25 , or aryl optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen; each R 25 is independently hydrogen or C 1 -C 6 alkyl; each w is independently 1 or 2; each R 30a , R 30b , R 30f , R 30k , and R 30l is independently halogen, —OH, —OR b , —NR c R d , —C(═O)OR b , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —OH, —OR a , or —NR c R d ; each R a is independently C 1 -C 6 alkyl; each R b is independently hydrogen or C 1 -C 6 alkyl; R c and R d are each independently hydrogen or C 1 -C 6 alkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen or C 1 -C 6 alkyl n is 0; and m is 1.

For any and all of the embodiments of Formula (II), substituents are selected from among a subset of the listed alternatives.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen, halogen, —OH, —OMe, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen, halogen, —OH, —NH 2 , or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 9 and R 10 are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 9 and R 10 are each hydrogen.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, m is 1. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, m is 1; and n is 0.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 4 is —O—. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 4 is —NH—. In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 4 is —N(CH 3 )—.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound of Formula (II) is of Formula (IIa):

In some embodiments of a compound of Formula (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

A is —O— or —CH 2 —; Q 1 is CW and Q 2 is N; or Q 1 is N and Q 2 is N; W is hydrogen, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; Z is —NR 1 R 2 , —OR 60 , —SR 61 , or —CR 62 R 63 R 64 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 60 is hydrogen, —C(═O)R 15e , —C(═O)OR 16e , —C(═O)NR 16e R 17e , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m ;

R 61 is hydrogen, —C(═O)R 15f , —C(═O)OR 16f , —C(═O)NR 16f R 17f , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n ;

R 62 , R 63 , and R 64 are each independently hydrogen, halogen, —CN, —OH, —OR 15g , —SH, —SR 15g , —S(═O)R 15g , —NO 2 , —NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —OC(═O)R 15g , —C(═O)OR 16g , —OC(═O)OR 16g , —C(═O)NR 16g R 17g , —OC(═O)NR 16g R 17g , —NR 16g C(═O)NR 16g R 17g , —NR 16c C(═O)R 15g , —NR 16g C(═O)OR 16g , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o ; R 3 is halogen, —CN, —OH, —OR 15b , —SR 18b , —NR 16b R 17b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, —OH, —OR 15d , —NR 16c S(═O) 2 R 15d , —NR 16d C(═O)R 15c , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30e ; X 1 is a bond; Y 1 is —S(═O) 2 —; Y 2 is —(CR 46 R 46 ) v2 —; R 45 and R 46 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; v2 is 1-3; R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30g ; R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 17a , R 17b , R 17e , R 17f , and R 17g are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30h . or R 16a and R 17a or R 16b and R 17b or R 16e and R 17e or R 16f and R 17f or R 16g and R 17g are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 18b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30i ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , (CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30g , R 30h , R 30i , R 30j , R 30k , R 30l , R 30m , R 30n , and R 30o are independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —CN, —OH, —OR b , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 1 is —(CR 42 R 43 ) v1 —. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 1 is —(CR 42 R 43 ) v1 —; and v is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 1 is —(CR 42 R 43 ) v1 —; and v1 is 1. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 1 is —(CR 42 R 43 ) v1 —; and v1 is 2. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 1 is —(CR 42 R 43 ) v1 —; and R 42 and R 43 are each independently hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 1 is —(CR 42 R 43 ) v1 —; and R 42 and R 43 are each hydrogen. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 1 is —(CR 42 R 43 ) v1 —; R 42 and R 43 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v1 is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y is —(CR 42 R 43 ) v1 —; R 42 and R 43 are each hydrogen; and v1 is 1.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 1 is —NR 44 —. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 1 is —NR 44 —; and R 44 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 1 is —NR 44 —; and R 44 is hydrogen. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 1 is —NR 44 —; and R 44 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 1 is —O—.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 1 is —S(═O) 2 —.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —C(═O)—. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —CR 40 R 41 —. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —CR 40 R 41 —; and R 40 and R 41 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —CR 40 R 41 —; and R 40 and R 41 are each independently hydrogen, halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —CR 40 R 41 —; and R 40 and R 41 are each independently C 1 -C 6 alkyl or —OH.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond, —C(═O)—, —S(═O) 2 —, or —CR 40 R 41 —; Y 1 is —(CR 42 R 43 ) v1 —, —NR 44 —, or —O—; and Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond or —CR 40 R 41 —; Y 1 is —(CR 42 R 43 ) v1 —, —S(═O) 2 —, —NR 44 —, or —O—; and Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —C(═O)—; Y 1 is —(CR 42 R 43 )—; and Y 2 is —(CR 45 R 46 ) v2 . In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —C(═O)—; Y 1 is —(CR 42 R 43 ) v1 —; Y 2 is —(CR 45 R 46 ) v2 —; R 42 and R 43 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; v1 is 1 or 2; R 45 and R 46 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v2 is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —C(═O)—; Y 1 is —(CR 42 R 43 ) v1 —; Y 2 is —(CR 45 R 46 ) v2 —; R 42 and R 43 are each hydrogen; v1 is 1; R 45 and R 46 are each hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X is —CR 40 R 41 —; Y 1 is —(CR 42 R 43 )—; and Y 2 is —(CR 45 R 46 ) 2 —. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —CR 40 R 41 —; Y 1 is —(CR 42 R 43 ) v1 —; Y 2 is —(CR 45 R 46 ) v2 —; R 40 and R 41 are each independently hydrogen, halogen, —OH, or C 1 -C 6 alkyl; R 42 and R 43 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; v1 is 1 or 2; R 45 and R 46 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v2 is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —CR 40 R 41 —; Y 1 is —(CR 42 R 43 ) v1 —; Y 2 is —(CR 45 R 46 ) v2 —; R 40 and R 41 are each independently hydrogen, —OH, or C 1 -C 6 alkyl; R 42 and R 43 are each hydrogen; v1 is 1; R 45 and R 46 are each hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —C(═O)—; Y 1 is —O—; and Y 2 is —NR 47 —. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —C(═O)—; Y 1 is —O—; Y 2 is —NR 47 —; and R 47 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —C(═O)—; Y 1 is —O—; Y 2 is —NR 47 —; and R 47 is hydrogen. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —C(═O)—; Y 1 is —O—; Y 2 is —NR 47 —; and R 47 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —(CR 42 R 43 )—; and Y 2 is —(CR 45 R 46 ) 2 —. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —(CR 42 R 43 ) v1 —; Y 2 is —(CR 45 R 46 ) v2 —; R 42 and R 43 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; v1 is 1 or 2; R 45 and R 46 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v2 is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —(CR 42 R 43 ) v1 —; Y 2 is —(CR 45 R 46 ) v2 —; R 42 and R 43 are each hydrogen; v1 is 1; R 45 and R 46 are each hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —NR 44 —; and Y 2 is —(CR 45 R 46 ) v2 —. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —NR 44 —; Y 2 is —(CR 45 R 46 ) 2 —; R 44 is hydrogen or C 1 -C 6 alkyl; R 45 and R 46 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v2 is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —NR 44 —; Y 2 is —(CR 45 R 46 ) v2 —; R 44 is hydrogen; R 45 and R 46 are each hydrogen; and v2 is 1. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —NR 44 —; Y 2 is —(CR 45 R 46 ) v2 —; R 44 is C 1 -C 6 alkyl; R 45 and R 46 are each hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —(CR 42 R 43 ) v1 —; and Y 2 is —NR 47 —. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —(CR 42 R 43 ) v1 —; Y 2 is —NR 47 —; R 42 and R 43 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; v1 is 1 or 2; and R 47 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —(CR 42 R 43 )—; Y 2 is —NR 47 —; R 42 and R 43 are each hydrogen; v1 is 1; and R 47 is hydrogen. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —(CR 42 R 43 ) v1 —; Y 2 is —NR 47 —; R 42 and R 43 are each hydrogen; v1 is 1; and R 47 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —NR 44 —; and Y 2 is —NR 47 —. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —NR 44 —; Y 2 is —NR 47 —; R 44 is hydrogen or C 1 -C 6 alkyl; and R 47 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —NR 44 —; Y 2 is —NR 47 —; R 44 is hydrogen; and R 47 is hydrogen. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —NR 44 —; Y 2 is —NR 47 —; R 44 is C 1 -C 6 alkyl; and R 47 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —NR 44 —; Y 2 is —NR 47 —; R 44 is hydrogen; and R 47 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is —S(═O) 2 —; Y 1 is —NR 44 —; Y 2 is —NR 47 —; R 44 is C 1 -C 6 alkyl; and R 47 is hydrogen.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond; Y 1 is —O—; and Y 2 is —(CR 45 R 46 ) v2 . In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond; Y 1 is —O—; Y 2 is —(CR 45 R 46 ) v2 —; R 45 and R 46 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v2 is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond; Y 1 is —O—; Y 2 is —(CR 45 R 46 ) v2 —; R 45 and R 46 are each hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond; Y 1 is —S(═O) 2 —; and Y 2 is —(CR 45 R 46 ) v2 —. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond; Y 1 is —S(═O) 2 —; Y 2 is —(CR 45 R 46 ) v2 —; R 45 and R 46 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v2 is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond; Y 1 is —S(═O) 2 —; Y 2 is —(CR 45 R 46 ) v2 —; R 45 and R 46 are each hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond; Y 1 is —NR 44 —; and Y 2 is —(CR 45 R 46 ) v2 —. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond; Y 1 is —NR 44 —; Y 2 is —(CR 45 R 46 ) v2 —; R 44 is hydrogen, C 1 -C 6 alkyl, —S(═O) 2 R a , or —C(═O)R a ; R 45 and R 46 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v2 is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond; Y 1 is —NR 44 —; Y 2 is —(CR 45 R 46 ) v2 —; R 44 is hydrogen or C 1 -C 6 alkyl, R 45 and R 46 are each hydrogen; and v2 is 1. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond; Y 1 is —NR 44 —; Y 2 is —(CR 45 R 46 ) v2 —; R 44 is —S(═O) 2 R a or —C(═O)R a , R 45 and R 46 are each hydrogen; and v2 is 1. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond; Y 1 is —NR 44 —; Y 2 is —(CR 45 R 46 ) v2 —; R 44 is —C(═O)R a , R 45 and R 46 are each hydrogen; and v2 is 1. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, X 1 is bond; Y 1 is —NR 44 —; Y 2 is —(CR 45 R 46 ) v2 —; R 44 is —C(═O)R a , R 45 and R 46 are each hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound of Formula (II) is of Formula (IIb):

In some embodiments of a compound of Formula (II) or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 3 is —(CR 48 R 49 ) v3 —. In some embodiments of a compound of Formula (II) or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 3 is —(CR 48 R 49 ) v3 —; R 4 and R 49 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v3 is 1 or 2. In some embodiments of a compound of Formula (II) or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 3 is —(CR 48 R 49 ) v3 —; R 4 and R 49 are each hydrogen; and v3 is 1.

In some embodiments of a compound of Formula (II) or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 3 is —NR 50 —. In some embodiments of a compound of Formula (II) or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 3 is —NR 50 —; and R 50 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 3 is —NR 50 —; and R 50 is hydrogen. In some embodiments of a compound of Formula (II) or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 3 is —NR 50 —; and R 50 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II) or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 3 is —O—.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 2 is —(CR 45 R 46 ) v2 —. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 2 is —(CR 45 R 46 ) v2 —; R 45 and R 46 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v2 is 1 or 2. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 2 is —(CR 45 R 46 ) v2 —; R 45 and R 46 are each hydrogen; and v2 is 1.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 2 is —NR 47 —. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 2 is —NR 47 —; and R 47 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 2 is —NR 47 —; and R 47 is hydrogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 2 is —NR 47 —; and R 47 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 2 is —O—.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 2 is —O— and Y 3 is —(CR 48 R 49 ) v3 —. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 2 is —O—; Y 3 is —(CR 48 R 49 ) v3 —; R 48 and R 49 are each independently hydrogen, halogen, or C 1 -C 6 alkyl; and v3 is 1 or 2. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Y 2 is —O—; Y 3 is —(CR 48 R 49 ) v3 —; R 48 and R 49 are each hydrogen; and v3 is 1.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 1 is N; and Q 2 is CW. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 1 is CW; and Q 2 is N. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 1 is N; and Q 2 is N. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 1 is CW; and Q 2 is CW.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl, is independently optionally substituted with one, two, or three R 30 . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl, is independently optionally substituted with one, two, or three R 30 ; and each R 30 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each W is independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each W is hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, A is —O—. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, A is —CH 2 —.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one, two, or three R 30e . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one, two, or three R 30e ; and each R 30e is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5 and R 6 are each hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d ; and each R 30d is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , or —NR 16c C(═O)R 15c . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , or —NR 16c C(═O)R 15c ; R 15c are each independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; and R 16c are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , or —NR 16c C(═O)R 15c ; R 15c are each independently C 1 -C 6 alkyl; and R 16c are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, or —OH. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently halogen or —OH. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each —OH.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is —NR 1 R 2 .

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, one of R 1 or R 2 is not hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; R 15a is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen; and R 16a and R 17a are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; R 15a is C 1 -C 6 alkyl; and R 16a and R 17a are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; R 15a is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen; and R 16a and R 17a are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; R 15a is C 1 -C 6 alkyl; and R 16a and R 17a are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15a is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen; and R 16a and R 17a are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15a is C 1 -C 6 alkyl; and R 16a and R 17a are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15a is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15a is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16a and R 17a are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16a and R 17a are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a .

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; and each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; and each R 30a is independently halogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; and each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; and each R 30a is independently halogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen or C 1 -C 6 alkyl; and R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen; and R 2 is hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 3 is independently halogen or C 1 -C 6 alkyl; and R 2 is hydrogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R 2 is hydrogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen; and R 2 is hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen or C 1 -C 6 alkyl; and R 2 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R 2 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen; and R 2 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen or C 1 -C 6 alkyl; and R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen; and R 2 is hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen or C 1 -C 6 alkyl; and R 2 is hydrogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R 2 is hydrogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen; and R 2 is hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen or C 1 -C 6 alkyl; and R 2 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R 2 is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a ; each R 30a is independently halogen; and R 2 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; each R 30b is independently aryl optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; and R 30b is aryl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one R 30b ; and R 30b is aryl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine or a pyrrolidine optionally substituted with one, two, or three R 30b . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine or a pyrrolidine optionally substituted with one, two, or three R 30b ; each R 30b is independently aryl optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine or a pyrrolidine optionally substituted with one, two, or three R 30b ; and R 30b is aryl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine or a pyrrolidine optionally substituted with one R 30b ; and R 30b is aryl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine optionally substituted with one, two, or three R 30b . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine optionally substituted with one, two, or three R 30b ; each R 30b is independently aryl optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine optionally substituted with one, two, or three R 30b ; and R 30b is aryl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine optionally substituted with one R 30b ; and R 30b is aryl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a pyrrolidine optionally substituted with one, two, or three R 30b . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a pyrrolidine optionally substituted with one, two, or three R 30b ; each R 30b is independently aryl optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a pyrrolidine optionally substituted with one, two, or three R 30b ; and R 30b is aryl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a pyrrolidine optionally substituted with one R 30b ; and R 30b is aryl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is —OR 60 .

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is hydrogen, —C(═O)R 15e , —C(═O)OR 16e , —C(═O)NR 16e R 17e , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is —C(═O)R 15e , —C(═O)OR 16e , C(═O)NR 16e R 17e , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m .

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is cycloalkyl or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is cycloalkyl optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30m .

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15e is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen; and R 16e and R 17e are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15e is C 1 -C 6 alkyl; and R 16e and R 17e are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15e is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15e is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16e and R 17e are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16e and R 17e are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is —SR 61 .

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is hydrogen, —C(═O)R 15f , —C(═O)OR 16f , —C(═O)NR 16f R 17f , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is —C(═O)R 15f , —C(═O)OR 16f , —C(═O)NR 16f R 17f , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is cycloalkyl or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is cycloalkyl optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 3 .

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15f is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen; and R 16f and R 17f are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15f is C 1 -C 6 alkyl; and R 16f and R 17f are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15f is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15f is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16f and R 17f are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16f and R 17f are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is —CR 62 R 63 R 64 .

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen, halogen, —CN, —OH, —OR 15g , —NR 16g R 17g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen, halogen, —CN, —OH, —OR 15g , —NR 16g R 17g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30o ; R 15g is C 1 -C 6 alkyl; and R 16g and R 17g are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen, halogen, or —OH. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen or halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen, halogen, —CN, —OH, —OR 15g , —NR 16g R 17g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen, halogen, —CN, —OH, —OR 15g , —NR 16g R 17g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30o ; R 15g is C 1 -C 6 alkyl; and R 16g and R 17g are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen, halogen, or —OH. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen or halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g , —SR 15g , —S(═O)R 15g , —NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g , —SR 15g , —S(═O)R 15g , —NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g , —NR 16g R 17g , —C(═O)R 15g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g , —NR 16g R 17g , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g or —NR 16g R 17g . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is aryl, or heteroaryl; wherein each aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o .

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15g is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen; and R 16g and R 17g are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15g is C 1 -C 6 alkyl; and R 16g and R 17g are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15g is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15g is C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16g and R 17g are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16g and R 17g are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; and each R 31 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 3 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , NR 16b R 17b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , NR 16b R 17b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; and R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl). In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl); and each R 30c is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl); and each R 30c is independently halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl); and each R 30c is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 3 ; and each R 3 is independently halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; and each R 30c is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; and R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl). In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl); and each R 30c is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl); and each R 30c is independently halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —SR 18b , C 1 -C 6 alkyl, or C 1 -C 6 alkyl(cycloalkyl); wherein each alkyl, and cycloalkyl is independently optionally substituted with one, two, or three R 30c ; R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl); and each R 30c is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is —NH 2 .

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each independently hydrogen, aryl, or —(CR 23 R 24 ) w OC(═O)OR 25 .

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each hydrogen.

In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each —(CR 23 R 24 ) w OC(═O)OR 25 . In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each —(CR 23 R 24 ) w OC(═O)OR 25 ; w is 1 or 2; each R 23 and R 24 are independently hydrogen, halogen, or C 1 -C 6 alkyl; and each R 25 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each —(CR 23 R 24 ) w OC(═O)OR 25 ; w is 1; R 23 and R 2 are hydrogen; and each R 25 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 2 are each —(CR 23 R 24 ) w OC(═O)OR 25 ; w is 1; R 23 and R 24 are hydrogen; and each R 25 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l . In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; and each R 30l is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; and each R 30l is independently halogen.

In some embodiments provided herein is a compound having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Q 3 and Q 4 are independently N or CW 1 ; provided that at least one of Q 3 or Q 4 is N; W 1 is hydrogen, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; A is —O— or —CH 2 —; Z is —NR 1 R 2 , —OR 60 , —SR 61 , or —CR 62 R 63 R 64 ; R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 60 is hydrogen, —C(═O)R 15e , —C(═O)OR 16e , —C(═O)NR 16e R 17e , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m . R 61 is hydrogen, —C(═O)R 15f , —C(═O)OR 16f , —C(═O)NR 16f R 17f , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n ; R 62 , R 63 , and R 64 are each independently hydrogen, halogen, —CN, —OH, —OR 15g , —SH, —SR 15g , —S(═O)R 15g , —NO 2 , —NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —OC(═O)R 15g , —C(═O)OR 16g , —OC(═O)OR 16g , —C(═O)NR 16g R 17g , —OC(═O)NR 16g R 17g , —NR 16g C(═O)NR 16g R 17g , —NR 16g C(═O)R 15g , —NR 16g C(═O)OR 16g , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o ; R 3 is halogen, —CN, —OH, —OR 15b , —SR 18b , —NR 16b R 17b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, —OH, —OR 15d , —NR 16d S(═O) 2 R 15d , —NR 16d C(═O)R 15d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30e ; R 8 is hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X 1 is bond, —C(═O)—, —S(═O) 2 —, —O—, or —CR 40 R 41 —; Y 1 is —C(═O)—, —(CR 42 R 43 ) v1 —, —S(═O) v2 —, —NR 44 —, —S—, or —O—; Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—; R 40 , R 41 , R 42 , R 43 , R 45 , and R 46 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30p ; R 44 and R 47 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; v1 and v2 are each independently 1-3; R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30g ; R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 17a , R 17b , R 17e , R 17f , and R 17g are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30h ; or R 16a and R 17a or R 16b and R 17b or R 16e and R 17e or R 16f and R 17f or R 16g and R 17g are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 18b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30i ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , (CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30j , R 30k , R 30l , R 30m , R 30n , R 30o , and R 30p are independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —CN, —OH, —OR b , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

In some embodiments provided herein is a compound having the structure of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Q 1 and Q 2 are independently N or CW; Q 3 and Q 4 are independently N or CW 1 ; provided that at least one of Q 3 or Q 4 is N; each W is independently hydrogen, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30 ; W 1 is hydrogen, halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; A is —O— or —CH 2 —; Z is —NR 1 R 2 , —OR 60 , —SR 61 , or —CR 62 R 63 R 64 R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a ; or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b ; R 60 is hydrogen, —C(═O)R 15e , —C(═O)OR 16e , —C(═O)NR 16e R 17e , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m .

R 61 is hydrogen, —C(═O)R 15f , —C(═O)OR 16f , —C(═O)NR 16f R 17f , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n ;

R 62 , R 63 , and R 64 are each independently hydrogen, halogen, —CN, —OH, —OR 15g , —SH, —SR 15g , —S(═O)R 15g , —NO 2 , —NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —OC(═O)R 15g , —C(═O)OR 16g , —OC(═O)OR 16g , —C(═O)NR 16g R 17g , —OC(═O)NR 16g R 17g , —NR 16g C(═O)NR 16g R 17g , —NR 16g C(═O)R 15g , —NR 16g C(═O)OR 16g , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o ; R 3 is halogen, —CN, —OH, —OR 15b , —SR 18b , —NR 16b R 17b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c ; R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d ; R 5 and R 6 are each independently hydrogen, halogen, —OH, —OR 15d , —NR 16d S(═O) 2 R 15d , —NR 16d C(═O)R 15d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d ; R 8 is hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 9 and R 10 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; X 1 is bond, —C(═O)—, —S(═O) 2 —, —O—, or —CR 40 R 41 —; Y 1 is —C(═O)—, —(CR 42 R 43 ) v1 —, —S(═O) 2 —, —NR 44 —, —S—, or —O—; Y 2 is —(CR 45 R 46 ) v2 —, —NR 47 —, or —O—; R 40 , R 41 , R 42 , R 43 , R 45 , and R 46 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30p ; R 44 and R 47 are each independently hydrogen, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30f ; v1 and v2 are each independently 1-3; R 15a , R 15b , R 15c , R 15d , R 15e , R 15f , R 15g are each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30g ; R 16a , R 16b , R 16c , R 16d , R 16e , R 16f , R 16g , R 17b , R 17e , R 17f , and R 17g are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30h . or R 16a and R 17a or R 16b and R 17b or R 16e and R 17e or R 16f and R 17f or R 16g and R 17g are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; R 18b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30i ; R 21 and R 22 are each independently hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —(CR 23 R 24 ) w C(═O)OR 25 , —(CR 23 R 24 ) w OC(═O)R 26 , —(CR 23 R 24 ) w SC(═O)R 26 , or —(CR 23 R 24 ) w OC(═O)OR 25 ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30k ; or R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l ; each R 23 and R 24 are independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 25 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each R 26 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 1 -C 6 heteroalkyl; each w is independently 1-4; each R 30 , R 30a , R 30b , R 30c , R 30d , R 30e , R 30f , R 30g , R 30h , R 30i , R 30j , R 30k , R 30l , R 30m , R 30n , R 30o , and R 30p are independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 ; each R 31 is independently halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —NO 2 , —NR c R d , —S(═O) 2 R a , —NHS(═O) 2 R a , —S(═O) 2 NR c R d , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR c R d , —OC(═O)NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

For any and all of the embodiments of Formula (III) or (IV), substituents are selected from among a subset of the listed alternatives.

In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, when

then one of R 45 or R 46 is not hydrogen.

In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound is not (1-((5-(2-chloro-6-(methylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2,2,2-trifluoroethyl)phosphonic acid or any stereoisomers thereof.

In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 1 is N; and Q 2 is CW. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 1 is CW; and Q 2 is N. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 1 is CW; and Q 2 is CW. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q is N; and Q 2 is N. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl, is independently optionally substituted with one, two, or three R 30 . In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each W is independently hydrogen, halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl, is independently optionally substituted with one, two, or three R 30 . In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each W is independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each W is hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30 is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30 is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30 is independently halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30 is independently halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30 is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen, halogen, —OH, —OMe, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen, halogen, —OH, —NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen, halogen, —OH, —NH 2 , or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 8 is hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 9 and R 10 are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 9 and R 10 are each hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 3 is N and Q 4 is CW 1 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 4 is N and Q 3 is CW 1 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Q 3 is N and Q 4 is N.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, W 1 is hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, W 1 is hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, A is —O—. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, A is —CH 2 —.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, v1 is 1 or 2. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, v1 is 1. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, v1 is 2.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, v2 is 1 or 2. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, v2 is 1. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, v2 is 2.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is

and when

then

R 45 is halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30p ; and R 46 is hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30p .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 40 and R 41 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30p . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 40 and R 41 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 40 and R 41 are each independently hydrogen, halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 40 and R 41 are each independently hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 40 and R 41 are each independently hydrogen or halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 40 and R 41 are each hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 42 and R 43 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30p . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 42 and R 43 are each independently hydrogen, halogen, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 42 and R 43 are each independently hydrogen, halogen, —OH, —OR a , or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 42 and R 43 are each hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 44 is hydrogen, —S(═O) 2 R a , —C(═O)R a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl(aryl). In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 44 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 44 is hydrogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 44 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 45 and R 46 are each independently hydrogen, halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30p . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 45 and R 46 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one, two, or three R 30p . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 45 and R 46 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(aryl), or cycloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 45 and R 46 are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 45 and R 46 are each hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 45 is halogen, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 30p ; and R 46 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 45 is halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one, two, or three R 30p ; and R 46 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 45 is halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(aryl), or cycloalkyl; and R 46 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 is C 1 -C 6 alkyl; and R 46 is hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 30p is halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 30p is halogen, —OH, —OR a , C 1 -C 6 alkyl, cycloalkyl, or aryl; wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 30p is —OH, cycloalkyl, or aryl; wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 30p is —OH, cycloalkyl, or aryl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30p is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30p is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30p is independently halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30p is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30p is independently halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30p is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 47 is hydrogen, —S(═O) 2 R a , —C(═O)R a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl(aryl). In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 47 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 47 is hydrogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 47 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one, two, or three R 3 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently optionally substituted with one, two, or three R 30e . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5 and R 6 are each hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15d is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15d is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15d is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16d is hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16d is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16d is hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30e is independently halogen, —CN, —OH, —OR a , —NR b CR d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30e is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30e is independently halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30e is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30e is independently halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30e is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30d . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , —NR 16c C(═O)R 15c , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 3 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, —OH, —OR 15c , —NR 16c S(═O) 2 R 15c , or —NR 16c C(═O)R 15c .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently hydrogen, halogen, or —OH. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each independently halogen or —OH. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 4 and R 7 are each —OH.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15c is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15c is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15c is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16c is hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16c is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16c is hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30d is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30d is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30d is independently halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30d is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30d is independently halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30d is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is —NR 1 R 2 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, one of R 1 or R 2 is not hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), —S(═O) 2 R 15a , —S(═O) 2 NR 16a R 17a , or —C(═O) 2 R 15a ; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15a is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15a is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15a is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16a and R 17a are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16a and R 17a are each independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16a and R 17a are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is cycloalkyl optionally substituted with one, two, or three R 30a . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30a .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30a is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is hydrogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 2 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30b .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form an azetidine, a piperidine, a morpholine, or a pyrrolidine, each optionally substituted with one, two, or three R 30b .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a piperidine optionally substituted with one, two, or three R 30b . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a pyrrolidine optionally substituted with one, two, or three R 30b .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30b is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or aryl; wherein the alkyl and aryl are optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30b is independently aryl optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30b is aryl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30b is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30b is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30b is independently halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30b is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30b is independently halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30b is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is —OR 0 .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is hydrogen, —C(═O)R 15e , —C(═O)OR 16e , —C(═O)NR 16e R 17e , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is —C(═O)R 15e , —C(═O)OR 16e , C(═O)NR 16e R 17e , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is cycloalkyl or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is cycloalkyl optionally substituted with one, two, or three R 30m . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 60 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30m .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15e is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15e is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 5 is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16e and R 17e are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16e and R 17e are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16e and R 17e are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30m is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is —SR 61 .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is hydrogen, —C(═O)R 15f , —C(═O)OR 16f , —C(═O)NR 16f R 17f , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 3 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is —C(═O)R 15f , —C(═O)OR 16f , —C(═O)NR 16f R 17f , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 3 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is C 1 -C 6 alkyl, cycloalkyl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 3 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is C 1 -C 6 alkyl, cycloalkyl, or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 30n . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is cycloalkyl or C 1 -C 6 alkyl(aryl); wherein each alkyl, cycloalkyl, and aryl is independently optionally substituted with one, two, or three R 3 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is cycloalkyl optionally substituted with one, two, or three R 3 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 61 is C 1 -C 6 alkyl(aryl); wherein alkyl and aryl are independently optionally substituted with one, two, or three R 30n .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15f is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15f is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15f is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16f and R 17f are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16f and R 17f are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16f and R 17f are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30n is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is —CR 62 R 63 R 64 .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen halogen, —CN, —OH, —OR 15g , —NR 16g R 17g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen, halogen, —CN, —OH, —OR 15g , —NR 16g R 17g , —C(═O)OR 16 , —C(═O)NR 16g R 17g , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen, halogen, or —OH. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen or halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 62 is hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen, halogen, —CN, —OH, —OR 15g , —NR 16g R 17g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen, halogen, —CN, —OH, —OR 15g , —NR 16g R 17g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , or C 1 -C 6 alkyl optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen, halogen, or —OH. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen or halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 63 is hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g , —SR 15g , —S(═O)R 15g , —NR 16g R 17g , —S(═O) 2 R 15 , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g , —SR 15g , —S(═O)R 15g , —NR 16g R 17g , —S(═O) 2 R 15g , —NHS(═O) 2 R 15g , —S(═O) 2 NR 16g R 17g , —C(═O)R 15g , —C(═O)OR 16 , —C(═O)NR 16g R 17g , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g , —NR 16g R 17g , —C(═O)R 15g , —C(═O)OR 16g , —C(═O)NR 16g R 17g , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g , —NR 16g R 17g , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is —OR 15g or —NR 16g R 17g . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is cycloalkyl or heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one, two, or three R 30o . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 64 is aryl, or heteroaryl; wherein each aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30o .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15g is C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15g is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15g is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16g and R 17g are each independently hydrogen, C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkyl(aryl); wherein each alkyl and aryl is optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16g and R 17g are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16g and R 17g are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen, —CN, —OH, —OR b , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30o is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 3 is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —OR 15b , —SR 18b , —NR 16b R 17b , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 30c . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen, —CN, —OR 15b , —NR 16b R 17b , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one, two, or three R 3 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 3 is halogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15b is C 1 -C 6 alkyl optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15b is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 15b is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16b and R 17b are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl optionally substituted with one, two, or three halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 16b and R 17b are each independently hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 18b is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(aryl), C 1 -C 6 alkyl(heteroaryl), C 1 -C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl). In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 18b is cycloalkyl or C 1 -C 6 alkyl(cycloalkyl).

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30c is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30c is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30c is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30c is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each independently hydrogen, aryl, or —(CR 23 R 24 ) w OC(═O)OR 25 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each hydrogen or —(CR 23 R 24 ) w OC(═O)OR 25 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each hydrogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are each —(CR 23 R 24 ) w OC(═O)OR 25 .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, w is 1 or 2. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, w is 2. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, w is 1.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 23 and R 24 are independently hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 23 and R 24 are hydrogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 25 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 25 is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 30l . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 21 and R 22 are taken together with the atoms to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three R 3 .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 30l is C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R 30l is aryl optionally substituted with one, two, or three R 31 .

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30l is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30l is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30l is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 31 is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30f , R 30g , R 30h , R 30i , R 30j , and R 30k is independently halogen, —CN, —OH, —OR a , —NR c R d , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R 31 . In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30f , R 30g , R 30h , R 30i , R 30j , and R 30k is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30d is independently halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30f , R 30g , R 30h , R 30i , R 30j , and R 30k is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30f , R 30g , R 30h , R 30i , R 30j , and R 30k is independently halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 30f , R 30g , R 30h , R 30i , R 30j , and R 30k is independently halogen.

In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 31 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 1 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 31 is independently halogen. In some embodiments of a compound of Formula (III) or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R 31 is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R a is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R b is hydrogen. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R b is independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d are each independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d are each hydrogen. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d are each independently C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two, or three halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d are taken together with the nitrogen atom to which they are attached to form a pyrrolidine optionally substituted with one, two, or three halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d are taken together with the nitrogen atom to which they are attached to form a piperidine optionally substituted with one, two, or three halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), (II), (IIa), (IIb), (III), or (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R c and R d are taken together with the nitrogen atom to which they are attached to form a piperazine optionally substituted with one, two, or three halogen or C 1 -C 6 alkyl.

Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

In some embodiments is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having a structure selected from:

Ex.

1

(2-(((2R,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)-2- oxoethyl)phosphonic acid

2

(2-((((2R,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)amino)-2-oxoethyl)phosphonic acid

3

((N-(((2R,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfamoyl)methyl)phosphonic acid

4

(2-((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-2,3- dihydro-1H-inden-1-yl)(methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)ethyl)phosphonic acid

5

(2-(((2R,3S,4R,5R)-5-(4- (benzyl(methyl)amino)-6-chloro-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)ethyl)phosphonic acid

6

(2-(((2R,3S,4R,5S)-5-(4- (benzyl(methyl)amino)-6-chloro-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)ethyl)phosphonic acid

7

((((2R,3S,4R,5R)-5-(4- (benzyl(methyl)amino)-6-chloro-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

8

(2-(((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-2,3- dihydro-1H-inden-1-yl)(methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)-2- oxoethyl)phosphonic acid

9

(2-((((2R,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)(methyl)amino)-2- oxoethyl)phosphonic acid

10

((((2R,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

11

(2-(((2R,3S,4R,5R)-5-(5-chloro-7-(((S)-2,3- dihydro-1H-inden-1-yl)(methyl)amino)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)-2- oxoethyl)phosphonic acid

12

((((2R,3S,4R,5R)-5-(5-chloro-7-(((S)-2,3- dihydro-1H-inden-1-yl)amino)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

13

(((((2S,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)thio)methyl)phosphonic acid

14

(((((2S,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

15

((((2R,3S,4R,5R)-5-(2-chloro-4- ((cyclopropylmethyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

16

((((2R,3S,4R,5R)-5-(5-chloro-7- ((cyclopropylmethyl)amino)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

17

((((2R,3S,4R,5R)-5-(4-((2- chlorobenzyl)amino)-6-(hydroxymethyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

18

((((2R,3S,4R,5R)-5-(4-((3- chlorobenzyl)amino)-6-cyano-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

19

((((2R,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4-dihydroxy-3- methyltetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

20

(2-((((2R,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)(isobutyl)amino)-2- oxoethyl)phosphonic acid

23

((((1R,2R,3S,4R)-4-(5-chloro-7-(((S)-2,3- dihydro-1H-inden-1-yl)amino)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,3- dihydroxycyclopentypmethoxy)methyl) phosphonic acid

24

((((2R,3S,4R,5R)-5-(5-chloro-7-((3- chlorobenzyl)pamino)-3H[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

25

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-2,3- dihydro-1H-inden-1-yl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

26

((((2R,3S,4R,5R)-5-(5-chloro-7-(((S)-2,3- dihydro-1H-inden-1-yl)(methyl)amino)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

27

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

28

(2-(benzyl(((2R,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)amino)-2-oxoethyl)phosphonic acid

29

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- fluorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

30

((((2R,3S,4R,5R)-5-(5-chloro-7-((2- chlorobenzyl)pamino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

31

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-2,3- dihydro-1H-inden-1-yl)(methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

32

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- (trifluoromethyl)benzyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

33

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(2- chlorophenyl)ethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

34

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(3- chlorophenyl)ethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

35

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(3- chlorophenyl)ethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

36

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(3- chlorophenyphenyl)(methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

37

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- chlorobenzyl)(methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

38

((((2R,3S,4R,5R)-5-(6-chloro-4- ((cyclopropylmethyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

39

((((2R,3S,4R,5R)-5-(5-chloro-7-((3- chlorobenzyl)(methyl)amino)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

40

((((2R,3S,4R,5R)-5-(2-chloro-4-((2- chlorobenzyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

41

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- methylbenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

42

((((2R,3S,4R,5R)-5-(6-chloro-4-morpholino- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

43

((((2R,3S,4R,5R)-5-(6-chloro-4-(ethylamino)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

44

((((2R,3S,4R,5R)-5-(4-((3- chlorobenzyl)amino)-6-methyl-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

45

((((2R,3S,4R,5R)-5-(6-chloro-4-((((R)- tetrahydrofuran-3-yl)methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

46

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- cyanobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

47

((((2R,3S,4R,5R)-5-(6-chloro-4-((2,3- dichlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4 dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

48

((((2R,3S,4R,5R)-5-(6-chloro-4-(((1-methyl- 1H-indazol-7-yl)methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

49

((((2R,3S,4R,5R)-5-(6-chloro-4-((naphthalen- 1-ylmethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

50

(((S)-1-((2S,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)ethoxy)methyl)phosphonic acid

51

((((2R,3S,4R,5R)-5-(6-chloro-4-((quinolin-5- ylmethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

52

((((2R,3S,4R,5R)-5-(6-chloro-4- (methylamino)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

53

((((2R,3S,4R,5R)-5-(6-chloro-4- (cyclopentyl(methyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

54

((((2R,3S,4R,5R)-5-(4-((3- chlorobenzyl)amino)-6-isobutoxy-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

55

((((2R,3S,4R,5R)-5-(4-((3- chlorobenzyl)amino)-6-(pyrrolidin-1-yl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

56

((((2R,3S,4R,5R)-5-(4-((3- chlorobenzyl)amino)-6-(methylamino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

57

((((2R,3S,4R,5R)-5-(4-amino-6-chloro-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

58

((((2R,3S,4R,5R)-5-(6-chloro-4-((3-chloro-2- fluorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

59

((((2R,3S,4R,5R)-5-(5-chloro-7-((2- chlorobenzyl)(methyl)amino)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

60

(((R)-1-((2S,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)ethoxy)methyl)phosphonic acid

61

(((((2S,3S,4R,5R)-5-(6-chloro-4-((3- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

62

(((((2S,3(((((2S,3S,4R,5R)-5-(6-chloro-4- ((cyclopropylmethyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

63

((((2R,3S,4R,5R)-5-(6-chloro-4- (isobutylamino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

64

((((2R,3S,4R,5R)-5-(6-chloro-4-((2- chlorobenzyl)(methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

65

((((2R,3S,4R,5R)-5-(6-chloro-4-((3- chlorobenzyl)oxy)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

66

(((((2S,3S,4R,5R)-5-(6-chloro-4- (cyclopentylamino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

67

((((2R,3S,4R,5R)-5-(4-((3- chlorobenzyl)amino)-6-(isobutylamino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

68

((((2R,3S,4R,5R)-5-(6-chloro-4- ((cyclobutylmethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

69

((((2R,3S,4R,5R)-5-(6-chloro-4-((((S)- tetrahydrofuran-2-yl)methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

70

((((2R,3S,4R,5R)-5-(6-chloro-4-((((R)- tetrahydrofuran-2-yl)methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

71

((((2R,3S,4R,5R)-5-(6-chloro-4-((((S)- tetrahydrofuran-3-yl)methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

72

((((2R,3S,4R,5R)-5-(6-chloro-4- ((cyclopropylmethyl)(methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

73

((((2R,3S,4R,5R)-5-(6-chloro-4-((tetrahydro- 2H-pyran-4-yl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

74

((((2R,3S,4R,5R)-5-(6-chloro-4- (isopropylamino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

75

((((2R,3S,4R,5R)-5-(6-chloro-4- (phenylamino)-1H-pyrazolo[3,4-d]pyrimidin- 1-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

76

((((2R,3S,4R,5R)-5-(6-chloro-4- (cyclopropylamino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

77

((((2R,3S,4R,5R)-5-(6-chloro-4-(((1s,3S)-3- hydroxy-3-methylcyclobutyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

78

((((2R,3S,4R,5R)-5-(6-chloro-4-(pentan-3- ylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)- 3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

79

((((2R,3S,4R,5R)-5-(6-chloro-4- (cyclobutylamino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

80

((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)- tetrahydrofuran-3-yl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

81

((((2R,3S,4R,5R)-5-(6-chloro-4-(pyrrolidin-1- yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

82

((((2R,3S,4R,5R)-5-(4- ((cyclopropylmethyl)amino)-6-methoxy-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

83

((((2R,3S,4R,5R)-5-(4-(azetidin-1-yl)-6- chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)- 3,4-dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

84

(((((2S,3S,4R,5R)-5-(6-chloro-4- ((cyclopropylmethyl)(methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

85

((2-((2R,3S,4R,5R)-5-(6-chloro-4- ((cyclopropylmethyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)ethoxy)methyl)phosphonic acid

86

((((2R,3S,4R,5R)-5-(6-chloro-4-(((3,3- difluorocyclobutypmethyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

87

((((2R,3S,4R,5R)-5-(6-chloro-4-((3,3- difluorocyclobutyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

88

(((2-((2R,3S,4R,5R)-5-(6-chloro-4- ((cyclopropylmethy)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)ethyl)sulfonyl)methyl)phosphonic acid

89

((((2R,3S,4R,5R)-5-(6-chloro-4-((((1s,3S)-3- hydroxy-3-methylcyclobutyl)methyl)amino)- 1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

90

((((2R,3S,4R,5R)-5-(6-chloro-4-((pyrimidin- 2-ylmethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

91

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-1- cyclopropylethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

92

((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-1- cyclopropylethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

93

((((2R,3S,4R,5R)-5-(6-chloro-4- (cyclohexylamino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

94

((((2R,3S,4R,5R)-5-(6-chloro-4-((2- cyclopropylethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

95

((((2R,3S,4R,5R)-5-(5-chloro-7- (cyclopentylamino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

96

((((2R,3S,4R,5R)-5-(6-chloro-4-(((1- methylcyclopropyl)methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

97

((((2R,3S,4R,5R)-5-(2-chloro-4- ((cyclopropylmethyl)amino)-6-methyl-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

98

((N-(((2R,3S,4R,5R)-5-(6-chloro-4- (cyclopentylamino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)-N- methylsulfamoyl)methyl)phosphonic acid

99

((((2R,3S,4R,5R)-5-(6-chloro-4-(N- cyclopentylacetamido)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

100

((((2R,3S,4R,5R)-5-(6-chloro-4-(5- methylfuran-2-yl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

101

(3-((2R,3S,4R,5R)-5-(6-chloro-4- (cyclopentylamino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)propyl)phosphonic acid

102

((((2R,3S,4R,5R)-5-(6-chloro-4-(((S)-2,2- dimethylcyclopentyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

103

((((2R,3S,4R,5R)-5-(6-chloro-4-(((R)-2,2- dimethylcyclopentyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

104

((((2R,3S,4R,5R)-5-(6-chloro-4-(((1S,2R)-2- methylcyclopentyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

105

((((2R,3S,4R,5R)-5-(6-chloro-4-(((1R,2S)-2- methylcyclopentyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

106

(((((2R,3S,4R,5R)-5-(5-chloro-7- (cyclopentylamino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)(methoxy)phosphoryl)methyl) phosphonic acid

107

(((((2S,3S,4R,5R)-5-(6-chloro-4- (cyclobutylamino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

108

(((((2S,3S,4R,5R)-5-(5-chloro-7- (cyclopentylamino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

109

(2-((((2R,3S,4R,5R)-5-(6-chloro-4- (cyclopentylamino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)(methyl)amino)-2- oxoethyl)phosphonic acid

110

(((((2S,3S,4R,5R)-5-(5-chloro-7- (cyclobutylamino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

111

(((((2S,3S,4R,5R)-5-(6-chloro-4- ((cyclobutylmethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

112

(((((2S,3S,4R,5R)-5-(2-chloro-6- (cyclopentylamino)-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

113

(((((2S,3S,4R,5R)-5-(5-chloro-7- ((cyclobutylmethyl)amino)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

114

(((((2S,3S,4R,5R)-5-(5-chloro-7-(((S)-1-(4- fluorophenypethyl)amino)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

115

(2-((((2R,3S,4R,5R)-5-(5-chloro-7- (cyclopentylamino)-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)(methyl)amino)-2- oxoethyl)phosphonic acid

116

(((((2S,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(4- fluorophenyl)ethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

117

(((((2S,3S,4R,5R)-5-(6-chloro-4-((4- fluorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

118

(((((2S,3S,4R,5R)-5-(5-chloro-7-((2- chlorobenzyl)amino)-3H[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

119

(((((2S,3S,4R,5R)-5-(5-chloro-7-((4- fluorobenzypamino)-3H[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

120

(((((2S,3S,4R,5R)-5-(5-chloro-7-((4- chlorobenzyl)amino)-3H[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

121

(((((2S,3S,4R,5R)-5-(5-chloro-7-((2,3- dihydro-1H-inden-2-yl)amino)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

122

(((((2S,3S,4R,5R)-5-(5-chloro-7-((3- chlorobenzypamino)-3H[1,2,3]triazolo[4,5- d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

123

(((((2S,3S,4R,5R)-5-(6-chloro-4-(((S)-2,3- dihydro-1H-inden-1-yl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

124

((((2R,3S,4R,5R)-5-(6-chloro-4- ((cyclopentylmethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

125

(((((2S,3S,4R,5R)-5-(4-(cyclopentylamino)-6- (hydroxymethyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

126

(((((2S,3S,4R,5R)-5-(6-chloro-4-((2,3- dihydro-1H-inden-2-yl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

127

(((((2S,3S,4R,5R)-5-(6-chloro-4-((4- chlorobenzyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

128

(((((2S,3S,4R,5R)-5-(6-chloro-4-((2- methylcyclopentyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

129

(((((2S,3S,4R,5R)-5-(6-chloro-4-(((S)-1-(2- chlorophenyl)ethyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

130

(((((2S,3S,4R,5R)-5-(5-chloro-7-(((S)-2,3- dihydro-1H-inden-1-yl)amino)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

131

(4S)-2-(((((2S,3S,4R,5R)-5-(6-chloro-4- (cyclopentylamino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)-4-(3- chlorophenyl)-1,3,2-dioxaphosphinane2- oxide

132

((((2R,3S,4R,5R)-5-(4-(cyclopentylamino)-6- (2-hydroxypropan-2-yl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

133

(((((2S,3S,4R,5R)-5-(6-chloro-4- (cyclopentyl(2-methoxyethypamino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

134

(((((2S,3S,4R,5R)-5-(6-chloro-4-(((1R,2S)-2- methylcyclopentyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

135

(((((2S,3S,4R,5R)-5-(6-chloro-4-(((1S,2R)-2- methylcyclopentyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

136

(((((2S,3S,4R,5R)-5-(6-chloro-4-(((R)-2,3- dihydro-1H-inden-1-yl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl)sulfonyl)methyl)phosphonic acid

137

((((2R,3S,4R,5R)-5-(2-chloro-4- (cyclopentylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

138

((((2R,3S,4R,5R)-5-(6-chloro-4-(((1- cyanocyclopropyl)methyl)amino)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methoxy)methyl)phosphonic acid

In some embodiments is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having a structure selected from:

wherein A is —O— or —CH 2 —.

In some embodiments is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having a structure selected from:

In some embodiments is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, having a structure selected from:

Further Forms of Compounds Disclosed Herein

Isomers/Stereoisomers

In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.

Labeled Compounds

In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein, or a solvate, or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively. Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is prepared by any suitable method.

In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.

Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

Solvates

In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Tautomers

In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Some examples of tautomeric interconversions include:

Preparation of the Compounds

The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), Crescent Chemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.), Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCI America (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.), and Wako Chemicals USA, Inc. (Richmond, Va.).

Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

In some embodiments, the compounds described herein are prepared as outlined in Schemes 1-9.

Pharmaceutical Compositions

In certain embodiments, the compound disclosed herein is administered as a pure chemical. In some embodiments, the compound disclosed herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, Pa. (2005)).

Accordingly, provided herein is a pharmaceutical composition comprising at least one compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof.

In certain embodiments, the compound disclosed herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.

Methods of Treatment

The compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, are useful as inhibitors of CD73 and, therefore, useful in the treatment of diseases or disorders in which it is believed CD73 activity plays a role. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is an infection. In some embodiments, the disease or disorder is a neurodegenerative disease. In some embodiments, the disease or disorder is a psychiatric disorder.

Disclosed herein are methods of treating a subject with a disorder mediated by CD73 comprising the step of administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

Cancer

CD73 has been found to be overexpressed in many cancer cell lines and tumor types including breast cancer, colorectal cancer, ovarian cancer, gastric cancer, and gallbladder cancer and associated with poor prognosis. Increasing evidence suggests that CD73 is a key protein molecule in cancer development.

Higher expression levels of CD73 are associated with tumor neovascularization, invasiveness, resistance to chemotherapy and metastasis, and with shorter patient survival time in cancer. In some embodiments, the compounds disclosed herein are useful in reducing tumor neovascularization, invasiveness, resistance to chemotherapy and metastasis, as well as to lengthen patient survival time in cancer patients. In some embodiments, the CD73 inhibitors disclosed herein are used to control tumor neovascularization, progression, resistance to chemotherapy, and metastasis.

One embodiment provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In some embodiments, the cancer is chemoresistant cancer, radio resistant cancer, anti-hormonal therapy resistant cancer, or treatment refractory cancer. In some embodiments, the cancer is relapsed cancer, persistent cancer, or recurrent cancer. Another embodiment provided herein describes a method of reducing incidences of cancer recurrence. Also provided here in some embodiments, is a method for treating a therapy-resistant cancer. In some embodiments, the cancer is metastasic cancer.

In certain embodiments, the cancer treatable with the methods provided herein includes, but is not limited to, (1) leukemias, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome or a symptom thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia, or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML); (2) chronic leukemias, including, but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas, including, but not limited to, Hodgkin's disease and non-Hodgkin's disease; (5) multiple myelomas, including, but not limited to, smoldering multiple myeloma, non-secretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma; (6) Waldenstrom's macroglobulinernia; (7) monoclonal gammopathy of undetermined significance; (8) benign monoclonal gammopathy; (9) heavy chain disease; (10) bone and connective tissue sarcomas, including, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11) brain tumors, including, but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, aligodendrogliorna, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; (12) breast cancer, including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mutinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget's disease, and inflammatory breast cancer; (13) adrenal cancer, including, but not limited to, pheochromocytom and adrenocortical carcinoma; (14) thyroid cancer, including, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer; (15) pancreatic cancer, including, but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; (16) pituitary cancer, including, but limited to, Cushing's disease, prol actin-secreting tumor, acromegaly, and diabetes insipius; (17) eye cancer, including, but not limited, to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; (18) vaginal cancer, including, but not limited to, squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvar cancer, including, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; (20) cervical cancers, including, but not limited to, squamous cell carcinoma, and adenocarcinoma; (21) uterine cancer, including, but not limited to, endometrial carcinoma and uterine sarcoma; (22) ovarian cancer, including, but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; (23) esophageal cancer, including, but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; (24) stomach cancer, including, but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, including, but not limited to, hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer, including, but not limited to, adenocarcinoma; (29) cholangiocarcinomas, including, but not limited to, pappillary, nodular, and diffuse; (30) lung cancer, including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma, and small-cell lung cancer; (31) testicular cancer, including, but not limited to, germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, and choriocarcinoma (yolk-sac tumor); (32) prostate cancer, including, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oral cancer, including, but not limited to, squamous cell carcinoma; (35) basal cancer; (36) salivary gland cancer, including, but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; (37) pharynx cancer, including, but not limited to, squamous cell cancer and verrucous; (38) skin cancer, including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma; (39) kidney cancer, including, but not limited to, renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, and transitional cell cancer (renal pelvis and/or uterer); (40) Wilms' tumor; (41) bladder cancer, including, but not limited to, transitional cell carcinoma, squamous cell cancer, adenocarcinoma, and carcinosarcoma; (42) reproductive cancers, such as cervical cancer, uterus cancer, ovarian cancer, or testicular cancer; (43) esophagus cancer; (44) laryngeal cancer; (45) head and neck cancers (including mouth, nose, throat, larynx, sinuses, or salivary glands cancers); and other cancer, including, not limited to, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangio-endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinomas (See Fishman et al., 1985, Medicine, 2d Ed., J. B. Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America).

In certain embodiments, the cancer treatable with the methods provided herein is a hematological malignancy. In certain embodiments, the hematological malignancy is a T-cell malignancy. In certain embodiments, T-cell malignancies include peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK/T-cell lymphomas, or treatment-related T-cell lymphomas.

In certain embodiments, the hematological malignancy is a B-cell malignancy. In certain embodiments, B-cell malignancies include acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), high-risk chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitfs lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In certain embodiments, the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL). In certain embodiments, the DLBCL is an activated B-cell DLBCL (ABC-DLBCL), a germinal center B-cell like DLBCL (GBC-DLBCL), a double hit DLBCL (DH-DLBCL), or a triple hit DLBCL (TH-DLBCL).

In certain embodiments, the cancer treatable with the methods provided herein is lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, or prostate cancer.

Infections

A number of studies have shown changes in the activity of the CD39/CD73 axis during infections induced by a variety of microorganisms. One embodiment provides a method of treating an infection in a subject in need thereof, comprising administering to the subject a compound of disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

In some embodiments, the infection is a viral infection, a bacterial infection, or a parasitic infection.

Parasitic Infections

In some embodiments, the infection is a parasitic infection. In some embodiments, the parasitic infection is caused by infection of the subject with a protozoan organism. In some embodiments, the protozoan organism selected from the group consisting of the genera Acanthamoeba, Babesia, Balantidium, Cryptosporidium, Dientamoeba, Eimeria, Entamoeba, Giardia, Isospora, Leishmania, Naegleria, Neospora, Plasmodium, Sarcocystis, Theileria, Toxoplasma, Trichomonas, Trypanosoma , or any combinations thereof. In some embodiments, the parasitic infection is caused by an infection with Toxoplasma gondii ( T. gondii ). In some embodiments, the parasitic infection is toxoplasmosis. In some embodiments, the toxoplasmosis is acute toxoplasmosis, latent toxoplasmosis, or cutaneous toxoplasmosis.

Acute toxoplasmosis: acute toxoplasmosis is often asymptomatic in healthy adults. However, symptoms may manifest and are often influenza-like: swollen lymph nodes, headaches, fever, fatigue, or muscle aches and pains that last for a month or more. Rarely will a human with a fully functioning immune system develop severe symptoms following infection. People with weakened immune systems are likely to experience headache, confusion, poor coordination, seizures, lung problems that may resemble tuberculosis or Pneumocystis jiroveci pneumonia (a common opportunistic infection that occurs in people with AIDS), or blurred vision caused by severe inflammation of the retina (ocular toxoplasmosis). Young children and immunocompromised people, such as those with HIV/AIDS, those taking certain types of chemotherapy, or those who have recently received an organ transplant, may develop severe toxoplasmosis. In some instances, toxoplasmosis causes damage to the brain (encephalitis) or the eyes (necrotizing retinochoroiditis). Infants infected via placental transmission may be born with either of these problems, or with nasal malformations, although these complications are rare in newborns. The toxoplasmic trophozoites causing acute toxoplasmosis are referred to as tachyzoites, and are typically found in bodily fluids.

Latent toxoplasmosis: due to its asymptomatic nature, it is easy for a host to become infected with Toxoplasma gondii and develop toxoplasmosis without knowing it. Although mild, flu-like symptoms occasionally occur during the first few weeks following exposure, infection with T. gondii produces no readily observable symptoms in healthy human adults. In most immunocompetent people, the infection enters a latent phase, during which only bradyzoites (tissue cysts) are present; these tissue cysts and even lesions can occur in the retinas, alveolar lining of the lungs (where an acute infection may mimic a Pneumocystis jirovecii infection), heart, skeletal muscle, and the central nervous system (CNS), including the brain. Cysts form in the CNS (brain tissue) upon infection with T. gondii and persist for the lifetime of the host. Most infants who are infected while in the womb have no symptoms at birth, but may develop symptoms later in life.

Cutaneous toxoplasmosis: in some embodiments, skin lesions occur in the acquired form of the disease, including roseola and erythema multiforme-like eruptions, prurigo-like nodules, urticaria, and maculopapular lesions. Newborns may have punctate macules or ecchymoses. Diagnosis of cutaneous toxoplasmosis is based on the tachyzoite form of T. gondii being found in the epidermis.

Viral Infections

In some embodiments, the infection is a viral infection. In certain embodiments, the viral infection treatable with the methods provided herein includes, but is not limited to, chickenpox, the flu (influenza), herpes, human immunodeficiency virus (HIV/AIDS), human papillomavirus (HPV), Infectious mononucleosis, mumps, measles, rubella, shingles, viral gastroenteritis (stomach flu), viral hepatitis, viral meningitis, and viral pneumonia.

Neurodegenerative Diseases

In the central nervous system, adenosine plays a critical role in controlling a multitude of neural functions. Through the activation of P1 receptors, adenosine is involved in diverse physiological and pathological processes such as regulation of sleep, general arousal state and activity, local neuronal excitability, and coupling of the cerebral blood flow to the energy demand. In some embodiments, the manipulation of adenosine production via CD73 inhibitors has therapeutic potential in neurodegenerative diseases. One embodiment provides a method of treating a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a compound of disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In certain embodiments, the neurodegenerative disease treatable with the methods provided herein includes, but is not limited to, Alzheimer's disease, Parkinson's disease, and Huntington's disease. One embodiment provides a method of treating a psychiatric disorder in a subject in need thereof, comprising administering to the subject a compound of disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the psychiatric disorder is schizophrenia or autism.

Combination Therapy

In certain instances, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is administered in combination with a second therapeutic agent.

In some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

In one specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is co-administered with a second therapeutic agent, wherein the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.

In certain embodiments, different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating a pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent. Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.

It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g., the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth. In additional embodiments, when co-administered with a second therapeutic agent, the compound provided herein is administered either simultaneously with the second therapeutic agent, or sequentially.

In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).

The compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.

In certain embodiments, the second therapeutic agent is an adjuvant. In certain embodiments, the second therapeutic agent is an anti-cancer agent. In certain embodiments, the second therapeutic agent is an antiemetic. In certain embodiments, the second therapeutic agent is an anti-infective agent. In certain embodiments, the second therapeutic agent is an antiviral agent. In certain embodiments, the second therapeutic agent is an antibacterial agent.

In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).

In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is administered in combination with an anti-cancer agent.

In some embodiments, the anti-cancer agent is a hormone blocking therapy. Hormone blocking therapy includes the use of agents that block the production of estrogens or block the estrogen receptors. In some embodiments, hormone blocking therapy includes the use of estrogen receptor modulators and/aromatase inhibitors. Estrogen receptor modulators include triphenylethylene derivatives (e.g., tamoxifen, toremifene, droloxifene, 3-hydroxytamoxifen, idoxifene, TAT-59 (a phosphorylated derivative of 4-hydroxytamoxifen) and GW5638 (a carboxylic acid derivative of tamoxifen)); non-steroidal estrogen receptor modulators (e.g., raloxifene, LY353381 (SERM3) and LY357489); steroidal estrogen receptor modulators (e.g., ICI-182,780). Aromatase inhibitors include steroidal aromatase inhibitors and non-steroidal aromatase inhibitors. Steroidal aromatase inhibitors include, but are not limited to, exemestane. Non-steroidal aromatase inhibitors include, but are not limited to, anastrozole and letrozole.

In certain embodiments, compounds disclosed herein are used in combination with one or more passive immunotherapies, including but not limited to, naked monoclonal antibody drugs and conjugated monoclonal antibody drugs. Examples of naked monoclonal antibody drugs that can be used include, but are not limited to, rituximab, an antibody against the CD20 antigen; trastuzumab, an antibody against the HER2 protein; alemtuzumab, an antibody against the CD52 antigen; cetuximab, an antibody against the EGFR protein; and bevacizumab which is an anti-angiogenesis inhibitor of VEGF protein.

Examples of conjugated monoclonal antibodies include, but are not limited to, radiolabeled antibody ibritumomab tiuxetan; radiolabeled antibody tositumomab; and immunotoxin gemtuzumab ozogamicin which contains calicheamicin; BL22, an anti-CD22 monoclonal antibody-immunotoxin conjugate; radiolabeled antibodies such as OncoScint (Registered trademark) and ProstaScint (Registered trademark); brentuximab vedotin; and ado-trastuzumab emtansine.

Further examples of therapeutic antibodies that can be used include, but are not limited to, abciximab, an antibody against the glycoprotein IIb/IIIa receptor on platelets; daclizumab, an immunosuppressive, humanized anti-CD25 monoclonal antibody; edrecolomab, a murine anti-17-IA cell surface antigen IgG2a antibody; BEC2, a murine anti-idiotype (GD3 epitope) IgG antibody; IMC-C225, a chimeric anti-EGFR IgG antibody; VITAXIN (Registered Trademark) a humanized anti-aVbeta 3 integrin antibody; Campath 1H/LDP-03, a humanized anti CD52 IgGI antibody; Smart M195, a humanized anti-CD33 IgG antibody; epratuzumab, a humanized anti-CD22 IgG antibody; Lymphoscan; visilizumab; CM3, a humanized anti-ICAM3 antibody; IDEC-114 a primatized anti-CD80 antibody; IDEC-131 a humanized anti-CD40L antibody; IDEC-151 a primatized anti-CD4 antibody; IDEC-152 a primatized anti-CD23 antibody; SMART anti-CD3, a humanized anti-CD3 IgG; 5G1.1, a humanized anti-complement factor 5 (C5) antibody; D2E7, a humanized anti-TNF-alpha antibody; CDP870, a humanized anti-TNF-alpha Fab fragment; IDEC-151, a primatized anti-CD4 IgGI antibody; MDX-CD4, a human anti-CD4 IgG antibody; CD20-streptdavidin (+biotin-yttrium 90); CDP571, a humanized anti-TNF-alpha IgG4 antibody; LDP-02, a humanized anti-alpha 4beta 7 antibody; OrthoClone OKT4A, a humanized anti-CD4 IgG antibody; ANTOVA (Registered Trademark), a humanized anti-CD40L IgG antibody; ANTEGREN (Registered Trademark), a humanized anti-VLA-4 IgG antibody; and CAT-152, a human anti-TGF-beta 2 antibody.

In some embodiments, the second therapeutic agent for use in combination with a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, include one or more of the following: abiraterone; abarelix; adriamycin; actinomycin; acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; alemtuzumab; allopurinol; alitretinoin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; aminolevulinic acid; amifostine; amsacrine; anastrozole; anthramycin; aprepitant; arsenic trioxide; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; bendamustine hydrochloride; benzodepa; bevacizumab; bexarotene; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin; bleomycin sulfate; bortezomib; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; capecitabine; cedefingol; cetuximab; chlorambucil; cirolemycin; cisplatin; cladribine; clofarabine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dasatinib; daunorubicin hydrochloride; dactinomycin; darbepoetin alfa; decitabine; degarelix; denileukin diftitox; dexormaplatin; dexrazoxane hydrochloride; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; eltrombopag olamine; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; epoetin alfa; erbulozole; erlotinib hydrochloride; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; everolimus; exemestane; fadrozole hydrochloride; fazarabine; fenretinide; filgrastim; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; fulvestrant; gefitinib; gemcitabine; gemcitabine hydrochloride; gemcitabine cisplatin; gemtuzumab ozogamicin; goserelin acetate; histrelin acetate; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; ibritumomab tiuxetan; idarubicin; ifosfamide; imatinib mesylate; imiquimod; interleukin I1 (including recombinant interleukin II, or rlL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; ixabepilone; lanreotide acetate; lapatinib; lenalidomide; letrozole; leuprolide acetate; leucovorin calcium; leuprolide acetate; levamisole; liposomal cytarabine; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; methoxsalen; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin C; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nandrolone phenpropionate; nelarabine; nilotinib; nocodazoie; nofetumomab; nogalamycin; ofatumumab; oprelvekin; ormaplatin; oxaliplatin; oxisuran; paclitaxel; palifermin; palonosetron hydrochloride; pamidronate; pegfilgrastim; pemetrexed disodium; pentostatin; panitumumab; pazopanib hydrochloride; pemetrexed disodium; plerixafor; pralatrexate; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; quinacrine; raloxifene hydrochloride; rasburicase; recombinant HPV bivalent vaccine; recombinant HPV quadrivalent vaccine; riboprine; rogletimide; rituximab; romidepsin; romiplostim; safingol; safingol hydrochloride; sargramostim; semustine; simtrazene; sipuleucel-T; sorafenib; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; sunitinib malate; talisomycin; tamoxifen citrate; tecogalan sodium; tegafur; teloxantrone hydrochloride; temozolomide; temoporfin; temsirolimus; teniposide; teroxirone; testolactone; thalidomide; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; topotecan hydrochloride; toremifene; tositumomab and I 131 Iodine tositumomab; trastuzumab; trestolone acetate; tretinoin; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; valrubicin; vapreotide; verteporfin; vinblastine; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorinostat; vorozole; zeniplatin; zinostatin; zoledronic acid; and zorubicin hydrochloride.

In some embodiments, the second therapeutic agent is an alkylating agent. Examples of alkylating agents for use in combination with a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), ortriazenes (decarbazine, etc.).

Other agents that are optionally used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide).

In some embodiments, the second therapeutic agent is an immunotherapy agent. Examples of immunotherapy agents for use in combination with a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, include, but are not limited to, checkpoint inhibitors (e.g., anti-PD1 and anti-PD-L1 inhibitors), cancer vaccines (e.g., sipuleucel-T), oncolytic viruses (e.g., talimogene laherparepvec), cytokines (e.g., IL-2 and INF-alpha), CAR-T cells.

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, is used in combination with anti-emetic agents to treat nausea or emesis, which results from the use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or steroisomer thereof, anti-cancer agent(s) and/or radiation therapy. Anti-emetic agents include, but are not limited to: neurokinin-1 receptor antagonists, 5HT3 receptor antagonists (such as ondansetron, granisetron, tropisetron, palonosetron, and zatisetron), GABAB receptor agonists (such as baclofen), corticosteroids (such as dexamethasone, prednisone, prednisolone, or others), dopamine antagonists (such as, but not limited to, domperidone, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide), antihistamines (H1 histamine receptor antagonists, such as but not limited to, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, hydroxyzine), cannabinoids (such as but not limited to, cannabis, marinol, dronabinol), and others (such as, but not limited to, trimeth