WO2022081912A2 - Heterocycles and uses thereof - Google Patents

Heterocycles and uses thereof Download PDF

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Publication number
WO2022081912A2
WO2022081912A2 PCT/US2021/055086 US2021055086W WO2022081912A2 WO 2022081912 A2 WO2022081912 A2 WO 2022081912A2 US 2021055086 W US2021055086 W US 2021055086W WO 2022081912 A2 WO2022081912 A2 WO 2022081912A2
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Prior art keywords
alkyl
heterocycloalkyl
aryl
optionally substituted
solvate
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PCT/US2021/055086
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French (fr)
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WO2022081912A3 (en
Inventor
Baogen Wu
Xiaoming Li
Xiangzhu Wang
Zhiyong Chen
Liansheng Li
Pingda Ren
Yi Liu
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Kumquat Biosciences Inc.
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Publication of WO2022081912A2 publication Critical patent/WO2022081912A2/en
Publication of WO2022081912A3 publication Critical patent/WO2022081912A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/34—Phthalazines with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • Cancer e.g., tumor, neoplasm, metastases
  • Tumor a malignant neoplasm, metastases
  • Many types of cancers are marked with mutations in one or more proteins involved in various signaling pathways leading to unregulated growth of cancerous cells. In some cases, about 25 to 30 percent (%) of tumors are known to harbor Rat sarcoma (Ras) mutations.
  • Ras Rat sarcoma
  • Ras in its GTP-bound state interacts with a number of effectors. Return to tire inactive state is driven by GTPase-activating proteins (GAPs), which down- regulate active Ras by accelerating the weak intrinsic GTPase activity.
  • GAPs GTPase-activating proteins
  • the GAP activity is impaired or greatly reduced, resulting in persistent activation, which drives the oncogenic Ras signaling through, e.g.. the RAS-RAF-MEK-ERK and RAS-PI3K-PDK1-AKT pathways, both essential to cell survival and proliferation.
  • SOS protein Son of Sevenless
  • S0S1 is a human homologue of the originally identified Drosophila protein Son of Sevenless.
  • S0S1 has two binding sites for Ras protents: a catalytic site tliat binds GDP-bound Ras proteins io promote guanine nucleotide exchange and an allosteric site that binds GTP-bound Ras to further promote activation of Ras proteins.
  • Son of Sevenless 2 (S0S2) is a homolog of SOS1 in mammalian cells. Double S0S1 and S0S2 knockout leads to rapid lethality in adult mice (Baitanas et al., Mol. Cell. Biol., 2013, 33(22):4562-78).
  • Ras proteins have long been considered to be “undruggable,” due to, in part, high affinity to their substrate Guanosine-5'-triphosphate (GTP) and/or their smooth surfaces without any obvious targeting region.
  • GTP Guanosine-5'-triphosphate
  • Recently, a specific G12C Ras gene mutation has been identified as a potential druggable target.
  • such therapeutic approach is still limiting, as the G12C mutation in Ras has a low prevalence rate (e.g., about 3% in pancreatic ductal adenocarcinoma) as compared to other known Ras mutations.
  • the disclosure provides a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R 10 ;
  • L 1 is a bond or C 1-6 alkyl
  • X and Y are selected from N(R 2 ) and C(O), wherein one of X and Y is N(R 2 ) and one of X and Y is C(O);
  • Z 1 , Z 2 , and Z 3 are each independently selected from N and C(R 3a ), wherein at least one of Z 1 , Z 2 , and Z 3 is N;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyI. and C 2-9 heterocycloalkyI wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three R 20a ;
  • R 3 is selected from halogen, CN, C 1-6 alkyl, C 2-6 alkeny 1, C 2-6 alkynyl, C 3-14 cycloalkyl, C 2-9 heterocycloalky 1, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), - N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , N(R 14 )S(O)R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), - C(O)C(O)N(R 12 )(
  • R 4 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 5 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 10 is independently selected from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyI. C 3-7 cycloalkyI. C 2 .
  • heterocycloalkyl C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20d ; each R 12 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI. C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryI. wherein C 1-6 alkyl, C 2-6 alkenyl. C 2-6 alkynyI. C 3-7 cycloalkyI. C 2-9 hetcrocycloalkyl.
  • C 6-10 aryl, and C 1-9 heleroaryI are optionally substituted with one, two, or three R 20e ; each R 13 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I: or R 12 and R 13 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 20f ; each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyI: each R 15 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI.
  • C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 hetcroaryI wherein C 1-6 alkyl, C 2-6 alkcnyl. C 2-6 alkynyl, C 3-7 cycloalkyI. C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 hetcroaryI are optionally substituted with one, two, or three R 20g ; each R 17 and each R 17a are each independently selected from C 1-6 alkyl and C 3-6 cycloalkyI.
  • each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 20h are each independently selected from halogen, oxo, -CN, C 1- 6 alkyl, C 2-6 alkenyl. C 2-6 alkynyl, C 3-10 cycloalkyl.
  • C 3-10 cycloalkyl, -CH 2 - C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 - C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyI. C 1-6 alkoxy.
  • each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkeny
  • each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl.
  • each R 23 is independently selected from H and C 1-6 alkyl
  • each R 24 is independently selected from H and C 1-6 alkyl
  • each R 25 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI.
  • R 1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R 10 ;
  • L 1 is a bond or C 1-6 alkyl
  • X and Y are selected from N(R 2 ) and C(O), wherein one of X and Y is N(R 2 ) and one of X and Y is C(O);
  • Z 1 , Z 2 , and Z 3 are each independently selected from N and C(R 3a ), wherein at least one of Z 1 , Z 2 , and Z 3 is N;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl. C 2-6 alkynyl, and C 3-10 cycloalkyl-wherein C 1-6 alkyl, C 2-6 alkeny 1, C 2-6 alkynyl, and C 3-10 cycloalkyl are optionally substituted with one, two, or three R 20a ;
  • R 3 is selected from halogen, C 1-6 alkyl, C 2-6 alkenyl. C 2-6 alkynyI. C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1- 9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), - N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O
  • R 4 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 5 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 10 is independently selected from halogen, -CN, C 1-6 alkyl, alkynyl, C,. -cycloalkyI. C 2 . sheterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl.
  • C 2-6 alkynyl, C 3-7 cycloalkyl C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20d ; each R 12 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI. C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryI. wherein C 1-6 alkyl, C 2-6 alkenyl . C 2-6 alkynyl, C 3-7 cycloalkyI.
  • C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryI are optionally substituted with one, two, or three R 20e ; each R 13 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 12 and R 13 , together with the nitrogen to which they are attached, form a C 2-9 lielerocycloalkyI ring optionally substituted with one, two, or three R 20f ; each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 15 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkynyl, C 3-7 cycloalkyI.
  • each R 17 and each R 17a are each independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, wherein C 1-6 alkyl and C 3 - 6 cycloalkyl are optionally substituted with one, two or three of R 20h ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 20h are each independently selected from halogen, oxo, -CN, C 1 - 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3
  • C 6-10 aryl, -CH 2 -C 3-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Ci- ehaloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), - OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O) 2 R 25 ,
  • each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI.
  • C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaiy k each R 23 is independently selected from H and C 1-6 alkyl; each R 24 is independently selected from H and C 1-6 alkyl; and each R 25 is selected from C 1-6 alkyl, C 2-6 alkenyl. C 2-6 alkynyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl.
  • Formula (la) is a compound of Formula (F) or Formula (I) having the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof: Formula (la).
  • R 3 is selected from -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , - C(O)N(R 12 )(R 13 ), -SR 12 , -SOR 12 , -SO 2 (R 12 )(R 13 ), -SO 2 N(R 12 )(R 13 ), -P(O)(R 17 )(R 17a ), C 1-6 alkyl, C 3-10 cycloalkyl, C 2 .
  • R 3 is selected from -C(O)R 15 , -C(O)N(R 12 )(R 13 ), C 2-9 helerocycloalkyI .
  • R 15 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20g .
  • [0017] is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20b .
  • R 3 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20b .
  • R 3 is C 6-10 aryl optionally substituted with one, two, or three R 20b .
  • each R 3a is independently selected from hydrogen, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-10 cycloalkyl, C 2 . gheterocycloalkyl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20c .
  • each R 3a is independently selected from hydrogen, halogen, and unsubstituted C 1-6 alkyl.
  • the disclosure provides a compound of Formula (II'), or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R 10 ;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-10 cycloalkyl wherein C 1-6 alkyl, C 2-6 alkenyl. C 2-6 alkynyl, and C 3-10 cycloalkyl are optionally substituted with one, two, or three R 20a ;
  • R 4 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 5 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 6 is independently selected from halogen, -CN, C 1-6 alkyl, Ch-.alkcny I. C 2-6 alkynyl, C . ocycloalkyI. C 2- 9 heterocycloalkyl.
  • R 7 is selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1 - sheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), - N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 13 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )
  • C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20d ; each R 12 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI.
  • each R 13 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I: or R 12 and R 13 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 20f ;
  • each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyI: each R 15 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyI. C 3-7 cycloalkyI.
  • C 2-9 heterocycloalkyI C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 1-6 alkeny 1, C 1-6 alky nyl, C 3-7 cycloalkyl.
  • C 2-9 heterocycloalky 1, C 3-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 2 ° B ; each R 17 and each R 17a are each independently selected from C 1-6 alkyl and C 3-6 , cycloalkyI.
  • C 1-6 alkyl and C 3- 6 cycloalkyl are optionally substituted with one, two or three of R 20h ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 20h are each independently selected from halogen, oxo, -CN, Ci- ealkyl, C;., alkenyl. C 1-6 alkynyl, C..iocycloalkyk -CH 2 -C 3-10 cycloalkyl, C 2- 9 heterocycloalkyl. -CH 2 -C 2- •.heterocycloalkyl.
  • each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl
  • each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl. C 2 .
  • R 1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R 10 ;
  • R 2 is selected from hydrogen, C 1-6 alkyI. C 2-6 alkenyl, C 2-6 alkynyl, and C 3-10 cycloalkyl wherein C 1-6 alkyI. C 2-6 alkenyl, C 2-6 alkynyl, and C 3-10 cy cloalky 1 are optionally substituted with one, two, or three R 20a ;
  • R 4 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 5 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • each R 6 is independently selected from halogen, -CN, C 1-6 alkyl, C 2-6 alkeny I. C 2-6 alkynyI. C 3-10 cycloalkyl, C 2- 9 heterocycloalkyl. C 6-10 aryl, C 1-9 heteroaryl.
  • R 7 is selected from halogen, C 1-6 alkyl, C 2-6 aIkenyl. C 2-6 alkynyl. C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1- 9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), - N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C
  • each R 10 is independently selected from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 2 .
  • each R 13 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 12 and R 13 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 20f ;
  • each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-9 ialoalky I: each R 15 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI.
  • C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI.
  • C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20g ;
  • each R 17 and each R 17a are each independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, wherein C 1-6 alkyl and C 3- ecy cloalkyl are optionally substituted with one, two or three of R 20h ;
  • each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 2011 are each independently selected from halogen, oxo, -CN, Ci- ealkyl, C 2-6 alkenyl, C 2-6 alkyny
  • each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl
  • each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C -cy cloalky I.
  • R 7 is selected from halogen, -OR 12 , -N(R 12 )(R 13 ), -SR 12 , -SOR 12 , -SO 2 (R 12 )(R 13 ), - SO 2 N(R 12 )(R 13 ), -P(O)(R 17 )(R 17a ), C 1-6 alkyl, C 3-10 cycloalkyl, Ci-yhclcrocycloalkyl. C 6-10 aryl, and Ci.Jictcroaiy I.
  • C 1-6 alkyl, C 3-10 cycloalkyl, C 2-6 heterocycloalkyl, C 6-10 aryl, and CiJictcroaryl are optionally substituted with one, two, or three R 20c .
  • R 7 is selected from C 1-6 alkyl, C ,. w cy cloalky 1, C 2 . ⁇ ;heterocycloalky I.
  • Ce- icaryl and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20c .
  • each R 6 is independently selected from halogen, C 1-6 alkyl, Cj.iocycloalkyl, C 2 . ⁇ Jictcrocvcloalky I. C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalky 1, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20b .
  • each R 6 is independently selected from halogen and optionally substituted with one, two, or three R 20b C 1-6 alkyl.
  • the disclosure provides a compound of Formula (III’), or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered atyl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R 10 ;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkeny 1, C 2-6 alkynyl, C 3-10 cycloalkyI. wherein C 1-6 alkyl, C 2 .oalkeny 1, C 2 - 6alkynyl, and C 3-10 cycloalkyl are optionally substituted with one, two, or three R 20a ;
  • R 4 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 5 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalky 1; each R 8 is independently selected from halogen, -CN, C 1-6 alky 1, C 2-6 alkenyl. C 2-6 alkynyl, C . ocycloalky I. C 2 .
  • sheterocycloalkyl C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), - N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , - C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O) 2 R 15 , -S(O) 2 N(R 12 )(R 13 ), -S(O)(O)(O
  • R 9 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, Ci- sheteroaryl, -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O) 2 R 15 , and - S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 hcteroary I are optionally substituted with one, two, or three R 20c ; each R 10 is independently selected from halogen,
  • each R 12 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Co.
  • each R 13 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I: or R 12 and R 13 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 20f ;
  • each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I: each R 15 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy.
  • -cycloalkyI C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI.
  • each R 17 and each R 17a are each independently selected from C 1-6 alkyl and Co.ocycloalkyl, wherein C
  • each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 2011 are each independently selected from halogen, oxo, -CN, Ci- ealkyl, Cwalkenyl, Cs-ealkynyl, C 3-10 cycloalkyl, -CHi-Ci-iocycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2 .
  • each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl
  • each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cy cloalky 1, C 2 .
  • heterocycloalkyl C 6-10 aryl, and C 1-9 heteroaryl; each R 23 is independently selected from H and C 1-6 alkyl; each R 24 is independently selected from H and C 1-6 alkyl; each R 25 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI. C 2-9 heterocycloalkyI. C 6-10 ary 1, and C 1- 9 heteroaryl: and p is 0, 1, or 2.
  • R 1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R 10 ;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyI. wherein C 1-6 alkyl, C 2-6 alkeny 1, C 2 - 6alkynyl, and C 3-10 cycloalkyl are optionally substituted with one, two, or three R 20a ;
  • R 4 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 5 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 8 is independently selected from halogen, -CN, C 1-6 alkyl, C 2- , alkenyl. C 2-6 alkynyl, C 3-10 cycloalkyI. C 2 .
  • R 9 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alky ny I. C 3-10 cycloalkyl, C 2-9 heterocycloalkyI. C 6-10 aryl, C 1- 9 heteroaryl, -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O) 2 R 15 , and - S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20c ; each R 10 is independently selected from halogen, -CN,
  • each R 12 is independently selected from hydrogen, C 1-9 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalky I.
  • C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 ictcroary I are optionally substituted with one, two, or three R 20e ;
  • each R 13 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I: or R 12 and R 13 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 20f ;
  • each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I:
  • each R 15 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C-,. -cycloalkyI.
  • each R 17 and each R 17a are each independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, wherein C 1-9 alky 1 and C 3- 6 cycloalkyl are optionally substituted with one, two or three of R 20h ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20 ®, and R 20h are each independently selected from halogen, oxo, -CN, C 1- 6 alkyl, C 2 ., alkenyl.
  • each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl
  • C 2-9 heterocycloalkyl, C 6-10 aryl, and Ci- • hcleroaiy k and p is 0, 1, or 2.
  • R 9 is selected from C 1-6 alkyl, C 3-10 cycloalky 1, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- gheteroaryl, wherein C 1-6 alkyl, Ci.iocycloalkyl. C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20c .
  • R 9 is selected from C 2-9 heterocycloalky 1, C 3-10 aryl, and C 1-9 heteroaryl, wherein C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20c .
  • each R 8 is independently selected from halogen, C 1-6 alkyl, C 3-10 cycloalkyl, Cz- gheterocycloalkyl, C 3-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alky 1, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20b .
  • each R 8 is independently selected from halogen and C 1-6 alkyl optionally substituted with one, two, or three R 20b .
  • each R 8 is independently selected from halogen and unsubstituted C 1-9 alky 1.
  • [0029] is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is selected from C 1-6 alkyl and C 1- 6 haloalkyl.
  • R 5 is selected from C 1-6 alkyl and C 1- 6 haloalkyl.
  • R 5 is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is -CH 3 .
  • [0030] is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is hydrogen.
  • [0031] is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from hydrogen and C 1-6 alkyl optionally substituted with one, two, or three R 20a .
  • R 2 is C 1-6 alkyl optionally substituted with one, two, or three R 20a .
  • R 2 is unsubstituted C 1-6 alkyl.
  • R 2 is a compound of Formula (!’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CH 3 .
  • In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is - hydrogen.
  • [0032] is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is a 6-10 membered aryl ring substituted with one or more R 10 .
  • R 1 is a 6-10 membered aryl ring substituted with one or more R 10 .
  • R 1 is phenyl substituted with one or more R 10 .
  • R 10 is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is phenyl substituted with one, two, or three R 10 .
  • R 1 is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or
  • R 1 is a 5-10 membered heteroaryl ring are substituted with one or more R 10 .
  • R 10 is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is a 5-10 membered heteroaryl ring are substituted with one, two, or three R 10 .
  • each R 10 is independently selected from halogen, C 1-6 alkyl, C 3-7 cycloalkyI. C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , and N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 3-7 cycloalkyI.
  • C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20d .
  • R 10 is independently selected from halogen, C 1-9 alkyl, and N(R 12 )(R 13 ), wherein C 1-6 alkyI is optionally substituted with one, two, or three R 20d .
  • each R 10 is independently selected from halogen, Ci- ealkyl, and N(R 12 )(R 13 ), wherein C 1-6 alky I is substituted with one, two, or three R 20d , and each R 20d is halogen.
  • Also provided in the present disclosure is a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a solid tumor or a hematological cancer.
  • Also provided herein is a method of reducing Ras signaling output comprising contacting a SOS 1 protein with an effective amount of a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, thereby reducing the Ras signaling output.
  • a compound of Formula (I’) comprising contacting a SOS 1 protein with an effective amount of a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, thereby reducing the Ras signaling output.
  • a method of reducing Ras signaling output of a SOS1 protein comprising contacting a S0S1 protein with an effective amount of a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein said reducing the Ras signaling output.
  • a subject compound interferes or disrupts the interaction or binding between a SOS protein (e.g., S0S1) with a Ras protein (e.g., wildtype or a mutant Ras).
  • a method of inhibiting cell growth comprising administering a cell expressing S0S1 with an effective amount of a compound of Formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, thereby inhibiting growth of said cells.
  • the method may further comprise administering to the cell an additional agent.
  • the additional agent can be an inhibitor against one or more targets including but not limited to: The method of claim 60, wherein the additional agent is an inhibitor against one or more targets including but not limited to: MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, FGFR4, mitotic kinase, topoisomerase, ALK, c-MET, ErbB2, AXL, NTRK1, RET, A-Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF1/2, IGF1-R, CDK9, SHC, GAB, GRB, PI3-kinase, MAPK, SHIP1, SHIP2, SHP1, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, wildtype KRas, KRas mutant (e.g., KrasG12C, K, K
  • the additional agent is a chemotherapeutic agent, a radioactive agent, or an immune modulator.
  • Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.
  • Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • C 1 -C x includes C 1 -C 2 , C 1 -C 3 . . . C 1 -C x .
  • C 1 -C x refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).
  • an "alkyl” group refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation.
  • the "alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “ 1 to 6" refers to each integer in the given range; e.g. , "1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group of the compounds described herein may be designated as "C 1 -C 6 alkyI" or similar designations.
  • “C 1 -C 6 alkyl” indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, and hexyl.
  • Alkyl groups can be substituted or unsubstituted.
  • an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).
  • alkoxy refers to a "-O-alkyl” group, where alkyl is as defined herein.
  • alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond.
  • an alkenyl groups may have 2 to 6 carbons.
  • Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).
  • alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond.
  • alkynyl group include -C ⁇ CH, -C ⁇ CCH 3 , -C ⁇ CCH 2 CH 3 and -C ⁇ CCH 2 CH 2 CH 3 .
  • an alkynyl group can have 2 to 6 carbons.
  • Alkynyl groups can be substituted or unsubstituted.
  • an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).
  • Amino refers to a -NH 2 group.
  • “Dialkylamino” refers to a -N(alkyl) 2 group, where alkyl is as defined herein.
  • aromatic refers to a planar ring having a delocalized 71 -electron system containing 4n+2 ⁇ electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted.
  • aromatic includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms.
  • Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e an arylene group).
  • Carboxy refers to -CO 2 H.
  • carboxy moieties may be replaced with a "carboxylic acid bioisostere", which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety.
  • a carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group.
  • a compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound.
  • a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group.
  • bioisosteres of a carboxylic acid include, but are not limited to, OH and the like.
  • cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated or partially unsaturated. In some embodiments, a cycloalkyl ring is fused with an aryl, heteroaryl, heterocycloalkyl, or a second cycloalkyl ring. In some embodiments, a cycloalkyl ring is a spirocyclic cycloalkyl ring. In some embodiments, cycloalkyl groups include groups having from 3 to 10 ring atoms. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (i.e., a cycloalkylene group).
  • heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, or tricyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated.
  • An V- containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
  • a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group).
  • heterocycloalkyl group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. Heterocycloalkyls may be saturated or partially unsaturated. In some embodiments, a heterocycloalkyl ring is fused with an aryl, heteroaryl, cycloalkyl, or a second heterocycloalkyl ring.
  • the term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl ring is a spirocyclic heterocycloalkyl ring. In some embodiments, a heterocycloalkyl ring is a bridged heterocycloalkyl ring. 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). Depending on the structure, a heterocycloalkyl group can be a monoradical or a diradical (i.e., a heterocycloalkylene group).
  • halo or, alternatively, "halogen” means fluoro, chloro, bromo and iodo.
  • haloalky 1 refers to an alkyl group that is substituted with one or more halogens.
  • the halogens may the same or they may be different.
  • Non-limiting examples of haloalkyls include -CH 2 C 1 , -CF 3 , -CHF 2 , - CH 2 CF 3 , -CF 2 CF 3 , and the like.
  • fluoroalkyl and “fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms.
  • fluoroalkyls include -CF 3 , -CHF 2 , -CH 2 F, - CH 2 CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CF(CH 3 ) 3 , and the like.
  • Non-limiting examples of fluoroalkoxy groups include - OCF 3 , -OCHF 2 , -OCH 2 F, -OCH 2 CF 3 , -OCF 2 CF 3 , -OCF 2 CF 2 CF 3 , -OCF(CH 3 ) 2 , and the like.
  • heteroalkyl refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.
  • the heteroatom(s) may be placed at any interior position of the heteroalkyl group.
  • heteroalkyl may have from 1 to 6 carbon atoms.
  • bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • substituent "R" appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalky 1, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.
  • the term "optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, - CN, alkyne, C -Galky lalkyne, halo, acyl, acyloxy, -CO 2 H, -COi-alkyl.
  • nitro, haloalkyl, fluoroalkyl, and amino including mono- and di-substituted amino groups (e.g. -NH 2 , -NHR, -N(R) 2 ), and the protected derivatives thereof.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, tiifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, V, V-dibcnzvlcthylcncdiaminc.
  • polypeptide refers to polymers of amino acids of any length.
  • the polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids.
  • the terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component.
  • amino acid refers to either natural and/or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics.
  • polynucleotide refers to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof.
  • Polynucleotides may have any three dimensional structure, and may perform any function, known or unknown.
  • polynucleotides coding or noncoding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers.
  • loci locus defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polyn
  • a polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acid (PNA), Morpholino and locked nucleic acid (LNA), glycol nucleic acid (GNA), threose nucleic acid (TNA), 2’-fluoro, 2’-OMe, and phosphorothiolated DNA. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.
  • modified nucleotides such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acid (PNA), Morpholino and locked nucleic acid (LNA), glycol nucle
  • expression refers to the process by which a polynucleotide is transcribed from a DNA template (such as into and mRNA or other RNA transcript) and/or the process by which a transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins.
  • Transcripts and encoded polypeptides may be collectively referred to as "gene product.” If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaiyotic cell.
  • subject means a vertebrate, preferably a mammal, more preferably a human.
  • Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.
  • therapeutic agent refers to a molecule or compound that confers some beneficial effect upon administration to a subject.
  • the beneficial effect includes enablement of diagnostic determinations; amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or pathological condition.
  • treatment or “treating,” or “palliating” or “ameliorating” are used interchangeably.
  • compositions may be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject reporting one or more of the physiological symptoms of a disease, even though the disease, condition, or symptom may not have yet been manifested.
  • prophylactic benefit includes reducing the incidence and/or worsening of one or more diseases, conditions, or symptoms under treatment (e.g. as between treated and untreated populations, or between treated and untreated states of a subject).
  • the term "effective amount” or “therapeutically effective amount” refers to the amount of an agent that is sufficient to effect beneficial or desired results.
  • the therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • An effective amount of an active agent may be administered in a single dose or in multiple doses.
  • a component may be described herein as having at least an effective amount, or at least an amount effective, such as that associated with a particular goal or purpose, such as any described herein.
  • the term “effective amount” also applies to a dose that will provide an image for detection by an appropriate imaging method.
  • the specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.
  • an "antigen” is a moiety or molecule that contains an epitope, and, as such, also specifically binds to an antibody.
  • An "antigen binding unit” may be whole or a fragment (or fragments) of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof.
  • a full-length antibody may be, for example, a monoclonal, recombinant, chimeric, deimmunized, humanized and human antibody.
  • Examples of a fragment of a full-length antibody may include, but are not limited to, variable heavy (VH), variable light (VL), a heavy chain found in camelids, such as camels, llamas, and alpacas (VHH or VHH), a heavy chain found in sharks (V-NAR domain), a single domain antibody (sdAb, i.e., "nanobody”) that comprises a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and "r IgG" (or half antibody).
  • VH variable heavy
  • VL variable light
  • VHH or VHH a heavy chain found in camelids
  • VHH or VHH a heavy chain found in sharks
  • V-NAR domain a single domain antibody (sdAb, i.e., "nanobody”) that comprises a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and "r
  • modified fragments of antibodies may include, but are not limited to scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single chain diabodies, tandem diabodies (Tandab's), tandem di-scFv, tandem tri-scFv, minibodies (e.g., (VH-VL-CH 3 )2, (scFv- CH 3 )2, ((scFv)2-CH 3 +CH 3 ), ((scFv)2-CH 3 ) or (scFv-CH 3 -scFv)2), and multibodies (e.g., triabodies or tetrabodies).
  • minibodies e.g., (VH-VL-CH 3 )2, (scFv- CH 3 )2, ((scFv)2-CH 3 +CH 3 ), ((sc
  • antibody encompass any antigen binding units, including without limitation: monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, and any other epitope-binding fragments.
  • in vivo refers to an event that takes place in a subject’s body.
  • ex vivo refers to an event that first takes place outside of the subject’s body for a subsequent in vivo application into a subject’s body.
  • ex vivo preparation may involve preparation of cells outside of a subject’s body for the purpose of introduction of the prepared cells into the same or a different subject’s body.
  • in vitro refers to an event that takes place outside of a subject’s body.
  • an in vitro assay encompasses any assay run outside of a subject’s body.
  • In vitro assays encompass cell-based assays in which cells alive or dead are employed.
  • In vitro assays also encompass a cell-free assay in which no intact cells are employed.
  • Ras refers to a protein in the Rat sarcoma (Ras) superfamily of small GTPases, such as in the Ras subfamily.
  • the Ras superfamily includes, but is not limited to, the Ras subfamily, Rho subfamily, Rab subfamily, Rap subfamily, Arf subfamily, Ran subfamily, Rheb subfamily, RGK subfamily, Rit subfamily, Miro subfamily, and Unclassified subfamily.
  • a Ras protein is selected from the group consisting of KRAS (K-Ras or K-ras or Kras), HRAS (or H-Ras), NRAS (or N-Ras), MRAS (or M-Ras), ERAS (or E-Ras), RRAS2 (or R-Ras2), RALA (or RalA), RALB (or RalB), RIT1, and any combination thereof, such as from KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.
  • KRAS K-Ras or K-ras or Kras
  • HRAS or H-Ras
  • NRAS or N-Ras
  • MRAS or M-Ras
  • ERAS or E-Ras
  • RRAS2 or R-Ras2
  • RALA or RalA
  • RALB or RalB
  • a mutant Ras refers to a Ras protein with one or more amino acid mutations, such as with respect to a common reference sequence such as a wild-type (WT) sequence.
  • a mutant Ras is selected from a mutant KRAS, mutant HRAS, mutant NRAS, mutant MRAS, mutant ERAS, mutant RRAS2, mutant RALA, mutant RALB, mutant RIT1, and any combination thereof, such as from a mutant KRAS, mutant HRAS, mutant NRAS, mutant RALA, mutant RALB, and any combination thereof.
  • a mutation can be an introduced mutation, a naturally occurring mutation, or a non-naturally occurring mutation.
  • a mutation can be a substitution (e.g., a substituted amino acid), insertion (e.g., addition of one or more amino acids), or deletion (e.g., removal of one or more amino acids).
  • two or more mutations can be consecutive, non-consecutive, or a combination thereof.
  • a mutation can be present at any position of Ras.
  • a mutation can be present at position 12, 13, 62, 92, 95, or any combination thereof of Ras relative to SEQ ID No. 1 when optimally aligned.
  • a mutant Ras may comprise about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more than 50 mutations. In some embodiments, a mutant Ras may comprise up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mutations.
  • the mutant Ras is about or up to about 500, 400, 300, 250, 240, 233, 230, 220, 219, 210, 208, 206, 204, 200, 195, 190, 189, 188, 187, 186, 185, 180, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 160, 155, 150, 125, 100, 90, 80, 70, 60, 50, or fewer than 50 amino acids in length.
  • an amino acid of a mutation is a proteinogenic, natural, standard, non-standard, non- canonical, essential, non-essential, or non-natural amino acid.
  • an amino acid of a mutation has a positively charged side chain, a negatively charged side chain, a polar uncharged side chain, a non-polar side chain, a hydrophobic side chain, a hydrophilic side chain, an aliphatic side chain, an aromatic side chain, a cyclic side chain, an acyclic side chain, a basic side chain, or an acidic side chain.
  • a mutation comprises a reactive moiety.
  • a substituted amino acid comprises a reactive moiety.
  • a mutant Ras can be further modified, such as by conjugation with a detectable label.
  • a mutant Ras is a full-length or truncated polypeptide.
  • a mutant Ras can be a truncated polypeptide comprising residues 1-169 or residues 11-183 (e.g., residues 11-183 of a mutant RALA or mutant RALB).
  • the disclosure provides a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof: wherein:
  • R 1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R 10 ;
  • L 1 is a bond or C 1-6 alkyl
  • X and Y are selected from N(R 2 ) and C(O), wherein one of X and Y is N(R 2 ) and one of X and Y is C(O);
  • Z 1 , Z 2 , and Z 3 are each independently selected from N and C(R 3a ), wherein at least one of Z 1 , Z 2 , and Z 3 is N;
  • R 2 is selected from hydrogen, C 1-6 alkyl, alkenyl. C 2-6 alkynyI. C 3 -10 cycloalkyI. and C 2-9 heterocycloalkyl wherein C 1-6 alkyl, C 2-6 alkenyl . C 1-9 alkynyl, C 3-10 cy cloalky 1, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three R 20a ;
  • R 3 is selected from halogen, CN, C 1-6 alkyl, C 2-6 alkeny 1, C 2-6 alkynyI. C 3-14 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), - N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , N(R 14 )S(O)R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), - C(O)C(O)N(R 12 )
  • each R 3a is independently selected from hydrogen, halogen, -CN, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), - N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -S(O)R 15 , -S(O)R 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 ,
  • R 4 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 5 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 10 is independently selected from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C,. -cycloalky I. C 2 .
  • each R 12 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl. C 2-6 alkynyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryI. wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI.
  • C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryI are optionally substituted with one, two, or three R 20e ;
  • each R 13 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I: or R 12 and R 13 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 20f ;
  • each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalky 1;
  • each R 15 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI.
  • C 1-6 alkyl, C 2-6 alkenyl, C C 2-6 alkynyl, C 3-7 cycloalkyI, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 2 ° B ;
  • each R 17 and each R 17a are each independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, wherein Ci-6 alkyl and C 3- 6 cy cloalky 1 are optionally substituted with one, two or three of R 20h ; or R 17 and R 17a form a C 2-9 cy cloalky 1 ring;
  • each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 20h are each independently selected from halogen, oxo
  • C 2-6 alkynyI C 3-10 cycloalkyl, -CH 2 -C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 - C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroary l are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyI. alkoxy. Ci.
  • each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl,
  • each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cy cloalky I.
  • C 2- sheterocycloalkyl, C 6-10 aryl, and CiJielcroary k each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cy cloalky I.
  • heterocycloalkyl C 6-10 aryl, and C 1-9 heteroaryl; each R 23 is independently selected from H and C 1-6 alkyl; each R 24 is independently selected from H and C 1-6 alkyl; and each R 25 is selected from C 1-6 aIky 1, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI. C 1-9 heterocycloalkyl, C 3-10 aryl, and Ci. siheteroaryl.
  • R 1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R 10 ;
  • L 1 is a bond or C 1-6 alkyl
  • X and Y are selected from N(R 2 ) and C(O), wherein one of X and Y is N(R 2 ) and one of X and Y is C(O);
  • Z 1 , Z 2 , and Z 3 are each independently selected from N and C(R 3a ), wherein at least one of Z 1 , Z 2 , and Z 3 is N;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl. C 2-6 alkynyl, and C 3- cycloalkyl -wherein C 1-6 alkyl, CS- .alkeny I. C 2-6 alkynyl, and C 3-10 cy cloalky 1 are optionally substituted with one, two, or three R 20a ;
  • R 3 is selected from halogen, C 1-6 alkyl, CYr, alkenyl. CY-,alky ny I. C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1- 9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), - N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )
  • R 4 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 5 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 10 is independently selected from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C-,. -cycloalkyI. C 2 .
  • C 3-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 2M ; each R 12 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI.
  • each R 13 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalky I: or R 12 and R 13 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 20f ;
  • each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalky 1;
  • each R 15 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C-,.
  • each R 17 and each R 17a are each independently selected from C 1-6 alkyl and C 3-6 cycloalkyI. wherein C 1-6 alky 1 and C-,.
  • cycloalkyl are optionally substituted with one, two or three of R 20h ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 20h are each independently selected from halogen, oxo, -CN, Ci- ralkyl.
  • sheterocycloalkyl C 6-10 aryl, -CH 2 -C 6-10 aryl, C 1-9 heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , - C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , - N(R 24 )C(O)R 25 , -N(R 24 )S(O) 2 R 25 , -C(O)R 25 , -S(O) 2 R 25 , -S(O) 2 N(R 22 )(R 23 ), -OCH 2 C(O)OR 22 , and -OC(
  • each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalky 1, C 2-6 alkenyl
  • [0090] is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is a bond.
  • Formula (lb) is a compound of Formula (I) having the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:
  • R 3 is selected from -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , - C(O)N(R 12 )(R 13 ), -SR 12 , -SOR 12 , -SO 2 (R 12 )(R 13 ), -SO 2 N(R 12 )(R 13 ), -P(O)(R 17 )(R 17a ), C 1-6 alkyl, C 3-10 cycloalkyl, C 2 .
  • R 3 is selected from -C(O)R 15 , -C(O)N(R 12 )(R 13 ), CS. sheterocycloalkyl, C 3-10 aryl, and C 1-9 heteroaryl, wherein C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20b .
  • R 15 is C 1-6 heterocycloalkyl optionally substituted with one, two, or three R 20g .
  • [00100] is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (F), (1), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is spirocyclic C 2- s>heterocycloalkyl optionally substituted with one, two, or three R 20b .
  • R 3 is C 6-10 aryl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1-9 heteroaryl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -C(O)N(R 12 )(R 13 ).
  • In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 15 is C 1-9 heterocycloalkyl optionally substituted with one, two, or three R 20g .
  • R 15 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceuticalty acceptable salt or solvate thereof, wherein R 15 is spirocyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20g .
  • R 15 is fused C 2- shelerocycloalkyI optionally substituted with one, two, or three R 20g .
  • [00102] is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1-6 alkyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -OR 12 .
  • R 3 is a compound of Formula (F), (I), (I- 1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is halogen.
  • [00103] is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is cyclopropyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is cyclobutyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is cyclohexyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is azetidinyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is piperidinyl optionally substituted with one, two, or three R 20b .
  • R 3 is piperizinyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is morpholinyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is tetrahydrofuranyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is pyridinyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is pyrimidinyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is phenyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is pyrrolyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is thianyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is thiazolyl optionally substituted with one, two, or three R 20b .
  • R 3 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is azepanyl optionally substituted with one, two, or three R 20b .
  • R 3 is 1,4-dioxapanyl optionally substituted with one, two, or three R 20b .
  • R 3 is 1,4-oxazepanyl optionally substituted with one, two, or three R 20b .
  • R 3 is 2,6-diazaspiro[3.3]heptanyl optionally substituted with one, two, or three R 20b .
  • R 3 is 2-oxa-6- azaspiro[3.3]heptanyl optionally substituted with one, two, or three R 20b .
  • R 3 is G.i icycloalkyI. including C 6-14 cycloalkyI. C 6-9 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyk and C 3-4 cycloalkyl, each of which being optionally substituted with one, two, or three R 20b .
  • R 3 is G, - icycloalkyI optionally substituted with one, two, or three R 20b .
  • R 3 is G.ecycloalkyl optionally substituted with one, two, or three R 20b .
  • R 3 is G. cycloalkyl optionally substituted with one, two, or three R 20b .
  • R 3 is G.ecycloalkyl optionally substituted with one, two, or three R 20b .
  • R 3 is C 3-5 cycloalkyI optionally substituted with one, two, or three R 20b .
  • R 3 is C 3-4 cycloalkyl optionally substituted with one, two, or three R 20b .
  • R 3 is C 3-14 cycloalky k including C 6-14 cycloalkyl C 6-9 cycloalky k C 3-7 cycloalkyl, G.ecycloalkyI. C 3-5 cycloalkyk and C 3-4 cycloalkyI. each of which being substituted with one, two, or three R 20b .
  • R 3 is C 6-14 cycloalkyI substituted with one, two, or three R 20b .
  • R 3 is C 6-9 cycloalkyl substituted with one, two, or three R 20b .
  • R 3 is C .K'ycloalkyl substituted with one, two, or three R 20b .
  • R 3 is C 3- 6 , cycloalkyl substituted with one, two, or three R 20b .
  • R 3 is C 3-5 cycloalkyl substituted with one, two, or three R 20b .
  • R 3 is C 3-4 cycloalkyl substituted with one, two, or three R 20b .
  • R 3 is C1-1 icycloalkyI. including C,-i icycloalkyI. Ce-gcycloalky 1, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl, and C 3-4 cycloalkyl, each of which being optionally substituted with one R 20b .
  • R 3 is C 6-14 cycloaIkyI optionally substituted with one R 20b .
  • R 3 is C 6-9 cycloalkyl optionally substituted with one R 20b .
  • R 3 is C 3-7 cycloalky I optionally substituted with one R 20b .
  • R 3 is C 3- 6 cycloalkyl optionally substituted with one R 20b .
  • R 3 is C 3-5 cycloalkyl optionally substituted with one R 20b .
  • R 3 is C i. icycloalkyI optionally substituted with one R 20b .
  • R 3 is C 3-14 cycloalkyI. including C 6-14 cycloalkyI. C 6-9 cycloalkyI. C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl, and C 3-4 cycloalkyl, each of which being optionally substituted with two R 20b .
  • R 3 is C 6-14 cycloalkyI optionally substituted with two R 20b .
  • R 3 is C 6-9 cycloalkyl optionally substituted with two R 20b .
  • R 3 is C 3-7 cycloalkyl optionally substituted with two R 20b .
  • R 3 is C 3- 6 , cycloalkyl optionally substituted with one R 20b .
  • R 3 is C 3-5 cycloalkyl optionally substituted with two R 20b .
  • R 3 is C 3-4 cycloalkyl optionally substituted with two R 20b .
  • R 20b is independently selected from amino, -CN, C 1-9 alkyl, C1.3 alkoxy, C 1-9 haloalkyl, -OH, -N(R 24 )C(O)R 25 , and -C(O)N(R 22 )(R 23 ).
  • R 20b is amino.
  • R 20b is -CN.
  • R 20b is Ci-aalkyl.
  • R 20b is Ci.ialkoxy .
  • R 20b is C 1 haloa Iky 1
  • R 20b is —OH.
  • R 20b is -N(R 24 )C(O)R 25 .
  • R 20b is -C(O)N(R 22 )(R 23 ).
  • R 20b is - NHC(O)R 25 .
  • R 20b is -C(O)NH(R 22 ).
  • R 20b is -NHC(O)R 25 and R 25 is C). ⁇ ;hetcrocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C 1-9 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 cycloalkyI. C 2-9 heterocycloalkyl. C 6-10 aryl, and C 1- 9 heteroaryl.
  • R 20b is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 20b is -NHC(O)R 25 and R 25 is C 2-5 heterocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 20b is -C(O)NH(R 22 ) and R 22 is C 2-5 heterocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 3 is C 6-14 cycloalkyI (including C 6-14 cycloalkyI. C 6-9 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyI. and C 3-4 cycloalkyl), optionally substituted with one, two, or three R 20b that is amino.
  • R 3 is C 6-14 cycloalkyI (including C 6-14 cycloalkyl, C 6-9 cycloalkyl, C 3-7 cycloalkyl. C 3-6 cycloalkyl, C 3-5 cycloalkyI, and C 3-4 cycloalkyl). optionally substituted with one, two, or three R 20b that is -CN.
  • R 3 is C 6-14 cycloalkyI (including G.i icycloalkyI. C 6-9 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl. C 3-5 cycloalkyl, and C 3-4 cycloalkyl), optionally substituted with one, two, or three R 20b that is C 1-9 alkyl.
  • R 3 is C 6-14 cycloalkyI (including C 6-14 cycloalkyI. C 6-9 cycloalkyl. C 3-4 cycloalkyl, C 3-6 cycloalkyl. C 3-5 cycloalkyl, and C 3-4 cycloalkyl). optionally substituted with one, two, or three R 20b that is C 1-3 alkoxy.
  • R 3 is C 6-14 cycloalkyI (including C 6-14 icycloalkyl, C 6-9 cycloalkyl. C 3-7 cycloalkyl. C 3-6 cycloalkyl. C 3-5 cycloalkyI, and C 3-4 cycloalkyl). optionally substituted with one, two, or three R 20b that is C -.haloalky I.
  • R 3 is C 6-14 cycloalkyI (including C 6-14 cycloalkyI. C 6-9 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl, and C 3-4 cycloalkyl), optionally substituted with one, two, or three R 20b that is -OH.
  • R 3 is C 6-14 cycloalkyI (including C 6-14 cycloalkyI. C 6-9 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyI, and C 3-4 cycloalkyl), optionally substituted with one, two, or three R 20b that is oxo.
  • R 3 is C 6-14 cycloalkyI (including C 6-14 cycloalkyI. C 6-9 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyI. and C 3-4 cycloalkyl), optionally substituted with one, two, or three R 20b that is -N(R 24 )C(O)R 25 .
  • R 3 is C 6-14 cycloalkyI (including C 6-14 cycloalkyI, G. scycloalkyl, C 3-7 cycloalkyl, C 3-5 cycloalkyI. C 3-5 cycloalkyI, and C 3-4 cycloalkyl). optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 .
  • R 3 is C 6-14 cycloalkyI (including C 6-14 cycloalkyI, C 6- 9 icycloalkyI. C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyI. and C 3-4 cycloalkyl).
  • R 20b that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalky I. C 1-6 alkoxy, G. -cycloalkyI. C 2- sheterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • R 3 is C 6-14 cycloalkyI (including C 6- 14 cycloalkyl, C 6-9 cycloalkyl. C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyI. and C 3-4 cycloalkyl). optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 2-5 heterocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 3 is C 6-14 cycloalkyI (including C 6-14 cycloalkyI. C 6-9 cycloalkyl, Cs-7cycloalkyl, Cs-gcycloalkyl, C 3-5 cycloalkyI. and C 3-4 cycloalkyl), optionally substituted with one, two, or three R 20b that is -C(O)N(R 22 )(R 23 ).
  • R 3 is C 6-1 4 cycloalkyI (including G.1 icycloalkyI.
  • R 3 is G,.i icycloalkyI (including C 6-14 cycloalkyl. C 6-9 cycloalkyl, G.-cycloalkyI.
  • R 3 is C 6-14 cycloalkyI (including C 6-14 cycloalkyI.
  • C 3-6 cycloalkyl, C 3-5 cycloalkyI. and C 3-4 cycloalkyl) optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 2-5 heterocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 3 is GGieterocycloalkyl. including C 6-9 heterocycloalkyI, C 3- 7 heterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, C 3-4 heterocycloalkyl, each of which being optionally substituted with one, two, or three R 20b .
  • R 3 is Cg. gheterocycloalkyl optionally substituted with one, two, or three R 20b .
  • R 3 is C 3- -heterocycloalkyI optionally substituted with one, two, or three R 20b .
  • R 3 is C 3- gheterocycloalkyl optionally substituted with one, two, or three R 20b .
  • R 3 is Cs- e heterocycloalkyl optionally substituted with one, two, or three R 20b .
  • R 3 is C 3- 5 heterocycloalkyl optionally substituted with one, two, or three R 20b .
  • R 3 is C3. iheterocycloalkyl optionally substituted with one, two, or three R 20b .
  • each of the R 3 described above including C 6-9 heterocycloalkyl, C 3-7 heterocycloalkyk C 3- 6 heterocycloalkyI.
  • C 3-4 heterocycloalkyl is optionally substitued with one R 20b .
  • C 3- gheterocycloalkyl, C 5-6 heterocycloalkyl , C 3-5 heterocycloalkyl, C 3-4 heterocycloalkyl is optionally substituted with two R 20b
  • C 5-6 heterocycloalkyl , C 3-5 heterocycloalkyl, C 3-4 heterocycloalkyl. is optionally substituted with three R 20b .
  • R 20b is independently selected from amino, -CN, C 1-9 alkyl, C 1-3 alkoxy, C 1- 3 haloalky I. -OH, -N(R 24 )C(O)R 25 , and -C(O)N(R 22 )(R 23 ).
  • R 20b is amino.
  • R 20b is -CN. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R 20b is Ci-aalkyl.
  • R 20b is C 1-3 alkoxy .
  • R 20b is C 1-9 haloalkyl.
  • R 20b is —OH. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R 20b is -N(R 24 )C(O)R 25 .
  • R 20b is -C(O)N(R 22 )(R 23 ). In some embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R 20b is - NHC(O)R 25 .
  • R 20b is -C(O)NH(R 22 ).
  • R 20b is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 reycloalky I.
  • R 20b is -C(O)NH(R 22 ) and R 22 is Cj-sheterocycloalky 1 optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 20b is -NHC(O)R 25 and R 25 is Ci.shctcrocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 20b is -C(O)NH(R 22 ) and R 22 is C 2-5 heterocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 3 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyI. C3. iheterocycloalkyl. C 3-6 heterocycloalkyI. C 5-6 heterocycloalkyI, C 3-5 heterocycloalkyI and C 3-4 heterocycloalkyI , optionally substituted with one, two, or three R 20b that is amino.
  • R 3 is C 2- shcterocycloalkyI (including C 6-9 heterocycloalkyl, C 3-7 hctcrocycloalkyI.
  • heterocycloalkyl) optionally substituted with one, two, or three R 20b that is -CN.
  • R 3 is CGhctcrocycloalkyI (including C 6-9 heterocycloalkyl, G. iheterocycloalkyl. C’-ehetcrocycloalkyl, C 5-6 heterocycloalkyl, C, -iheterocycloalkyl. and G. iheterocycloalkyl). optionally substituted with one, two, orthree R 20b that is Cijalkyl.
  • R 3 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, G. iheterocycloalkyl. G- ⁇ hcterocycloalkyI. C 5-6 heterocycloalkyl, G.sheterocycloalky I. and C 3- ihctcrocycloalkyl), optionally substituted with one, two, or three R 20b that is Cwalkoxy .
  • R 3 is C 2-9 helerocycloalkyI (including C 6-9 heterocycloalkyl, G ⁇ heterocycloalkyl, G.dtclerocycloalky I . C5. eheterocycloalkyl, G.-JictcrocycloalkyI. and G. iheterocycloalkyl). optionally substituted with one, two, or three R 20b that is C -’.haloalky I.
  • R 3 is C 2- sheterocycloalkyl (including C 6-9 heterocycloalkyl, C 3- 7heterocycloalkyl, C’,. iheterocycloalkyl. Cj-eheterocycloalkyl, G.sheicrocycloalkyk and C.. iheterocycloalkyl). optionally substituted with one, two, or three R 20b that is -OH.
  • R 3 is C 2- sheterocycloalkyl (including C 6-9 heterocycloalkyl, G.-hctcrocycloalkyI. C 3- 6 heterocycloalkyl, Cs.,, heterocycloalky I. G.sheterocycloalkyI. and G. iheterocycloalkyl). optionally substituted with one, two, orthree R 20b that is oxo.
  • R 3 is C 2- sheterocycloalkyl (including C 6-9 heterocycloalkyl, C 3- 7heterocycloalkyl, G-eheterocycloalkyl, C 5-6 heterocycloalkyl, G.-hctcrocycloalkyI. and G. ihctcrocvcloalkyl). optionally substituted with one, two, orthree R 20b that is -N(R 24 )C(O)R 25 .
  • R 3 is C 2- sheterocycloalkyl (including C 6-9 heterocycloalkyl, G. iheterocycloalkyl. C 3-6 heterocycloalkyl, G-e heterocycloalkyl, C 3- sheterocycloalkyI. and Ci- iheterocycloalkyl). optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 .
  • R 3 is C 2- sheterocycloalkyl (including C 6-9 heterocycloalkyl, C 3- 7heterocycloalkyl, C-,. iheterocycloalkyl.
  • ihetcrocycloalkyl optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, Ci-dialoalky I. C' R, alkoxy . Ci-cycloalky I. C 2- Uictcrocycloalkyl. C 3-10 aryl, and C 1-9 heteroaryl.
  • R 3 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3-7 hctcrocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalky 1, and C 3- ihctcrocycloalkyl), optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 2- sheterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 3 is C 2- oheterocycloalkyl (including C f ,. ⁇ ;heterocycloalkyI. C,.-hctcrocycloalkyI. C 3- 6 heterocycloalkyl, C5-6 heterocycloalky 1, Ci.sheterocycloalkyI. and C’,.
  • R 3 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3- dielcrocycloalkyI. C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and Ci-ihelcrocycloalky 1), optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ).
  • R 3 is C 2- sheterocycloalkyl (including C 6-9 heterocycloalkyl, C 3-7 hctcrocycloalkyI.
  • R 3 is C 2-9 heterocycloalkyl (including Ce- sheterocycloalkyl, C 3- 7heterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalky 1, and C 3- ⁇ iheterocycloalkyl), optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 2- sheterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 3 is thianyl substituted with one, two, or three R 20b .
  • R 3 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide substituted with one, two, or three R 20b .
  • R 3 is monovalent 4 ⁇ 2 -thiomorpholine substituted with two R 20b .
  • R 3 is tetrahydro-2H-thiopyranyl 1,1-dioxide.
  • R 3 is 4 ⁇ 2 -thiomorpholinyl substituted with two R 20b .
  • R 3 is piperidinyl substituted with one R 20b .
  • R 3 is piperazinyl substituted with one R 20b .
  • R 3 is pyrrolidinyl substituted with one R 20b .
  • R 3 is C 2-9 heterocycloalkyl substituted with one methyl.
  • R 3 is C 6-9 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 3 is C 3-7 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 3 is C 3-6 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 3 is C 5-6 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 3 is C 5-6 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 3 is C 3-4 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 3 is C 3-7 heterocycloalkyI substituted with one methyl, one ethyl, or one propyl.
  • R 3 is C
  • R 3 is C 1-9 hcicrocycloalkyI substituted with one methyl, one ethyl, or one propyl.
  • R 3 is C 5 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 3 is CihctcrocycloalkyI substituted with one methyl, one ethyl, or one propyl.
  • R 3 is C 6-9 heterocycloalkyI substituted with one propyl.
  • R 3 is C 3-7 heicrocycloalkyI substituted with one propyl.
  • R 3 is C ..,, heterocycloalkyI substituted with one propyl.
  • R 3 is C 5- 6 heterocycloalkyl substituted with one propyl.
  • R 3 is C 5-6 heterocycloalkyl substituted with one propyl.
  • R 3 is Ch.iheterocycloalkyl substituted with one propyl.
  • R 3 is C 4-5 heterocycloalkyI substituted with one propyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R 3 is C 5 heterocycloalkyl substituted with one propyl.
  • R 3 is C 4 heterocycloalkyl substituted with one propyl.
  • R 3 is C 2-9 heterocycloalkyl substituted with one isopropyl.
  • R 3 is C 3-7 hcicrocycloalkyl substituted with one isopropyl.
  • R 3 is C4-7heterocycloalkyl substituted with one isopropyl.
  • R 3 is C4- sheterocycloalkyl substituted with one isopropyl.
  • R 3 is Cshcicrocycloalkyl substituted with one isopropyl.
  • R 3 is C4heterocycloalkyl substituted with one isopropyl.
  • R 3 is C 2-9 heterocycloalkyI substituted with two oxo.
  • R 3 is C 2-7 heterocycloalkyI substituted with two oxo.
  • R 3 is C ⁇ heterocycloalkyl substituted with two oxo.
  • R 3 is C 6-
  • R 3 is Ch.-helerocycloalkyl substituted with two oxo.
  • R 3 is C 1-6 heterocycloalkyl substituted with two oxo.
  • R 3 is C 5-6 heterocycloalkyI substituted with two oxo. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R 3 is C 5-6 heterocycloalkyI substituted with two oxo.
  • R 3 is C 3- ihctcrocycloalkyl substituted with two oxo.
  • R 3 is C 1-9 heterocycloalkyI substituted with two oxo.
  • R 3 is Csheterocycloalkyl substituted with two oxo.
  • R 3 is C 4 heterocycloalkyl substituted with two oxo.
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is amino.
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is -CN.
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is C 1-3 alkoxy.
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is C 1-9 alkoxy.
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is C .’, haloalky I.
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is -OH.
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is oxo.
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is -N(R 24 )C(O)R 25 .
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 .
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1- 6 haloalky I. C 1-6 alkoxy, C 3-7 cycloalkyl. C 2-9 heterocycloalkyI. C 6- 10 aryl, and C 1-9 heteroaryl.
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 2- sheterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is -C(O)N(R 22 )(R 23 ).
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is - C(O)NH(R 22 ).
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 2-5 heterocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 3 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R 20b that is amino.
  • R 3 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R 20b that is -CN.
  • R 3 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, orthree R 20b that is Ci-jalkyl.
  • R 3 is monovalent tetrahydro-2H- thiopyran 1, 1-dioxide, optionally substituted with one, two, orthree R 20b that is C 1-3 alkoxy.
  • R 3 is thianyl, optionally substituted with one, two, or three R 20b that is C 1-3 haloalky 1.
  • R 3 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R 20b that is -OH.
  • R 3 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R 20b that is oxo.
  • R 3 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20b that is -N(R 24 )C(O)R 25 .
  • R 3 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 .
  • R 3 is monovalent tetrahydro-2H- thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 2- 9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, Cb.ehctcrocycloalkyl.
  • R 3 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 2-5 heterocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 3 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20b that is -C(O)N(R 22 )(R 23 ).
  • R 3 is monovalent tetrahydro-2H- thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ).
  • R 3 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 3 is monovalent tetrahydro-2H- thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is Ck- shctcrocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 3 is 4 ⁇ 2 -thiomorphol i ny 1, optionally substituted with one, two, or three R 20b that is amino.
  • R 3 is 4 ⁇ 2 -thiomorpholiny 1, optionally substituted with one, two, or three R 20b that is -CN.
  • R 3 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20b that is C 1-9 alkyl.
  • R 3 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20b that is Ci-’.alkoxy.
  • R 3 is 4 ⁇ . 2 - thiomorpholinyl, optionally substituted with one, two, or three R 20b that is C 1-3 haloalkyl.
  • R 3 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20b that is -OH.
  • R 3 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20b that is oxo.
  • R 3 is 4 ⁇ 2 -thiomorpholi ny 1, optionally substituted with one, two, or three R 20b that is -N(R 24 )C(O)R 25 .
  • R 3 is 4 ⁇ 2 -thiomorpholiny 1, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 .
  • R 3 is 4 V-thiomorpholinyl, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-9 haloalky 1, C 1-9 alkoxy, C 3-7 cycloalkyI. C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • R 3 is 4 ⁇ 2 -thiomorpholiny 1, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 2- 5heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 3 is 4 ⁇ 2 -thiomoipholiny 1, optionally substituted with one, two, or three R 20b that is -C(O)N(R 22 )(R 23 ).
  • R 20b is 4 ⁇ 2 -thiomoipholiny 1, optionally substituted with one, two, or three R 20b that is -C(O)N(R 22 )(R 23 ).
  • R 3 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ).
  • R 3 is 4 ⁇ 2 - thiomorpholinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 2- sheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and Ci- ,,alkyl.
  • R 3 is 4 ⁇ 2 -thiomorpholiny 1, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 2- 5heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is amino.
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is -CN.
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is Ci-jalkyl.
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is C1.3 alkoxy.
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is C . ,haloalkyl.
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is -OH.
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is oxo.
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is -N(R 24 )C(O)R 25 .
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is -N(R 24 )C(O)R 25 .
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 .
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 1-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-9 haloalkyl, C 1-9 alkoxy, C 3-7 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 2-5 heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is -C(O)N(R 22 )(R 23 ).
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ).
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ).
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 1-6 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 3 is piperidinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 2-5 heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is amino.
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is -CN.
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is Ci-jalkyl.
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is Ci-3 alkoxy.
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is C 1-9 haloalkyl.
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is -OH.
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is oxo. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is -N(R 24 )C(O)R 25 . In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 .
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 1-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 2- 5heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is -C(O)N(R 22 )(R 23 ).
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ).
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ).
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ).
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 1-6 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 3 is piperazinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 2-5 heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is amino.
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is -CN.
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is C 1-9 alkyl.
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is Ci-3 alkoxy.
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is C 1-3 haloalkyl.
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is -OH.
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is -OH.
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is oxo.
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is -N(R 24 )C(O)R 25 .
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is -N(R 24 )C(O)R 25 .
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is -N(R 24 )C(O)R 25 .
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 .
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalky 1, C 1-6 alkoxy, C 3-7 cycloalky I.
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is -NHC(O)R 25 and R 25 is C 2-5 heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is -C(O)N(R 22 )(R 23 ).
  • R 20b is -C(O)N(R 22 )(R 23 ).
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ).
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 1-6 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 3 is pyrrolidinyl, optionally substituted with one, two, or three R 20b that is -C(O)NH(R 22 ) and R 22 is C 2-5 heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • [00126] is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is [00127] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
  • [00128] is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
  • [00130] is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
  • [00131] is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is [00132] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
  • [00133] is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
  • [00134] is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
  • [00135] is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is [00136]
  • R 3 is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
  • [00138] is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
  • [00139] is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
  • [00140] is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is
  • R 3 is some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (II), or a pharmaceutically acceptable salt or solvate thereof, some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof,
  • R 3a is selected from hydrogen, C 1-6 alkyl, C 3- 10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-10 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl are optionally substituted with one, two, or three R 20c .
  • R 3a is selected from hydrogen and C 1-6 alkyl optionally substituted with one, two, or three R 20c .
  • R 3a is C 1-6 alkyl optionally substituted with one, two, or three R 20c .
  • R 1 is a 6-10 membered aryl ring optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three R 20b
  • each R 3a is hydrogen
  • R 4 is hydrogen
  • R 5 is C 1-6 alkyl.
  • R 1 is phenyl optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three R 20b
  • each R 3a is hydrogen
  • R 4 is hydrogen
  • R 5 is C 1-6 alkyl.
  • R 1 is phenyl optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is C 2-9 heterocycloalkyI selected from piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, wherein piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl are optionally substituted with one, two, or three R 20b , each R 3a is hydrogen, R 4 is hydrogen, and R 5 is C 1-6 alkyl.
  • R 1 is phenyl optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is C 2-9 heterocycloalkyI selected from piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, wherein piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl are optionally substituted with one, two, or three R 20b , each R 3a is hydrogen, R 4 is hydrogen, R 5 is C 1-6 alkyl, and each R 10 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalky 1.
  • R 1 is phenyl optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is C 2-9 heterocycloalkyl selected from piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, wherein piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl are optionally substituted with one, two, or three R 20b , each R 3a is hydrogen, R 4 is hydrogen, R 5 is C 1-6 alkyl, each R 10 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl, and each R 20b is independently
  • R 1 is phenyl optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is C 2-9 heterocycloalkyI selected from piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, wherein piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl are unsubstituted, each R 3a is hydrogen, R 4 is hydrogen, R 5 is C 1-6 alkyl, and each R 10 is independently selected from halogen, C 1-9 alkyl, and Ci-6 haloalky 1.
  • R 1 is a 6-10 membered aryl ring optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is - N(R 12 )(R 13 ) or -C(O)N(R 12 )(R 13 )
  • R 4 is hydrogen
  • R 5 is C 1-6 alkyl.
  • R 1 is phenyl optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is -N(R 12 )(R 13 ) or -C(O)N(R 12 )(R 13 )
  • each R 3a is hydrogen
  • R 4 is hydrogen
  • R 5 is C 1-6 alkyl.
  • R 1 is phenyl optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is -N(R 12 )(R 13 )
  • each R 3a is hydrogen
  • R 4 is hydrogen
  • R 5 is C 1-6 alkyl
  • R 12 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20e
  • R 13 is hydrogen.
  • R 1 is phenyl optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is -N(R 12 )(R 13 )
  • each R 3a is hydrogen
  • R 4 is hydrogen
  • R 5 is C 1-6 alkyl
  • each R 10 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalky I.
  • R 12 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three R 20e
  • R 13 is hydrogen.
  • R 1 is phenyl optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is -N(R 12 )(R 13 )
  • each R 3a is hydrogen
  • R 4 is hydrogen
  • R 5 is C 1-6 alkyl
  • each R 10 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 12 is unsubstituted C 2-9 heterocycloalkyl
  • R 13 is hydrogen.
  • R 1 is phenyl optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is -C(O)N(R 12 )(R 13 )
  • each R 3a is hydrogen
  • R 4 is hydrogen
  • R 5 is C 1-6 alkyl
  • R 12 and R 13 together with the nitrogen to which they are attached, form a C 1-6 heterocycloalkyl ring optionally substituted with one, two, or three R 20f .
  • R 1 is phenyl optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is -C(O)N(R 12 )(R 13 )
  • each R 3a is hydrogen
  • R 4 is hydrogen
  • R 5 is C 1-6 alkyl
  • each R 10 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 12 and R 13 together with the nitrogen to which they are attached, form a Ci-'JielerocycloalkyI ring optionally substituted with one, two, or three R 20f .
  • R 1 is phenyl optionally substituted with one or more R 10
  • R 2 is C 1-6 alkyl
  • R 3 is -C(O)N(R 12 )(R 13 )
  • each R 3a is hydrogen
  • R 4 is hydrogen
  • R 5 is C 1-6 alkyl
  • each R 10 is independently selected from halogen, C 1-6 alkyl, and Ci., haloalky I. and R 12 and R 13 , together with the nitrogen to which they are attached, form an unsubstituted C 1-9 heterocycloalkyl ring.
  • the disclosure provides a compound of Formula (II’), or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R 10 ;
  • R 2 is selected from hydrogen, C 1-6 alkyl, Ch-.alkeny I. C 2-6 alkynyl, and C 3-10 cycloalkyl wherein C 1-6 alkyl, C 1-9 alkenyl, C 2-6 alkynyl, and C 3-10 cycloalkyl are optionally substituted with one, two, or three R 20a ;
  • R 4 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 5 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 6 is independently selected from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl. C 2-6 alkynyl.
  • R 7 is selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, Ci- sheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), - N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(
  • each R 10 is independently selected from halogen, -CN, C 1-6 alkyl, alkynyl, C 3-7 cycloalkyl, C 2 . sheterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryI.
  • each R 12 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl. C 2-6 alkynyl, C-,. -cycloalky 1, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryI.
  • each R 17 and each R 17a are each independently selected from C 1-6 alkyl and C 3-6 cycloalkyI. wherein C 1-6 alkyl and C;.
  • ecy cloalky 1 are optionally substituted with one, two or three of R 20h ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 20h are each independently selected from halogen, oxo, -CN, Ci. ealkyl, C 2 ., alkenyl. C 2.( ,alkynyl. C 3-10 cycloalkyl, -CH 2 - C 3-10 cycloalkyl, C 2-9 heterocycloalkyl. -CH 2 -C 2 .
  • each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalky 1,
  • each R 22 is independently selected from H, C 1-6 alkyl, C . ehaloalky 1, CL.,, alkenyl. C 2-6 alkynyl, CL.-cy cloalky I. C 2 .
  • each R 23 is independently selected from H and C 1-6 alky I: each R 24 is independently selected from H and C 1-6 alkyl; each R 25 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CL.ecycloalkyI. C 2-9 heterocycloalkyl, C 6-10 aryl, and Ci-
  • R 1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R 10 ;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 2- 6 alkenyl. CL-ealky ny 1, and CL. i >cycloalkyl wherein C 1-6 alky 1, CL-, alkenyl. CL. f ,alky ny 1, and C 3-10 cy cloalky 1 are optionally substituted with one, two, or three R 20a ;
  • R 4 is selected from hydrogen, C 1-6 alky I. and C 1-6 haloalkyl
  • R 5 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 6 is independently selected from halogen, -CN, C 1-6 alkyl, C 2- 6 alkenyl.
  • R 7 is selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, CL.ghcicrocycloalkyI.
  • -cycloalky I. C 2 . gheterocycloalkyl, C 6-10 aryl, Ci-9heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), - N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , - C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O) 2 R 15 , -S(O) 2 N(R 12 )
  • each R 12 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C-,. -cycloalky I. C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryI. wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl. C 3-7 cycloalky I.
  • C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryI are optionally substituted with one, two, or three R 20e ;
  • each R 13 is independently selected from hydrogen, C 1-6 alkyl, and C . f , haloalky I: or R 12 and R 13 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 20f ;
  • each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C .
  • each R 15 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyI.
  • C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 hcteroary k wherein C 1-6 alkyl, Ch-,, alkenyl. C 2-6 alkynyl, C . -cycloalkyI. C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 hcteroary I are optionally substituted with one, two, or three R 2 ° B ; each R 17 and each R 17a are each independently selected from C 1-6 alkyl and Cw, cycloalkyI. wherein C . fl a 1 ky 1 and C-,.
  • ecy cloalky 1 are optionally substituted with one, two or three of R 20h ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 20h are each independently selected from halogen, oxo, -CN, Ci. ealkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl -CH 2 -C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2 .
  • sheterocycloalkyl C 6-10 aryl, -CH 2 -C 6 -ioaryl, C 1-9 heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , - C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , - N(R 24 )C(O)R 25 , -N(R 24 )S(O) 2 R 25 , -C(O)R 25 , -S(O) 2 R 25 , -S(O) 2 N(R 22 )(R 23 ), -OCH 2 C(O)OR 22 , and -
  • each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cy cloalky I.
  • each R 23 is independently selected from H and C 1-6 alkyl
  • each R 24 is independently selected from H and C 1-6 alkyl
  • each R 25 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C’..-cycloalkyI.
  • p is 0, 1, or 2.
  • R 6 is selected from hydrogen, halogen, C 1-9 alkyl, C 3-10 cycloalkyl, C 1-9 heterocycloalky 1, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl.
  • C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20b .
  • R 6 is selected from hydrogen, halogen, and C 1-6 alkyl optionally substituted with one, two, or three R 20b .
  • R 6 is selected from hydrogen, halogen, and unsubstituted C 1-6 alkyl.
  • R 7 is selected from halogen, -OR 12 , -N(R 12 )(R 13 ), -SR 12 , -SOR 12 , -SO 2 (R 12 )(R 13 ), - SO 2 N(R 12 )(R 13 ), -P(O)(R 17 )(R 17a ), C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 iheterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20c .
  • R 7 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl.
  • Cc-ioaryl, and Ci- sheteroaryl wherein C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20c .
  • R 7 is selected from -C(O)R 15 , -C(O)N(R 12 )(R 13 ), C 2- sheterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryI are optionally substituted with one, two, or three R 20c .
  • R 7 is selected from -C(O)R 15
  • R 15 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20g .
  • a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof wherein R 7 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20c .
  • a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof wherein R 7 is spirocyclic C2. ⁇ >heterocycloalkyl optionally substituted with one, two, or three R 20c .
  • a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof wherein R 15 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20g .
  • a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof wherein R 15 is spirocyclic C 1-6 heterocycloalkyl optionally substituted with one, two, or three R 20g .
  • R 15 is fused C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20g .
  • R 7 is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is -OR 12 .
  • R 7 is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is -N(R 12 )(R 13 ).
  • R 7 is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is halogen.
  • a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof wherein R 7 is cyclopropyl optionally substituted with one, two, or three R 20c .
  • a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof wherein R 7 is cyclobutyl optionally substituted with one, two, or three R 20c .
  • a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof wherein R 7 is 1,4-dioxapanyl optionally substituted with one, two, or three R 20c .
  • a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof wherein R 7 is 1,4-oxazepanyl optionally substituted with one, two, or three R 20c .
  • a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof wherein R 7 is 2,6- diazaspiro[3.3]heptanyl optionally substituted with one, two, or three R 20c .
  • a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof wherein R 7 is 2-oxa-6- azaspiro[3.3]heptanyl optionally substituted with one, two, or three R 20c .
  • R 7 is C3.1 icvcloalkvl. including G5-1 icvcloalkvl. G,- ⁇ iCycioalky 1, Cg-jcycloalkyl, C 3-6 cycloalkyl, C 3- scycloalkyl, and G. icvcloalkvl. each of which being optionally substituted with one, two, or three R 20c .
  • R 7 is G,.1 icvcloalkvl optionally substituted with one, two, or three R 20c .
  • R 7 is GvicycloalkyI optionally substituted with one, two, or three R 20c .
  • R 7 is G,.
  • R 7 is C 1-6 cycloalkyI optionally substituted with one, two, or three R 20c .
  • R 7 is G. scycloalkyl optionally substituted with one, two, or three R 20c .
  • R 7 is C 3-4 cycloalkyl optionally substituted with one, two, or three R 20c .
  • R 7 is Ci-ucy cloalky 1, including Ce-ucycloalkyl, Ce-icycloalkyl, G.-cycloalkyI. G.rcycloalky 1, C3. scycloalkyI. and G.icycloalkyl. each of which being substituted with one, two, or three R 20c .
  • R 7 is G>.
  • R 7 is C 6-9 cycloalkyl substituted with one, two, or three R 20c .
  • R 7 is G.-cycloalkyI substituted with one, two, or three R 20c .
  • R 7 is C3.6 cycloalkyl substituted with one, two, or three R 20c .
  • R 7 is C 3-5 cycloalkyI substituted with one, two, or three R 20c .
  • R 7 is C 3-4 cycloalkyl substituted with one, two, or three R 20c .
  • R 7 is C3.1 icycloalkyl, including C 6-14 cycloalkyI. G,. ⁇ cycloalkyI. G.-cycloalkyI. G.rcycloalky I. C 3- scycloalkyl, and C 3-4 cycloalkyl. each of which being optionally substituted with one R 20c .
  • R 7 is Cs-
  • R 7 is G.-cycloalkyI optionally substituted with one R 20c .
  • R 7 is G. -cycloalkyI optionally substituted with one R 20c .
  • R 7 is G.-cycloalkyI optionally substituted with one R 20c .
  • R 7 is C .scycloalkyl optionally substituted with one R 20c .
  • R 7 is C 3-4 cycloalkyl optionally substituted with one R 20c .
  • R 7 is C3.1 icycloalkyl, including G-ucycloalkyl, G,. icycloalkyI. G.-cycloalkyl, G.-cycloalky I. G- scy cloalky 1, and Gi. icycloalkyI. each of which being optionally substituted with two R 20c .
  • R 7 is G>.
  • R 7 is G.-cycloalkyl optionally substituted with two R 20c .
  • R 7 is C 3-7 cycloalkyl optionally substituted with two R 20c .
  • R 7 is Ci.ecycloalkyl optionally substituted with one R 20c .
  • R 7 is C .-scycloalkyl optionally substituted with two R 20c .
  • R 7 is C ,.icycloalkyl optionally substituted with two R 20c .
  • R 20c is independently selected from amino, -CN, C 1-9 alkyl, C 1-9 alkoxy, C 1-9 haloalkyl, -OH, -N(R 24 )C(O)R 25 , and -C(O)N(R 22 )(R 23 ).
  • R 20c is amino.
  • R 20c is -CN.
  • R 20c is C 1-9 alkyl. In some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R 20c is C i-salkoxy . In some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R 20c is Ci-ihaloalky 1.
  • R 20c is --OH. In some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R 20c is -N(R 24 )C(O)R 25 . In some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R 20c is -C(O)N(R 22 )(R 23 ).
  • R 20c is - NHC(O)R 25 . In some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R 20c is -C(O)NH(R 22 ).
  • R 20c is -NHC(O)R 25 and R 25 is C 1-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, Ci .ealkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Ck.-cycloalkyl. C 2-9 heterocycloalkyl , C 6-10 aryl, and Ci.Jiclcroary I .
  • R 20c is -C(O)NH(R 22 ) and R 22 is Ci-'Jieterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 20c is -NHC(O)R 25 and R 25 is Cz-jheterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 20c is -C(O)NH(R 22 ) and R 22 is Cj.JictcrocycloalkyI optionally substituted with one Ci- salkyl.
  • R 7 is C 6-14 cycloalkyl (including C ( ,.
  • R 7 is G,.
  • R 7 is Cg-i icycloalkyl (including Ce i icycloalkyI. Cs-scycloalkyl, C.. -cycloalkyI. C-.,, cycloalkyl.
  • R 7 is Ce-ncycloalkyl (including Ce-wcycloalkyl, G,. gcycloalkyl, C 3-7 cycioalky I. Cs-scycloalkyl, C 3-5 cycloalkyl, and Gi-icy cloalky 1), optionally substituted with one, two, or three R 20c that is Ci-aalkoxy.
  • R 7 is G-i icycloalkyl (including C 6-14 cycloalkyI. Ce-scycloalky 1, C 3-7 cycloalkyl, G-ecycloalkyl, Gi.scy cloalky 1, and C 3-4 cycloalkyl), optionally substituted with one, two, or three R 20c that is C .’, haloalky I.
  • R 7 is C 6-14 cycloalkyl (including G,-i icycloalkyl. C 6-9 cycloalkyl, C 3-7 cycloalkyl, G- 6 cycloalkyl, C .scy cloalky 1, and C 3-4 cycloalkyl), optionally substituted with one, two, or three R 20c that is -OH.
  • R 7 is C 6-14 cycloalkyI (including Cs-i 4cycloalkyl, C 6-9 cycloalkyl, C 3- 7cycloalkyl, Ch-ecy cloalky 1, G-scycloalkyl, and C 3-4 cycloalkyl), optionally substituted with one, two, or three R 20c that is oxo.
  • R 7 is Ce-ucy cloalky 1 (including G,.1 icycloalkyI. G, -icycloalkyI. C 3-7 cycloalkyl, G-ecycloalkyl, G.scycloalkyl, and C 3-4 cycloalkyl). optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 7 is G-i icycloalkyl (including G.
  • R 7 is C,.
  • G.scycloalkyk G-scycloalkyl, and C 3-4 cycloalkyl). optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, G-salkyl, G-Galoalky 1. G-e alkoxy, Cs-scy cloalky 1, C 2- sheterocycloalkyl, G-ioaryl, and C 1-9 heteroaryl.
  • R 7 is G-i icycloalkyl (including G, - icycloalkyl. G-scycloalkyl, G-scycloalkyl, G-ecy cloalky 1, G.scycloalkyl. and C 3-4 cycloalkyl), optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is G-shclcrocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 7 is G- 1 icycloalkyl (including C,,-i icycloalkyl. G,->.cycloalkyl. G-scycloalkyl, G-ecycloalkyl, G.scycloalkyk and G- 4cycloalkyl), optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ). In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is G- 1 icycloalkyl (including C,,-i icycloalkyl. G,->.cycloalkyl. G-scycloalkyl, G-ecycloalkyl, G.scycloalkyk and G- 4cycloalkyl), optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ). In embodiment
  • R 7 is Ce- ucycloalkyl (including G-ucycloalkyl, G-scycloalkyl. G-7cycloalkyl, G-ecycloalkyl, C 3-5 cycloalkyl.
  • G- 4cycloalkyl optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is G-Gctcrocycloalky 1 optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 7 is Ce-ucycloalkyl (including G-ucycloalkyl, C 6-9 cycloalkyl, G-7Cycloalkyl, G-ecy cloalky 1, G-scycloalkyl, and G-4cycloalkyl), optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is G- sheterocycloalkyI optionally substituted with one G-ealkyl.
  • R 7 is C 2-9 heterocycloalkyl, including C 6-9 heterocycloalkyl, G-7heterocycloalkyl, G- eheterocycloalkyl, G-e heterocycloalkyl, G-sheterocycloalkyl, G-4heterocycloalkyl, each of which being optionally substituted with one, two, or three R 20c .
  • R 7 is C 6-9 heterocycloalkyl optionally substituted with one, two, or three R 20c .
  • R 7 is C 3-7 heterocycloalkyl optionally substituted with one, two, or three R 20c .
  • R 7 is C 3- 6 heterocy cloalky 1 optionally substituted with one, two, or three R 20c .
  • R 7 is C 5-6 heterocycloalkyl optionally substituted with one, two, or three R 20c .
  • R 7 is C 3-5 heterocycloalkyl optionally substituted with one, two, or three R 20c .
  • R 7 is C 3-4 heterocycloalkyl optionally substituted with one, two, or three R 20c .
  • each of the R 7 described above including C 6-9 heterocycloalkyl, C 3-7 heterocycloalkyl. C 3- 6 heterocycloalkyI. C 5-6 heterocycloalkyl,C 3-5 heterocycloalkyl. C 3-4 heterocycloalkyl, is optionally substitued with one R 20c .
  • C 5-6 heterocycloalkylC 3-5 heterocycloalkyl, C 3-4 heterocycloalkyl is optionally substituted with two R 20c .
  • each of the R 7 described above including C 6-9 heterocycloalkyl.
  • C 3- 4heterocycloalkyl is optionally substituted with three R 20c .
  • R 20c is independently selected from amino, -CN, C 1-6 alkyl, Ci.yilkoxy. C 1-9 haloalkyl, -OH, -N(R 24 )C(O)R 25 , and -C(O)N(R 22 )(R 23 ).
  • R 20c is amino.
  • R 20c is -CN.
  • R 20c is Cualkyl. In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is C i. ialkoxy . In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is C1.3 haloalky 1.
  • R 20c is —OH. In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is -N(R 24 )C(O)R 25 . In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is -C(O)N(R 22 )(R 23 ).
  • R 20c is -NHC(O)R 25 . In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is -C(O)NH(R 22 ).
  • R 20c is -NHC(O)R 25 and R 25 is C 2- 9 heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C 1- 6 alkyl. C 1-6 haloalkyl, C 1-6 alkoxy, Cy.-cycloalkyI. Cx-Jictcrocycloalkyl. C 6-10 aryl, and C .Uieteroaryl.
  • R 20c is -C(O)NH(R 22 ) and R 22 is C 2-9 iheterocy cloalky 1 optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 20c is -NHC(O)R 25 and R 25 is C 2- 5heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 20c is -C(O)NH(R 22 ) and R 22 is C 2- 5heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 7 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3-7 heterocycloalkyl.
  • R 7 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3- 7 hetcrocycloalkyI.
  • R 7 is C 2-9 heterocycloalkyl (including Ce- sheterocycloalkyl, Ci-dictcrocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalky 1, and C 3- 4 heterocycloalkyl), optionally substituted with one, two, or three R 20c that is C 1-9 alkyl.
  • R 7 is C 2- 9 heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3-7 heterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and C 3-4 heterocycloalkyl), optionally substituted with one, two, or three R 20c that is C 1-9 alkoxy.
  • R 7 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3-7 heterocycloalkyl.
  • C 3-6 heterocycloalkyl, Cs- eheterocycloalkyl, C 3-5 heterocycloalkyl, and C 3-4 heterocycloalkyl) optionally substituted with one, two, or three R 20c that is C 1-9 haloalkyl.
  • R 7 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3-7 heterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and C 3-4 heterocycloalkyl). optionally substituted with one, two, or three R 20c that is -OH.
  • R 7 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3- 7 heterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and Ci. ihelerocycloalky I), optionally substituted with one, two, or three R 20c that is oxo.
  • R 7 is C 2-9 heterocycloalkyl (including C 6- 9heterocycloalkyl, C 3-7 heterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and Cs- 4heterocycloalkyl), optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 7 is C 2- 9heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3-7 heterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and C 3-4 heterocycloalkyl), optionally substituted with one, two, or three R 20c that is - NHC(O)R 25 .
  • R 7 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3-7 heterocycloalkyl, Cs- eheterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and C 3-4 heterocycloalkyl), optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Cs-scycloalkyl, C2- sheterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • R 7 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, Cs- sheterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and C 3-4 heterocycloalkyl), optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is Cs-sheterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 7 is Ch.Jictcrocycloalkyl (including C 6-9 heterocycloalkyl, C 3-7 heterocycloalky 1, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, Ci.dicterocycloalkyI. and Ci. iheterocycloalkyl). optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ).
  • R 7 is C 2-9 heterocycloalkyl (including C (1 . sheterocycloalkyl, C 3-7 heterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl and C.- ihctcrocycloalkyl), optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ).
  • R 7 is C 2- 4 heterocycloalkyI (including Ce-gheterocycloalkyl, C 3-7 heterocycloalkyI.
  • C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and C 3-4 heterocycloalkyl optionally substituted with one, two, or three R 20c that is - C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 7 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3- -hclcrocycloalkyI. C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and C 3-4 heterocycloalkyl), optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 7 is thianyl substituted with one, two, or three R 20c .
  • R 7 is monovalent tetrahydro-2H- thiopyran 1,1-dioxide substituted with one, two, or three R 20c .
  • R 7 is monovalent 4 ⁇ 2 -thiomorpholine substituted with two R 20c .
  • R 7 is tetrahydro-2H-thiopyranyl 1,1-dioxide.
  • R 7 is 4k 2 -thiomorpholinyl substituted with two R 20c .
  • R 7 is piperidinyl substituted with one R 20c . In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is piperazinyl substituted with one R 20c . In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is pyrrolidinyl substituted with one R 20c .
  • R 7 is C 2-9 heterocycloalkyl substituted with one methyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 6-9 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 7 is C 3-7 hetcrocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 7 is C 3-6 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 7 is Cs-JieterocycloalkyI substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 5-6 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 7 is C 3-4 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 7 is C 3-7 hcicrocycloalkyI substituted with one methyl, one ethyl, or one propyl.
  • R 7 is C4-7heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 7 is C 4-5 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 7 is CshctcrocycloalkyI substituted with one methyl, one ethyl, or one propyl.
  • R 7 is CiliclerocycloalkyI substituted with one methyl, one ethyl, or one propyl.
  • R 7 is C 6-9 heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 3-7 heterocycloalkyI substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 3-6 heterocycloalkyl substituted with one propyl.
  • R 7 is C 5-6 heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 5-6 heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C >. iheterocycloalkyl substituted with one propyl.
  • R 7 is C 1-9 hctcrocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R 7 is CshctcrocycloalkyI substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C4heterocycloalkyl substituted with one propyl.
  • R 7 is C 2-9 heterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is Ci.-lieterocycloalky I substituted with one isopropyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 4-7 heterocycloalkyl substituted with one isopropyl.
  • R 7 is C4- sheterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 5 heterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C4heterocycloalkyl substituted with one isopropyl.
  • R 7 is C 2-9 heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 2-7 heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 4-7 heterocycloalkyl substituted with two oxo.
  • R 7 is C 6-9 heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 3-7 heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 3-6 heterocycloalkyl substituted with two oxo.
  • R 7 is C 5-6 heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 5-6 heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 3-4 heterocycloalkyl substituted with two oxo.
  • R 7 is C 1-9 hctcrocycloalkyI substituted with two oxo. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C 5 heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is C ihcterocycloalkyI substituted with two oxo.
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is amino.
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is -CN.
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is C 1-3 alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is thianyl, optionally substituted with one, two, or three R 20c that is C ., alkoxy.
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is C ., haloalky I.
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is -OH.
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is oxo. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is thianyl, optionally substituted with one, two, or three R 20c that is - N(R 24 )C(O)R 25 .
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 .
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 cycloalkyl. C 2-9 heterocycloalkyl. C 6-10 aryl, and Ci.Jictcroary I.
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-5 heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ).
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ).
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C'z-shctcrocycloalky I optionally substituted with one C 1-6 alkyl.
  • R 7 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R 20c that is amino.
  • R 7 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R 20c that is -CN.
  • R 7 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R 20c that is C 1-9 alkyl.
  • R 7 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R 20c that is C 1-9 alkoxy.
  • R 7 is thianyl, optionally substituted with one, two, or three R 20c that is Ci- .lialoalkyl.
  • R 7 is monovalent tetrahydro-2H-thiopyran 1,1- dioxide, optionally substituted with one, two, or three R 20c that is -OH.
  • R 7 is monovalent tetrahydro-2H- thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R 20c that is oxo.
  • R 7 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 7 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R 20c that is - NHC(O)R 25 .
  • R 7 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalky 1, C 1-6 alkoxy, C 3-7 cycloalkyI. C 2-9 heterocycloalkyI, C 6 - 10 aryl, and C 1-9 heteroaryl.
  • R 7 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is CF-shctcrocycloalky 1 optionally substituted with one Ci. ealkyl.
  • R 7 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ).
  • R 7 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ).
  • R 7 is monovalent tetrahydro-2H- thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C1- 9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1- 6 alkyl.
  • R 7 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 7 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20c that is amino.
  • R 7 is 4 ⁇ 2 -thiomorpholiny I. optionally substituted with one, two, or three R 20c that is -CN.
  • R 7 is 4 ⁇ 2 - thiomorpholinyl, optionally substituted with one, two, or three R 20c that is C 1-9 alkyl.
  • R 7 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20c that is Ci- . alkoxy.
  • R 7 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20c that is C 1-3 haloalkyl.
  • R 7 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20c that is -OH.
  • R 7 is 4 ⁇ 2 -thiomorpholiny 1, optionally substituted with one, two, or three R 20c that is oxo.
  • R 7 is 4 ⁇ 2 - thiomorpholinyl, optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 7 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20c that is - NHC(O)R 25 .
  • R 7 is 4 ⁇ 2 -thiomorpholiny 1, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C 1-9 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, Ck. -cycloalkyl. Cz-pheterocycloalkyl, C 6-10 aryl, and C 6-9 heteroaryI.
  • R 7 is 4 ⁇ 2 -thiomorpholiny I. optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2- 5 heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 7 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ).
  • R 7 is 4 ⁇ 2 -thiomorpholiny 1, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ).
  • R 7 is 4 ⁇ 2 -thiomorpholiny 1, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is Cz-pheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 7 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2-5 heterocycloalkyl optionally substituted with one Ci- ealkyl.
  • R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is amino.
  • R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is -CN.
  • R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is C 1-9 alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is C .ialkoxy .
  • R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is Ci-ihaloalkyl.
  • R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is -OH.
  • R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is oxo. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 .
  • R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalky 1. C 1-6 alkoxy, C 3-7 cycloalkyl, C 2- sheterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is CF-shcterocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ).
  • R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ).
  • R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 7 is piperidinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is Ci.shelerocycloalkyI optionally substituted with one Ci. ealkyl.
  • R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is amino.
  • R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is -CN.
  • R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is C 1-9 alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is C ., alkoxy .
  • R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is C 1-3 haloalkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is -OH.
  • R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is oxo. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 .
  • R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2- ⁇ >heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-9 haloalkyl, C 1-9 alkoxy, C 3- 7cycloalkyl, C 2- oheterocycloalkyl, C 6-10 aryl, and Ci- shete roaryl.
  • R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2- 5heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ).
  • R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ).
  • R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 7 is piperazinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2-5 heterocycloalkyl optionally substituted with one C 1- 6 alkyl.
  • R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is amino.
  • R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -CN.
  • R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is C 1-9 alkyl.
  • R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is C 1-3 alkyl .
  • R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is C 1-9 haloalkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -OH.
  • R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is oxo. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 .
  • R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, CiHialoalky I. C 1-6 alkoxy, C 3- 7cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2- 5heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ).
  • R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ).
  • R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 7 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2- sheterocycloalkyl optionally substituted with one C 1-9 alkyl.
  • [00175] is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is
  • [00176] is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is [00177]
  • [00181] is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is [00182] In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is
  • the disclosure provides a compound of Formula (111’), or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R 10 ;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkeny 1, C 2-6 alkynyl, C 3-10 cycloalkyl-wherein C 1-6 alkyl, C 2- 6 alkenyl. C 2 - 6alkynyl, and C 3-10 cycloalkyl are optionally substituted with one, two, or three R 20a ;
  • R 4 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl
  • R 5 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 8 is independently selected from halogen, -CN, C 1-6 alkyl, C 2- 6 alkenyl.
  • sheterocycloalkyl C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), - N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 13 , -OC(O)R 15 , - C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O) 2 R 15 , -S(O) 2 N(R 12 )(R 13 ), -S(O)(O)(O
  • R 9 is selected from C 1-6 alky 1, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl.
  • C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20c ; each R 10 is independently selected from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 2 - 9heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl.
  • C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 hcteroary I are optionally substituted with one, two, or three R 2M ; each R 12 is independently selected from hydrogen, C 1-6 alkyl. C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 7 cycloalkyI. C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl. wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 7 cycloalkyI.
  • each R 13 is independently selected from hydrogen, C 1-6 alkyl. and C 1-6 haloalky 1; or R 12 and R 13 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 20f ;
  • each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-9 haloalkyl: each R 15 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alky ny I. C-,. -cycloalkyI.
  • C 2-9 heterocycloalkyl I C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 1-6 alkenyl, C 2-6 alky nyl.
  • C ,--cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20g ; each R 17 and each R 17a are each independently selected from C
  • C 1-6 alkyl and C 3- ecycloalkyl are optionally substituted with one, two or three of R 20h ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 20h are each independently selected from halogen, oxo, -CN, Ci- ealkyl, C 2-9 alkenyl, Ci-ealkynyl. C 3-10 cycloalkyl, -CH 2 -C 3-10 cycloalkyl, C 2-9 heterocycloalkyl.
  • each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl
  • each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C-.-cy cloalky I. C 2 .
  • [00193] is a compound of Formula (III’) having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R 10 ;
  • R 2 is selected from hydrogen, C 1-6 alky I. Ci.,, alkenyl. C 2-6 alkynyl, C-. ocy cloalky 1, -wherein C 1-6 alkyl, C 2-6 alkenyl, C 2 . ealkynyl, and C 3-10 cycloalkyl are optionally substituted with one, two, or three R 20a ;
  • R 4 is selected from hydrogen, C 1-6 alky I. and C 1-6 haloalkyl
  • R 5 is selected from hydrogen, C 1-6 alky 1, and C 1-6 haloalkyl; each R 8 is independently selected from halogen, -CN, C 1-6 alkyl, Ch.-alkcny I. C 2-6 alkynyl, C . ocycloalky 1. C 2 - sheterocycloalkyl, C 6-10 aryl, C .Uietcroaryl.
  • R 9 is selected from C 1-9 alkyl, C;. , alkenyl. C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, Ci. sheteroaryl, -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O) 2 R 1J , and - S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 3-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20c ; each R 10 is independently selected from halogen,
  • C 2-6 alkynyl, Ch. -cycloalkyI. C 2 . ⁇ >heterocycloalkyl, C 6-10 aryl, and Ch-dieleroary I are optionally substituted with one, two, or three R 20d ; each R 12 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ch. -cycloalky I. C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 ieteroary I. whereinC 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ch, .-cycloalky I.
  • C 2-9 heterocycloalkyl, C 6-10 aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 20e ; each R 13 is independently selected from hydrogen, C 1-6 alkyl, and Ch .,, haloalky 1; or R 12 and R 13 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 20f ; each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalky 1; each R 15 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ch. -cycloalkyI.
  • alkyl. Ch. alkenyl. C 2.( ,alkynyl. C-.iocycloalkyl. -CH 2 -C 3- wcycloalkyl, Ch.Jieterocycloalkyl. -CH 2 -C 2 .
  • each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalky I
  • each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalky 1, C 1-6 alkeny 1, C 2-6 alkynyl, C'-.-cy cloalky I.
  • [00194] is a compound of Formula (III) having the structure of Formula (III-l), or a pharmaceutically acceptable salt or solvate thereof:
  • each R 8 is independently selected from halogen, C 1-6 alkyl, C 3-10 cycloalky 1, C 2- sheterocycloalkyl, C 6-10 aryl, and C
  • Jieteroary I are optionally substituted with one, two, or three R 20b .
  • each R 8 is independently selected from halogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 ieteroary I. wherein C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20b .
  • each R 8 is independently selected from halogen and C 1-6 alky I optionally substituted with one, two, or three R 20b .
  • [00196] is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is selected from C 1-6 alkyl, C 3- wcycloalkyl, C 1-9 heterocycloalkyl, C 6-10 aryl, and Ci- 9heteroaryl, wherein C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20c .
  • R 9 is selected from C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20c .
  • In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and Ci- gheteroaryl, wherein C 1-9 alkyl, C 3-10 cycloalkyl, C 2-9 heterocycloalkyl. C 3-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20c .
  • In some embodiments is a compound of Formula (III’), (III), or (III- 1), wherein R 9 is selected from -C(O)R 15 .
  • R 15 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20g .
  • [00198] in some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is C 1-6 heterocycloalkyl optionally substituted with one, two, or three R 20c .
  • a compound of Formula (III'), (III), or (III- 1) is a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is fused C 6-10 aryl optionally substituted with one, two, or three R 20c .
  • a compound of Formula (III'), (III), or (III- 1) is a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is C 1-9 heteroaryl optionally substituted with one, two, or three R 20c .
  • [00199] is a compound of Formula (I), (1-1), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 15 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20g .
  • R 15 is a compound of Formula (I), (1-1), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 15 is spirocyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20g .
  • R 15 is fused CL-Jictcrocycloalkyl optionally substituted with one, two, or three R 20g .
  • [00200] is a compound of Formula (I), (1-1), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is C 1-6 alkyl optionally substituted with one, two, or three R 20c .
  • R 9 is C 1-6 alkyl optionally substituted with one, two, or three R 20c .
  • R 9 is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is cyclopropyl optionally substituted with one, two, or three R 20c .
  • R 9 is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is pyrrolyl optionally substituted with one, two, or three R 20c .
  • R 9 is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is thianyl optionally substituted with one, two, or three R 20c .
  • 1.4-oxazepanyl optionally substituted with one, two, or three R 20c .
  • R 9 is C 3-14 cycloalkyI. including C 6-14 cycloalkyl. C 6-9 cycloalkyI. CF. cycloalky 1, C 3-6 cycloalkyl, C 3-5 cycloalkyl.
  • R 9 is C 6-14 cycloalkyl optionally substituted with one, two, or three R 20c .
  • R 9 is Cs- gcycloalkyl optionally substituted with one, two, or three R 20c .
  • R 9 is C . icycloalkyI optionally substituted with one, two, or three R 20c .
  • R 9 is C 3-6 cycloalkyl optionally substituted with one, two, or three R 20c .
  • R 9 is C 3-5 cycloalkyl optionally substituted with one, two, or three R 20c .
  • R 9 is C.F.
  • R 9 is C 3-14 cycloaIkyl. including C 6-14 cycloalkyl. C 6-9 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl, and C 3-4 cycloalkyl, each of which being substituted with one, two, or three R 20c .
  • R 9 is CF, - icycloalkyI substituted with one, two, or three R 20c .
  • R 9 is C 6-9 cycloalkyl substituted with one, two, or three R 20c .
  • R 9 is C 3-7 cycloalkyl substituted with one, two, or three R 20c .
  • R 9 is C 3- cycloalkyl substituted with one, two, or three R 20c .
  • R 9 is C 3-5 cycloalkyI substituted with one, two, or three R 20c .
  • R 9 is CF,. icycloalkyl substituted with one, two, or three R 20c .
  • R 9 is CF-i icycloalkyI. including CF-i icycloalkyI. CGcycloalkyI. CF.-cycloalkyl, CF,. icycloalky I. C 3- scycloalkyl, and CF,. icycloalkyI. each of which being optionally substituted with one R 20c .
  • R 9 is C,.
  • R 9 is C 6-9 cycloalkyl optionally substituted with one R 20c .
  • R 9 is C 3-7 cycloalkyl optionally substituted with one R 20c .
  • R 9 is CF.,, cycloalkyI optionally substituted with one R 20c .
  • R 9 is C 3-5 cycloalkyl optionally substituted with one R 20c .
  • R 9 is C 3-4 cycloalkyl optionally substituted with one R 20c .
  • R 9 is C3.1 icycloalkyl, including C 6-14 cycloalkyI. C 6-9 cycloalkyl, C 3-7 cycloalkyI, C 3-6 cycloalkyI. C 3- 5 cycloalkyl, and C 3-4 cycloalkyI each of which being optionally substituted with two R 20c .
  • R 9 is Cg.
  • R 9 is C 6-9 cycloalkyl optionally substituted with two R 20c .
  • R 9 is C . -cycloalkyI optionally substituted with two R 20c .
  • R 9 is C 3- 6 cycloalkyl optionally substituted with one R 20c . In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C 3-5 cycloalkyl optionally substituted with two R 20c . In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C-,. icycloalky I optionally substituted with two R 20c .
  • R 20c is independently selected from amino, -CN, C 1-9 alkyl, C 1-9 alkoxy, C
  • R 20c is amino.
  • R 20c is -CN.
  • R 20c is C 1-9 alkyl. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is C 1-3 alkoxy . In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is C 1-3 haloalkyl. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is --OH.
  • R 20c is -N(R 24 )C(O)R 25 . In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is -C(O)N(R 22 )(R 23 ). In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is -NHC(O)R 25 .
  • R 20c is -C(O)NH(R 22 ).
  • R 20c is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, CF. -cycloalkyI. C 2-9 heterocycloalkyI.
  • R 20c is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 20c is -NHC(O)R 25 and R 25 is C 2-5 heterocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 20c is -C(O)NH(R 22 ) and R 22 is CGshctcrocycloalky I optionally substituted with one C 1-6 alkyl.
  • R 9 is C 6-14 cycloalkyI (including C 6-14 cycloalkyI. C 6-9 cycloalkyl, C 3-7 cycloalkyI C 3-6 cycloalkyI C 3- 5 cycloalkyI.
  • R 9 is Ce- 14 cycloalkyI (including C 6-14 cycloalkyl, C 6-9 cycloalkyl.
  • C 3-7 cycloalkyI C 3-6 cycloalkyI C 3-5 cycloalkyI and C 3- 4 cycloalkyl optionally substituted with one, two, or three R 20c that is -CN.
  • R 9 is C 6-14 cycloalkyl (including C 6-14 cycloalkyl. C 6-9 cycloalkyl, C 3-7 cycloalkyI. C 3-6 cycloalkyI. C 3-5 cycloalkyI. and C 3-4 cycloalkyl), optionally substituted with one, two, or three R 20c that is C 1-9 alkyl.
  • R 9 is G-i icycloalkyl (including Cg.
  • R 9 is C 6-14 cycloalkyl (including G.i icycloalky I. G,. ecycloalkyI. C 3-7 cycloalkyI.
  • R 9 is C 6-14 cycloalkyl (including G, - icycloalkyl. G.ecycloalkyk C 3-7 cycloalkyl, C 3-6 cycloalkyI G.scycloalkyl, and C 3-4 cycloalkyl). optionally substituted with one, two, or three R 20c that is -OH.
  • R 9 is C'e-i icycloalkyI (including C 6-14 cycloalkyl. C 6-9 cycloalkyl. C 3-7 cycloalkyl, C 3-6 cycloalkyI, C 3- scycloalkyI. and C3 - icycloalkyl), optionally substituted with one, two, or three R 20c that is oxo.
  • R 9 is Cg.
  • R 9 is G- 1 icycloalkyI (including C 6-14 cycloalkyI. C 6-9 cycloalkyl.
  • R 9 is C 6-14 cycloalkyI (including G.i icycloalkyI. C 6-9 cycloalkyl, G. -cycloalkyI.
  • R 9 is C 6-14 cycloalkyl (including G- 1 icycloalkyI. C 6-9 cycloalkyl, C 3- 7 cycloalkyl. C 3-6 cycloalkyI C 3-5 cycloalkyl, and C 3-4 cycloalkyl). optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-5 heterocycloalkyI optionally substituted with one G -ealky I.
  • R 9 is C 6-14 cycloalkyI (includingC 6-14 cycloalkyl.
  • C 3-6 cycloalkyI Cs-scycloalky 1, C 3- 6 cycloalkyI.
  • C 3-5 cycloalkyI and C 3-4 cycloalkyl optionally substituted with one, two, or three R 20c that is - C(O)N(R 22 )(R 23 ).
  • R 9 is G-i icycloalky l (including C 6-14 cycloalkyl. C 6-9 cycloalkyl, C 3-7 cycloalkyI C 3- 6 cycloalkyI. C 3-5 cycloalkyI. and C 3-4 cycloalkyl), optionally substituted with one, two, or three R 20c that is - C(O)NH(R 22 ).
  • R 9 is C 6-14 cycloalkyl (including C 6-14 cycloalkyl. C 6-9 cycloalkyl, C 3- 7Cycloalkyl, C 3- ecycloalkyl, C .scycloalkyl. and Csucycloalkyl), optionally substituted with one, two, or three R 20c that is - C(O)NH(R 22 ) and R 22 is Ci-Jictcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 9 is C 6-14 cycloalkyl (including G,- icycloalkyL C 6-9 cycloalkyl, C 3- 7Cycloalkyl, Ci.ecy cloalky 1, Ci.scycloalkyI. and C 3-4 cycloalkyl), optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is Ck-sheterocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 9 is Ck-'JieicrocycloalkyI. including C 6-9 heterocycloalkyl, Ckdieterocycloalkyl, C 3-
  • R 9 is C 6-9 heterocycloalkyl optionally substituted with one, two, or three R 20c .
  • R 9 is Cs ⁇ heterocycloalkyl optionally substituted with one, two, or three R 20c .
  • R 9 is C3. ijictcrocycloalkyl optionally substituted with one, two, or three R 20c .
  • R 9 is Cs-r, heterocycloalkyl optionally substituted with one, two, or three R 20c .
  • R 9 is C 3- 5 heterocycloalkyl optionally substituted with one, two, or three R 20c .
  • R 9 is Ci.ihctcrocycloalkyI optionally substituted with one, two, or three R 20c .
  • each of the R 9 described above including C Cons.)heterocycloalkyl.
  • G.-dicicrocycloalkyk C 3- sheterocycloalkyl, C5.6 heterocycloalkyl, Cs.jheterocycloalkyl, C.ihclerocycloalky 1, is optionally substitued with one R 20c .
  • Cg-rheterocycloalkyl is optionally substituted with two R 20c .
  • Cs-r, heterocycloalkyl, Cs-jheterocycloalkyl, C 3-4 heterocycloalkyl is optionally substituted with three R 20c .
  • R 20c is independently selected from amino, -CN, Cj.ialky I. C 1-9 alkoxy, C 1-9 haloalkyk -OH, -N(R 24 )C(O)R 25 , and -C(O)N(R 22 )(R 23 ).
  • R 20c is amino.
  • R 20c is -CN.
  • R 20c is Chalky 1. In some embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is C i.salkoxy . In some embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is Ci-, haloalky I. In some embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is -OH.
  • R 20c is -N(R 24 )C(O)R 25 . In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is -C(O)N(R 22 )(R 23 ). In some embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 20c is -NHC(O)R 25 .
  • R 20c is -C(O)NH(R 22 ).
  • R 20c is -NHC(O)R 25 and R 25 is Ch-UieterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-9 haloalkyl, C 1-6 alkoxy, Ch. -cycloalkyI.
  • R 20c is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 20c is -NHC(O)R 25 and R 2i is Cs-sheterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 20c is -C(O)NH(R 22 ) and R 22 is Cs-sheterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 9 is C 2-9 heterocycloalkyI (including C 6-9 heterocycloalkyI, C 3-7 heterocycloalkyI, C3.
  • R 9 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl. C3. -helerocycloalkyI. C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyI.
  • R 9 is C 2-9 heterocycloalkyl (including C,,- sheterocycloalkyl, C 3- -heterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalky 1, and Cs- ⁇ iheterocycloalkyl), optionally substituted with one, two, or three R 20c that is C 1-9 alkyl.
  • R 9 is C 2- siheterocycloalkyl (including C 6-9 heterocycloalkyI. C 3-7 heterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl. and C 3-4 heterocycloalkyI). optionally substituted with one, two, or three R 20c that is C 3-7 .alkoxy.
  • R 9 is C 2-9 heterocycloalkyI (including C 6-9 heterocycloalkyI. C 3-7 heterocycloalkyI. C 3-6 heterocycloalkyl, C 5- 6 heterocycloalkyl, C 3-5 heterocycloalkyI, and C 3-4 heterocycloalkyI), optionally substituted with one, two, or three R 20c that is C 1-9 haloalkyl.
  • R 9 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyI.
  • R 9 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3- 7 heterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and C 3-4 heterocycloalkyI), optionally substituted with one, two, or three R 20c that is oxo.
  • R 9 is C 2-9 heterocycloalkyl (including C 6- 9 heterocycloalkyl, C 3-7 heterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and Cs- iheterocycloalkyI), optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 9 is C 2- 9 heterocycloalkyl (including C 6-9 heterocycloalkyl. C 3-7 heterocycloalkyl, C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and C 3-4 heterocycloalkyl), optionally substituted with one, two, or three R 20c that is - NHC(O)R 25 .
  • R 9 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3-7 heterocycloalkyl.
  • C 3- 6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and C 3- 4heterocycloalkyl) optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1- 6 alkyl.
  • R 9 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl. C 3 . 7 heterocycloalkyI.
  • R 9 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl.
  • R 9 is C 2-9 heterocycloalkyl (including C 6-9 heterocycloalkyl, C 3- -hetcrocycloalkyl, C 3-6 heterocycloalkyl.
  • R 9 is C 2-9 heterocycloalkyl (including Ce-gheterocycloalkyl, C 3-7 heterocycloalkyl, Cs- eheterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalkyl, and C 3-4 heterocycloalkyl), optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 9 is C 2-9 heterocycloalkyl (including C 6- 9 heterocycloalkyl, C 3-7 heterocycloalkyl .
  • C 3-6 heterocycloalkyl, C 5-6 heterocycloalkyl, C 3-5 heterocycloalky 1, and C 3- 4 heterocycloalkyl) optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2- 5 heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 9 is thianyl substituted with one, two, or three R 20c .
  • R 9 is monovalent tetrahydro-2H- thiopyran 1,1-dioxide substituted with one, two, or three R 20c .
  • R 9 is monovalent 4 ⁇ 2 -thiomorpholine substituted with two R 20c .
  • R 9 is tetrahydro-2H-thiopyranyl 1,1-dioxide.
  • R 9 is 4 ⁇ 2 -thiomorpholiny 1 substituted with two R 20c .
  • R 9 is piperidinyl substituted with one R 20c . In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is piperazinyl substituted with one R 20c . In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is pyrrolidinyl substituted with one R 20c .
  • R 9 is C 2-9 heterocycloalkyl substituted with one methyl.
  • R 9 is Cs-sheterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 9 is C 3-7 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 9 is C’,. ( ,hcicrocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 9 is Cs- JictcrocycloalkyI substituted with one methyl, one ethyl, or one propyl.
  • R 9 is Cs- sheterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 9 is C’,.
  • R 9 is C 2-7 heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 9 is Cmheicrocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C 1-9 hcterocycloalkyI substituted with one methyl, one ethyl, or one propyl.
  • R 9 is Csheterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C4heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
  • R 9 is C 6-9 heterocycloalkyl substituted with one propyl.
  • R 9 is C;.?heterocycloalkyl substituted with one propyl.
  • R 9 is C 3-6 heterocycloalkyl substituted with one propyl.
  • R 9 is Cs-Jieterocycloalky I substituted with one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C 5-6 heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C3. 4heterocycloalkyl substituted with one propyl.
  • R 9 is C 4-5 heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C 5 heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C4heterocycloalkyl substituted with one propyl.
  • R 9 is C 1-6 heterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C 2-7 heterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C 4-7 heterocycloalkyl substituted with one isopropyl.
  • R 9 is C 1-9 heterocycloalkyI substituted with one isopropyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C-hctcrocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C4heterocycloalkyl substituted with one isopropyl.
  • R 9 is C 2-9 heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C 2-7 heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C 4-7 heterocycloalkyl substituted with two oxo.
  • R 9 is C 6-9 heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C 3-7 heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C 3 6 heterocycloalkyl substituted with two oxo.
  • R 9 is C 5-6 heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is Cs.Jictcrocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C 3-4 heterocycloalkyl substituted with two oxo.
  • R 9 is C 1-9 heicrocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C 5 heterocycloalkyI substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is C4heterocycloalkyl substituted with two oxo.
  • R 9 is thianyl, optionally substituted with one, two, or three R 20c that is amino. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is thianyl, optionally substituted with one, two, or three R 20c that is -CN.
  • R 9 is thianyl, optionally substituted with one, two, or three R 20c that is Ci.jalkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is thianyl, optionally substituted with one, two, or three R 20c that is C .’.alkoxy. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is thianyl, optionally substituted with one, two, or three R 20c that is Ci.
  • R 9 is thianyl, optionally substituted with one, two, or three R 20c that is -OH.
  • R 9 is thianyl, optionally substituted with one, two, or three R 20c that is oxo.
  • R 9 is thianyl, optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 9 is thianyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 .
  • R 9 is thianyl, optionally substituted with one, two, or three R 20c that is - NHC(O)R 25 and R 25 is C 1-9 heterocy cloalky 1 optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 cycloalkyI. C 1-9 heterocycloalkyl, Cg-ioaryl, and Ci- sheteroaryl.
  • R 9 is thianyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is Ci. sheterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 9 is thianyl, optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ).
  • R 9 is thianyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ).
  • R 9 is thianyl, optionally substituted with one, two, or three R 20c that is - C(O)NH(R 22 ) and R 22 is CF-sheterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 9 is thianyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 1-9 heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 9 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R 20c that is amino.
  • R 9 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R 20c that is -CN.
  • R 9 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R 20c that is C 1-9 alkyl.
  • R 9 is monovalent tetrahydro -2H- thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20c that is C 1-9 alkoxy.
  • R 9 is thianyl, optionally substituted with one, two, or three R 20c that is Ci- , haloalky I.
  • R 9 is monovalent tetrahydro -2H- thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20c that is -OH.
  • R 9 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20c that is oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 9 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 .
  • R 9 is monovalent tetrahydro-2H-thiopyran 1, 1 -dioxide, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl. C 6-10 aryl, and C 1-9 heteroaryl.
  • R 9 is monovalent tetrahydro-2H-thiopyran 1, 1 -dioxide, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-5 heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 9 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ).
  • R 9 is monovalent tetrahydro- 2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ).
  • R 9 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20c that is - C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 9 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is Cj-sheterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 9 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20c that is amino.
  • R 9 is 4 ⁇ 2 -thiomorpholiny 1, optionally substituted with one, two, or three R 20c that is -CN.
  • R 9 is 4 ⁇ 2 - thiomorpholinyl, optionally substituted with one, two, or three R 20c that is C 1-9 alkyl.
  • R 9 is 4V-thiomorpholinyl, optionally substituted with one, two, or three R 20c that is Ci.yilkoxy.
  • R 9 is 4 ⁇ 2 -thiomorpholiny 1, optionally substituted with one, two, or three R 20c that is C 1- 3 haloalky I.
  • R 9 is 4 ⁇ 2 -thiomorpholinyl. optionally substituted with one, two, or three R 20c that is -OH.
  • R 9 is 4 ⁇ 2 -thiomorphol i ny 1, optionally substituted with one, two, or three R 20c that is oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is 4 ⁇ 2 -thiomorpholi ny 1, optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 9 is 4 ⁇ 2 -thiomorpholi ny I. optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 .
  • R 9 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20c that is - NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl. C 6-10 aryl, and C 1- 9 heteroaryl.
  • R 9 is 4 ⁇ 2 -thiomorpholiny 1, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one C 1-6 alkyl.
  • R 9 is 4 ⁇ 2 -thiomorpholiny 1, optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ).
  • R 9 is 4 ⁇ 2 -thiomorpholiny 1, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ).
  • R 9 is 4 ⁇ 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 9 is 4k 2 -thiomorpholinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is Ck-shetcrocycloalky I optionally substituted with one C 1-6 alkyl.
  • R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is amino.
  • R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is -CN.
  • R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is C 1-9 alkyl. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is C ., alkoxy .
  • R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is C 1-3 haloalkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is -OH.
  • R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 .
  • R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1 -6 aloalkyI.
  • R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-5 heterocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ). In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ).
  • R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2-9 heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 9 is piperidinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2- 5 heterocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is amino.
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is -CN.
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is Ci- 3 alkyl.
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is C ., alkoxy .
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is C 1-3 haloalkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is -OH.
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is oxo.
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 2i .
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocy cloalky 1 optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one Ci. ealkyl.
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ).
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ).
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2-9 hctcrocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 9 is piperazinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is CF- slielerocycloalkyI optionally substituted with one C 1-6 alkyl.
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is amino.
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -CN.
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is Ci-3alkyl. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is Ci- 3 alkoxy .
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is Ci-, haloalky I.
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -OH.
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is oxo.
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -N(R 24 )C(O)R 25 .
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 .
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C 1-6 alkyl, C 1-6 haloalky 1, C 1-6 alkoxy, C 3-7 cycloalkyl, C 1-6 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -NHC(O)R 25 and R 25 is C 2-9 heterocycloalkyl optionally substituted with one Ci- ealkyl.
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -C(O)N(R 22 )(R 23 ).
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ).
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is R 20c that is optionally substituted with one, two, or three groups independently selected from halogen and C 1-6 alkyl.
  • R 9 is pyrrolidinyl, optionally substituted with one, two, or three R 20c that is -C(O)NH(R 22 ) and R 22 is C 2- 5 heterocycloalkyI optionally substituted with one C 1-6 alkyl.
  • [00223] is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is [00224] In some embodiments is a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is
  • [00231] is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is [00232] In some embodiments is a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 is
  • R 9 is In some embodiments of a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof,
  • In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (II), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is selected from C 1-6 alky 1 and C 1-6 haloalkyl.
  • R 5 is a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is -CH 3 .
  • [00239] is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is hydrogen.
  • [00240] is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from hydrogen and C 1-6 alkyl optionally substituted with one, two, or three R 20a .
  • R 2 is C 1-6 alkyl optionally substituted with one, two, or three R 20a .
  • In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted C 1-6 alkyl.
  • In some embodiments is a compound of (F), (I), (I- 1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CH 3 .
  • R 2 is a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is hydrogen.
  • R 2 is C
  • alkyl e.g., methyl, ethyl, or propyl
  • R 20a is C 1-9 heterocycloalkyl
  • R 2 is C 2 - sheterocycloalkyI optionally substituted with one, two, or three R 20a and R 20a is -N(R 22 )(R 23 ) and R 22 and R 23 are independently selected from H and C 1-6 alkyl (e.g., methyl).
  • R 2 is -OR 12 , R 12 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20e and R 20e is C 1-6 alkyl (e.g., methyl, ethyl, or propyl).
  • R 2 is -OR 12 , R 12 is C 1-6 alkyl optionally substituted with one, two, or three R 20e , and R 20e is CF- shctcrocycloalkyl optionally substituted with one, two, or three C 1-6 alkyl (e.g., methyl, ethyl, or propyl).
  • [00241] is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is a 6-10 membered aryl ring substituted with one or more R 10 .
  • In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is phenyl substituted with one or more R 10 .
  • In some embodiments is a compound of Formula (F), (I), (I- 1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is phenyl substituted with one, two, or three R 10 .
  • In some embodiments is a compound of Formula (F), (I), (I- 1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is a 5-10 membered heteroaryl ring are substituted with one or more R 10 .
  • R 1 is a 5-10 membered heteroaryl ring are substituted with one, two, or three R 10 .
  • each R 10 is independently selected from halogen, C 1-6 alkyl, C 3-7 cycloalkyI.
  • C 2- 9 heterocycloalkyI C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , and N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 3-7 cycloalkyI.
  • C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 20d .
  • R 20d is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 10 is independently selected from halogen, C
  • each R 10 is independently selected from halogen, C 1-6 alkyl, and N(R 12 )(R 13 ), wherein C 1-6 alky I is substituted with one, two, or three R 20d , and each R 20d is halogen.
  • R 20b is C 1-6 alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one, two, or three - N(R 22 )(R 23 ) and R 22 and R 23 are independently selected from H and C
  • R 20b is Ci. ealkyl (e g., methyl, ethyl, or propyl) optionally substituted with one, two, or three -OR 21 and R 21 is independently selected from H and C 1-6 alky.
  • R 20b is selected from -CH 2 -C 6-10 aryl and -CN.
  • R 20b is C 2-9 heterocycloalkyI.
  • R 20b is -C(O)R 25 and R 25 is Ci- 6 alkyl.
  • R 20b is -C(O)R 25 and R 25 is C 2-6 heterocycloalkyl optionally substituted with one, two, or three C 1-6 alkyl.
  • R 20b is C 1-6 alkyl optionally substituted with one, two, or three groups independently selected from oxo, - OR 21 , and -N(R 22 )(R 23 ), R 21 is H, and R 22 and R 23 are independently selected from H and C
  • alkyl e.g., methyl
  • R 20c is C 1-6 alky 1 (e.g., methyl, ethyl, or propyl) optionally substituted with one, two, or three - N(R 22 )(R 23 ) and R 22 and R 23 are independently selected from H and C
  • R 20c is Ci-numbered alkyl (e g., methyl, ethyl, or propyl) optionally substituted with one, two, or three -OR 21 and R 21 is independently selected from H and C 1-6 alky.
  • R 20c selected from -CH 2 -C 6-10 aryl and -CN.
  • R 20c is C 2-9 heterocycloalkyl.
  • R 20c is -C(O)R 25 and R 25 is C 1-6 alkyl.
  • R 20c is -C(O)R 25 and R 25 is C 2-6 hetcrocycloalkyl optionally substituted with one, two, or three C 1-6 alkyl.
  • R 20c is C 1-6 alkyl optionally substituted with one, two, or three groups independently selected from oxo, - OR 21 , and -N(R 22 )(R 23 ), R 21 is H, and R 22 and R 23 are independently selected from H and C 1-6 alky I (e.g., methyl).
  • [00245] is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III'), (III), or (III-l), wherein R 1 is benzothiazolyl optionally substituted with one or more R 10 .
  • R 1 is 1 //-benzo [ ⁇ /
  • R 1 is benzo [c]thiophenyl optionally substituted with one or more R 10 .
  • R 1 is benzo [b ]thiophenyl optionally substituted with one or more R 10 .
  • R 1 is benzo [b ]thiophenyl optionally substituted with one or more R 10 .
  • R 1 is indanyl optionally substituted with one or more R 10 .
  • In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R 1 is indenyl optionally substituted with one or more R 10 .
  • In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R 1 is tetrahnyl optionally substituted with one or more R 10 .
  • R 1 is coumaranyl optionally substituted with one or more R 10 .
  • R 1 is furanyl optionally substituted with one or more R 10 .
  • R 1 is thiophenyl optionally substituted with one or more R 10
  • R 1 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R 1 is thiophenyl optionally substituted with one or more R 10
  • R 1 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R 1 is oxazolyl optionally substituted with one or more R 10 .
  • In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R 1 is thiazolyl optionally substituted with one or more R 10 .
  • R 1 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R 1 is 1H -indazolyl optionally substituted with one or more R 10 .
  • R 1 is imidazo[ 1 ,2- ⁇ ]pyridinyl optionally substituted with one or more R 10 .
  • In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R 1 is pyrazolyl optionally substituted with one or more R 10 .
  • R 1 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R 1 is l//-indolyl optionally substituted with one or more R 10 .
  • In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R 1 is pyridinyl optionally substituted with one or more R 10 .
  • R 1 is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (HI’), (III), or (III-l), wherein R 1 is pyrimidinyl optionally substituted with one or more R 10 .
  • In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R 1 is pyrizinyl optionally substituted with one or more R 10 .
  • R 1 is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), wherein R 1 is l//-imidazolyl optionally substituted with one or more R 10 .
  • R 1 is 1,4-benzodioxanyl optionally substituted with one or more R 10 .
  • R 1 is 3,4-dihydrobenzo[l,4]oxazinyl optionally substituted with one or more R 10 .
  • In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (III), or (III-l), wherein R 1 is benzo [b]
  • In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (nF), (III), or (III-l), wherein R 1 is benzo [c]furanyl optionally substituted with one or more R 10 .
  • In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R 1 is phenyl optionally substituted with one or more R 10 .
  • R 1 is a compound of Formula (I'), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R 1 is naphthalenyl optionally substituted with one or more R 10 .
  • R 1 is (benzo[d][l,3]dioxol-4-yl, l,8a-dihydroimidazo[l,2-a]pyridin-8-yl, 1H- indazol-4-yl, lH-indazol-5-yl, lH-indazol-6-yl, lH-indazol-7-yl, lH-inden-4-yl, lH-inden-5-yl, lH-inden-6-yl, 1H- inden-7-yl, 2,3-dihydro-lH-inden-4-yl, 2,3 -dihydro- lH-inden-4-yl, 2,3 -dihydro- lH-inden), 2,3 -dihydro- lH-inden), 2,3 -dihydro- lH-inden), 2,3 -dihydro- lH-inden), 2,3 -di
  • [00247] is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-
  • [00248] is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III’), (III), or (III-l), wherein R 1 is
  • R 20d is C 1-6 alkyl optionally substituted with one, two, or three groups independently selected from halogen and -OR 21 .
  • R 20d is C 1-6 alkyl optionally substituted with one, two, or three groups independently selected from halogen and -OH.
  • R 20d is C 1-6 alkyl optionally substituted with one, two, or three groups independently selected from F and -OH.
  • R 20d is C 1-6 alkyl optionally substituted with one - OH.
  • R 20d is C 1-6 alkyl optionally substituted with one, two, or three F.
  • R 20d is Ci.ialkyl optionally substituted with one, two, or three groups independently selected from halogen and -OR 21 .
  • R 20d is C 1-3 alkyI optionally substituted with one, two, or three groups independently selected from halogen and -OH.
  • R 20d is Ci.mlkyl optionally substituted with one, two, or three groups independently selected from F and -OH.
  • R 20 ' 1 is Ci-,al ky 1 substituted with one, two, or three groups independently selected from halogen and -OR 21 .
  • R 2M is Ci- 3 alkyl substituted with one, two, or three groups independently selected from halogen and -OH.
  • R 20d is Ci.
  • R 20d is Ci- 3 alkyl substituted with one -OH.
  • R 20d is Ci- 3 alkyl substituted with one, two, or three F.
  • R 20d is isopropyl optionally substituted with one, two, or three groups independently selected from halogen and -OR 21 .
  • R 20d is isopropyl optionally substituted with one, two, or three groups independently selected from halogen and -OH.
  • R 20d is isopropyl optionally substituted with one, two, or three groups independently selected from halogen and -OH.
  • R 20d is isopropyl optionally substituted with one, two, or three groups independently selected from F and -OH.
  • R 20d is isopropyl substituted with one, two, or three groups independently selected from halogen and -OR 21 .
  • R 20d is isopropyl substituted with one, two, or three groups independently selected from halogen and -OH.
  • R 20d is isopropyl substituted with one, two, or three groups independently selected from F and -OH.
  • R 20d is isopropyl substituted with one, two, or three groups independently selected from F and -OH.
  • R 20d is isopropyl substituted with one -OH.
  • R 20d is isopropyl substituted with one, two, or three F.
  • R 20d is ethyl optionally substituted with one, two, or three groups independently selected from halogen and -OR 21 .
  • R 20d is ethyl optionally substituted with one, two, or three groups independently selected from halogen and -OH.
  • R 20d is ethyl optionally substituted with one, two, or three groups independently selected from F and -OH.
  • R 20d is ethyl optionally substituted with one, two, or three groups independently selected from F and -OH.
  • R 20d is ethyl substituted with one, two, or three groups independently selected from halogen and -OR 21 .
  • R 20d is ethyl substituted with one, two, or three groups independently selected from halogen and -OR 21 .
  • R 20d is ethyl substituted with one, two, or three groups independently selected from halogen and -OH.
  • R 20d is ethyl substituted with one, two, or three groups independently selected from F and -OH.
  • R 20d is ethyl substituted with one -OH.
  • R 20d is ethyl substituted with one, two, or three F.
  • R 20d is methyl optionally substituted with one, two, or three groups independently selected from halogen and -OR 21 .
  • R 20d is methyl optionally substituted with one, two, or three groups independently selected from halogen and -OH.
  • R 20d is methyl optionally substituted with one, two, or three groups independently selected from F and -OH.
  • R 20d is methyl substituted with one, two, or three groups independently selected from halogen and -OR 21 .
  • R 20d is methyl substituted with one, two, or three groups independently selected from halogen and -OH.
  • R 20d is methyl substituted with one, two, or three groups independently selected from F and -OH.
  • R 20d is methyl substituted with one -OH.

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Abstract

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

Description

HETEROCYCLES AND USES THEREOF
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/092,490, filed October 15, 2020, which is entirely incorporated herein by reference.
BACKGROUND
[0002] Cancer (e.g., tumor, neoplasm, metastases) is the second leading cause of death worldwide estimated to be responsible for about 10 million deaths each year. Many types of cancers are marked with mutations in one or more proteins involved in various signaling pathways leading to unregulated growth of cancerous cells. In some cases, about 25 to 30 percent (%) of tumors are known to harbor Rat sarcoma (Ras) mutations.
[0003] Activated by guanine nucleotide exciiatrge factors (GEFs), Ras in its GTP-bound state interacts with a number of effectors. Return to tire inactive state is driven by GTPase-activating proteins (GAPs), which down- regulate active Ras by accelerating the weak intrinsic GTPase activity. For oncogenic Ras mutants, however, the GAP activity is impaired or greatly reduced, resulting in persistent activation, which drives the oncogenic Ras signaling through, e.g.. the RAS-RAF-MEK-ERK and RAS-PI3K-PDK1-AKT pathways, both essential to cell survival and proliferation.
[0004] The most-studied GEF for Ras is the protein Son of Sevenless (SOS) for which two human isoforms, SOS I and S0S2, are known. S0S1 is a human homologue of the originally identified Drosophila protein Son of Sevenless. S0S1 has two binding sites for Ras protents: a catalytic site tliat binds GDP-bound Ras proteins io promote guanine nucleotide exchange and an allosteric site that binds GTP-bound Ras to further promote activation of Ras proteins. Son of Sevenless 2 (S0S2) is a homolog of SOS1 in mammalian cells. Double S0S1 and S0S2 knockout leads to rapid lethality in adult mice (Baitanas et al., Mol. Cell. Biol., 2013, 33(22):4562-78).
[0005] Although Kras is known to be an oncogenic driver, there is no clinically approved targeted therapy for Ras mutant cancers thus far. Ras proteins have long been considered to be "undruggable," due to, in part, high affinity to their substrate Guanosine-5'-triphosphate (GTP) and/or their smooth surfaces without any obvious targeting region. Recently, a specific G12C Ras gene mutation has been identified as a potential druggable target. However, such therapeutic approach is still limiting, as the G12C mutation in Ras has a low prevalence rate (e.g., about 3% in pancreatic ductal adenocarcinoma) as compared to other known Ras mutations.
SUMMARY
[0006] In view of the foregoing, there remains a considerable need for a new design of therapeutics and diagnostics that can specifically inhibit Ras pathway signaling by, e.g., inhibiting a GEF such as a SOS protein. Such compositions and methods can be particularly useful for treating a variety of the diseases including, but not limited to, cancers and neoplasia conditions. The present disclosure addresses these needs, and provides additional advantages applicable for diagnosis, prognosis, and treatment for a wide diversity of diseases.
[0007] In one aspect, the disclosure provides a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000003_0001
Formula (I’); wherein:
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
L1 is a bond or C1-6alkyl;
X and Y are selected from N(R2) and C(O), wherein one of X and Y is N(R2) and one of X and Y is C(O);
Z1, Z2, and Z3 are each independently selected from N and C(R3a), wherein at least one of Z1, Z2, and Z3 is N;
R2 is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyI. and C2-9heterocycloalkyI wherein C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20a;
R3 is selected from halogen, CN, C1-6alkyl, C2-6alkeny 1, C2-6 alkynyl, C3-14cycloalkyl, C2-9heterocycloalky 1, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, N(R14)S(O)R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(O)N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)JR15, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), CH2S(O) R15, -CH2S(O)N(R12)(R13), -CH2N(R12)S(O)(R13) and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 1 4cycloalkyk C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b; each R3a is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyI. C2-9heterocycloalkyl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R13, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2. 9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c;
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyI. C3-7cycloalkyI. C2. 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C1- 6 alkenyl. C2-6alkynyl, C3-7cycloalkyI. C2.
9, heterocycloalkyl. C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryI. wherein C1-6alkyl, C2-6 alkenyl. C2-6alkynyI. C3-7cycloalkyI. C2-9hetcrocycloalkyl. C6-10aryl, and C1-9heleroaryI are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky I: or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyI: each R15 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9hetcroaryI. wherein C1-6alkyl, C2-6alkcnyl. C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9hetcroaryI are optionally substituted with one, two, or three R20g; each R17 and each R17a are each independently selected from C1-6alkyl and C3-6cycloalkyI. wherein C1-6alkyl and C3- 6cycloalkyI are optionally substituted with one, two or three of R20h; or R17 and R17a form a C2-9cycloalkyl ring; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, C1- 6alkyl, C2-6 alkenyl. C2-6alkynyl, C3-10cycloalkyl. -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-ioaryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alky ny I. C3-10cycloalkyl, -CH2- C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyI. C1-6 alkoxy. C1- 6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyl. C2- gheterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl. C2. gheterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; and each R25 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl.
[0008] In some embodiments is a compound of Formula (I’) having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000005_0001
wherein:
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
L1 is a bond or C1-6alkyl;
X and Y are selected from N(R2) and C(O), wherein one of X and Y is N(R2) and one of X and Y is C(O);
Z1, Z2, and Z3 are each independently selected from N and C(R3a), wherein at least one of Z1, Z2, and Z3 is N;
R2 is selected from hydrogen, C1-6alkyl, C2-6alkenyl. C2-6alkynyl, and C3-10cycloalkyl-wherein C1-6alkyl, C2-6alkeny 1, C2-6alkynyl, and C3-10cycloalkyl are optionally substituted with one, two, or three R20a;
R3 is selected from halogen, C1-6alkyl, C2-6 alkenyl. C2-6alkynyI. C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1- 9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), - CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryI are optionally substituted with one, two, or three R20b; each R3a is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, CY alky ny I. C3- wcycloalkyl, C2-9heterocycloalkyl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R1J, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl. C3-10cycloalkyl. C2-9heterocycloalkyl, and C1- 9heteroaryl are optionally substituted with one, two, or three R20c;
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R10 is independently selected from halogen, -CN, C1-6alkyl, alkynyl, C,. -cycloalkyI. C2. sheterocycloalkyl, C6-10aryl, C1-9 heteroaryl. -OR12, -SR12, -N( O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15 (O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, - )2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)
Figure imgf000005_0002
2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6, alkenyl. C2-6alkynyl, C3-7cycloalkyl. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryI. wherein C1-6alkyl, C2-6alkenyl . C2-6alkynyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryI are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12 and R13, together with the nitrogen to which they are attached, form a C2-9lielerocycloalkyI ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R15 is independently selected C1-6alkyl, C2-6alkenyl, C1-6alkynyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6alkenyl, C2-6alkynyl, C3-7cycloalkyI, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; each R17 and each R17a are each independently selected from C1-6alkyl and C3-6 cycloalkyl, wherein C1-6alkyl and C3- 6 cycloalkyl are optionally substituted with one, two or three of R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -Clfe-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9 heterocycloalkyl. C6-10aryl, -CH2-C6-10aryl, C1-9 heteroary l. -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyI. C6-10aryl, -CH2-C3-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, Ci- ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaiy k each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; and each R25 is selected from C1-6alkyl, C2-6 alkenyl. C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl.
[0009] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is a bond.
[0010] In some embodiments is a compound of Formula (F) or Formula (I) having the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000006_0001
Formula (la).
[0011] In some embodiments is a compound of Formula (I’) or Formula (I) having the structure of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000007_0001
Formula (lb).
[0012] In some embodiments is a compound of Formula (F) or Formula (I) having the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000007_0002
Formula (Ic).
[0013] In some embodiments is a compound of Formula (I’) or Formula (I) having the structure of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000007_0003
Formula (Id).
[0014] In some embodiments is a compound of Formula (I’) or Formula (I) having the structure of Formula (le), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000007_0004
Formula (le).
[0015] In some embodiments is a compound of Formula (I’) or Formula (I) having the slriicuire of Formula (If), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000008_0001
Formula (If).
[0016] In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from -OR12, -N(R12)(R13), -C(O)R15, - C(O)N(R12)(R13), -SR12, -SOR12, -SO2(R12)(R13), -SO2N(R12)(R13), -P(O)(R17)(R17a), C1-6alkyl, C3-10cycloalkyl, C2. 9heterocycloalkyl, C3-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b.
In some embodiments is a compound of Formula (F), (I), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from -C(O)R15, -C(O)N(R12)(R13), C2-9helerocycloalkyI . C6- 10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le) or (If), wherein R3 is selected from -C(O)R15. In some embodiments is a compound of Formula (F), (I), (la), (lb), (Ic), (Id), (le) or (If), wherein R15 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20g.
[0017] In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C6-10aryl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C1-9heteroaryl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -C(O)N(R12)(R13).
[0018] In some embodiments is a compound of Formula (F), (I), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3a is independently selected from hydrogen, halogen, C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-10cycloalkyl, C2. gheterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3a is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3a is hydrogen.
[0019] In another aspect, the disclosure provides a compound of Formula (II'), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000009_0001
Formula (II');
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
R2 is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-10cycloalkyl wherein C1-6alkyl, C2-6 alkenyl. C2-6alkynyl, and C3-10cycloalkyl are optionally substituted with one, two, or three R20a;
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R6 is independently selected from halogen, -CN, C1-6alkyl, Ch-.alkcny I. C2-6alkynyl, C . ocycloalkyI. C2- 9 heterocycloalkyl. C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl. C2-9 heterocycloalkyl, C6- 10aryl, and C1-9 heteroaryI are optionally substituted with one, two, or three R20b;
R7 is selected from halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1- sheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R13, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), - CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyI. C2. 9heterocycloalkyl, C6-10aryl, C1-9heleroaryl -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkcnyl. C2-6alkynyl, C-. -cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky I: or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalkyI: each R15 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyI. C3-7cycloalkyI. C2-9 heterocycloalkyI. C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6alkeny 1, C1-6alky nyl, C3-7 cycloalkyl. C2-9heterocycloalky 1, C3-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R2°B; each R17 and each R17a are each independently selected from C1-6alkyl and C3-6, cycloalkyI. wherein C1-6alkyl and C3- 6cycloalkyl are optionally substituted with one, two or three of R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, Ci- ealkyl, C;., alkenyl. C1-6alkynyl, C..iocycloalkyk -CH2-C3-10cycloalkyl, C2- 9heterocycloalkyl. -CH2-C2- •.heterocycloalkyl. C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl. -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9>heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyI. C1-6 alkoxy. C1- 6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2. •.heterocycloalkyl. C6-10aryl, and C1-9heteroaryl each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl. C2.
• heterocycloalkyl. C6-10aryl, and C1-9heteroaryl each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; each R25 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl; and p is 0, 1, or 2.
[0020] In some embodiments is a compound of Formula (II’) having the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000010_0001
Formula (II);
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
R2 is selected from hydrogen, C1-6alkyI. C2-6alkenyl, C2-6alkynyl, and C3-10cycloalkyl wherein C1-6alkyI. C2-6alkenyl, C2-6alkynyl, and C3-10cy cloalky 1 are optionally substituted with one, two, or three R20a;
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R6 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkeny I. C2-6alkynyI. C3-10cycloalkyl, C2- 9 heterocycloalkyl. C6-10aryl, C1-9heteroaryl. -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R1J, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6 alkenyl. C2-6alkynyl, C3-10cycloalkyk C2-9heterocycloalkyl. C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b;
R7 is selected from halogen, C1-6alkyl, C2-6aIkenyl. C2-6alkynyl. C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1- 9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), - CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2.6alkenyl, C2-6alkynyl, C3-10cycloalkyl . C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2. 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R2M; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalky I. C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyI. C3-7 cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-9 ialoalky I: each R15 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; each R17 and each R17a are each independently selected from C1-6alkyl and C3-6cycloalkyl, wherein C1-6alkyl and C3- ecy cloalkyl are optionally substituted with one, two or three of R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R2011 are each independently selected from halogen, oxo, -CN, Ci- ealkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2. gheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9 hctcroaryl. -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, and C1-9heteroaryI are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalky I. C1-6 alkoxy. Ci- ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2. sheterocycloalkyl, C6-10aryl, and Ci-ehctcroaiyk each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C -cy cloalky I. C2. sheterocycloalkyl, C6-10aryl, and CiJietcroary k each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; each R25 is selected from C1-6alkyl, C2-6alkeny 1, C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl. C6-10ary 1, and Ci- •.heteroaryl: and p is 0, 1, or 2.
[0021] In some embodiments is a compound of Formula (II’) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from halogen, -OR12, -N(R12)(R13), -SR12, -SOR12, -SO2(R12)(R13), - SO2N(R12)(R13), -P(O)(R17)(R17a), C1-6alkyl, C3-10cycloalkyl, Ci-yhclcrocycloalkyl. C6-10aryl, and Ci.Jictcroaiy I. wherein C1-6alkyl, C3-10cycloalkyl, C2-6heterocycloalkyl, C6-10aryl, and CiJictcroaryl are optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II') or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from C1-6alkyl, C ,. wcy cloalky 1, C2.<;heterocycloalky I. Ce- icaryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c.
[0022] In some embodiments is a compound of Formula (II') or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, C1-6alkyl, Cj.iocycloalkyl, C2. ■Jictcrocvcloalky I. C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalky 1, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (II’) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and optionally substituted with one, two, or three R20b C1-6alkyl.
[0023] In some embodiments is a compound of Formula (II’) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[0024] In another aspect, the disclosure provides a compound of Formula (III’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000012_0001
Formula (III’);
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered atyl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10; R2 is selected from hydrogen, C1-6alkyl, C1-6alkeny 1, C2-6alkynyl, C3-10cycloalkyI. wherein C1-6alkyl, C2.oalkeny 1, C2- 6alkynyl, and C3-10cycloalkyl are optionally substituted with one, two, or three R20a;
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alkyl, and C1-6 haloalky 1; each R8 is independently selected from halogen, -CN, C1-6alky 1, C2-6 alkenyl. C2-6alkynyl, C . ocycloalky I. C2. sheterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, Cj-salkenyl, C2-6alkynyl, C . ocycloalkyl. C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b;
R9 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, Ci- sheteroaryl, -C(O)OR12, -C(O)R15, -S(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, and - S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9hcteroary I are optionally substituted with one, two, or three R20c; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2- sheterocycloalkyl, Uioaryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C . -cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R2M; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, Co. -cycloalky 1, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky I: or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky I: each R15 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Cy. -cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C3-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; each R17 and each R17a are each independently selected from C1-6alkyl and Co.ocycloalkyl, wherein C|.,,alky I and C3- ocycloalkyl are optionally substituted with one, two or three of R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R2011 are each independently selected from halogen, oxo, -CN, Ci- ealkyl, Cwalkenyl, Cs-ealkynyl, C3-10cycloalkyl, -CHi-Ci-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2. gheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CHs-C6-10aryl, and Ci.Jictcroary l are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalky I. C1-6 alkoxy. C1- 6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C-.-cy cloalky I. C2.
•.heterocycloalkyl. C6-10aryl, and C1-9heteroaryl: each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cy cloalky 1, C2.
• heterocycloalkyl. C6-10aryl, and C1-9heteroaryl; each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; each R25 is selected from C1-6alkyl, C2-6 alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyI. C6-10ary 1, and C1- 9 heteroaryl: and p is 0, 1, or 2.
[0025] In some embodiments is a compound of Formula (III’) having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000014_0001
Formula (III);
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
R2 is selected from hydrogen, C1-6alkyl, C2-6 alkenyl, C2-6alkynyl, C3-10cycloalkyI. wherein C1-6alkyl, C2-6alkeny 1, C2- 6alkynyl, and C3-10cycloalkyl are optionally substituted with one, two, or three R20a;
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R8 is independently selected from halogen, -CN, C1-6alkyl, C2- , alkenyl. C2-6alkynyl, C3-10cycloalkyI. C2.
9 heterocycloalkyl. C6-10aryl, C1-9heteroaryl. -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R1J, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-9alkenyl, C2-6alkynyl, C3-10cycloaIkyl . C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b;
R9 is selected from C1-6alkyl, C2-6alkenyl, C2-6alky ny I. C3-10cycloalkyl, C2-9heterocycloalkyI. C6-10aryl, C1- 9heteroaryl, -C(O)OR12, -C(O)R15, -S(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, and - S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2.salkynyl, C-,. -cycloalky I. C2- sheterocycloalkyl, C6-10aryl, C .dictcroaryl. -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R1J, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CHjC(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C . -cycloalkyI. C2-9heterocycloalkyl. C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three R20d; each R12 is independently selected from hydrogen, C1-9alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryl. wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl. C3-7 cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9 ictcroary I are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky I: or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky I: each R15 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C-,. -cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9hctcroaiy l. wherein C1-6alkyl, G-ealkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; each R17 and each R17a are each independently selected from C1-6alkyl and C3-6 cycloalkyl, wherein C1-9alky 1 and C3- 6 cycloalkyl are optionally substituted with one, two or three of R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20®, and R20h are each independently selected from halogen, oxo, -CN, C1- 6alkyl, C2., alkenyl. C2-6alkynyl, C3-10cycloalkyl, -CH2- C3-10cycloalkyl, Cwheterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -Clt-C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6 haloalkyI. C1-6 alkoxy. C1- 6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C1-6alkenyl, C2-6alkynyl, C3-7 cy cloalky 1, C2- gheterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C-.-cy cloalky I. C2. gheterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; each R25 is selected from C1-6alkyl, C2-6 alkenyl. C2.(,alkynyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and Ci- • hcleroaiy k and p is 0, 1, or 2.
[0026] In some embodiments is a compound of Formula (III’) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is selected from C1-6alkyl, C3-10cycloalky 1, C2-9heterocycloalkyl, C6-10aryl, and C1- gheteroaryl, wherein C1-6alkyl, Ci.iocycloalkyl. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is selected from C2-9heterocycloalky 1, C3-10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c.
[0027] In some embodiments is a compound of Formula (III’) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen, C1-6alkyl, C3-10cycloalkyl, Cz- gheterocycloalkyl, C3-10aryl, and C1-9heteroaryl, wherein C1-6alky 1, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (III’) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen and C1-6 alkyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (III’) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen and unsubstituted C1-9alky 1.
[0028] In some embodiments is a compound of (III’) or Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
[0029] In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from C1-6alkyl and C1- 6haloalkyl. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CH3.
[0030] In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen.
[0031] In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three R20a. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C1-6alkyl optionally substituted with one, two, or three R20a. In some embodiments is a compound of Formula (I’),
(I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (!’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is - hydrogen.
[0032] In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a 6-10 membered aryl ring substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’),
(II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl substituted with one, two, or three R10. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or
(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a 5-10 membered heteroaryl ring are substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a 5-10 membered heteroaryl ring are substituted with one, two, or three R10.
[0033] In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R10 is independently selected from halogen, C1-6alkyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, and N(R12)(R13), wherein C1-6alkyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R10 is independently selected from halogen, C1-9alkyl, and N(R12)(R13), wherein C1-6alkyI is optionally substituted with one, two, or three R20d. In some embodiments is a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R10 is independently selected from halogen, Ci- ealkyl, and N(R12)(R13), wherein C1-6alky I is substituted with one, two, or three R20d, and each R20d is halogen.
[0034] Also provided in the present disclosure is a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a solid tumor or a hematological cancer.
[0035] Also provided herein is a method of reducing Ras signaling output comprising contacting a SOS 1 protein with an effective amount of a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, thereby reducing the Ras signaling output. In some embodiments is a method of reducing Ras signaling output of a SOS1 protein comprising contacting a S0S1 protein with an effective amount of a compound of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein said reducing the Ras signaling output. In some embodiments, a subject compound interferes or disrupts the interaction or binding between a SOS protein (e.g., S0S1) with a Ras protein (e.g., wildtype or a mutant Ras).
[0036] Further provided herein is a method of inhibiting cell growth, comprising administering a cell expressing S0S1 with an effective amount of a compound of Formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, thereby inhibiting growth of said cells. The method may further comprise administering to the cell an additional agent. Where desired, the additional agent can be an inhibitor against one or more targets including but not limited to: The method of claim 60, wherein the additional agent is an inhibitor against one or more targets including but not limited to: MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, FGFR4, mitotic kinase, topoisomerase, ALK, c-MET, ErbB2, AXL, NTRK1, RET, A-Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF1/2, IGF1-R, CDK9, SHC, GAB, GRB, PI3-kinase, MAPK, SHIP1, SHIP2, SHP1, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, wildtype KRas, KRas mutant (e.g., KrasG12C, KRas G12D, KRas G12S, KRas G12V, KRas G13D, KRas G13C, or KRas G13V)„ ROS1, CDK4/6, and a mutant of any target thereof. In some embodiments, the additional agent is a chemotherapeutic agent, a radioactive agent, or an immune modulator. [0037] Also provided herein is a modified SOS 1 protein bound by a compound of Formula (F), (I), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein interaction of the S0S1 protein with a Ras protein is reduced as compared to a S0S1 protein unbound to said compound.
INCORPORATION BY REFERENCE
[0038] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
DETAILED DESCRIPTION
[0039] The practice of some embodiments disclosed herein employ, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA, which are within the skill of the art. See for example Sambrook and Green, Molecular Cloning: A Laboratory Manual, 4th Edition (2012); the series Current Protocols in Molecular Biology (F. M. Ausubel, et al. eds.); the series Methods In Enzymology (Academic Press, Inc.), PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6th Edition (R.I. Freshney, ed. (2010)).
[0040] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet Reference thereto evidences the availability and public dissemination of such information.
[0041] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.
[0042] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
[0043] Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg "Advanced Organic Chemistry 4th Ed." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology.
[0044] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification. [0045] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein.
[0046] As used herein, C1-Cx includes C1-C2, C1-C3 . . . C1-Cx. C1-Cx refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).
[0047] An "alkyl" group refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. In some embodiments, the "alkyl" group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as " 1 to 6" refers to each integer in the given range; e.g. , "1 to 6 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group of the compounds described herein may be designated as "C1-C6alkyI" or similar designations. By way of example only, "C1-C6alkyl" indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).
[0048] An "alkoxy" refers to a "-O-alkyl" group, where alkyl is as defined herein.
[0049] The term "alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2 and -C(CH3)=CHCH3. In some embodiments, an alkenyl groups may have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).
[0050] The term "alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond. Non-limiting examples of an alkynyl group include -C≡CH, -C≡CCH3, -C≡CCH2CH3 and -C≡CCH2CH2CH3. In some embodiments, an alkynyl group can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).
[0051] "Amino" refers to a -NH2 group.
[0052] The term "alkylamine" or "alkylamino" refers to the -N(alkyl)xHy group, where alkyl is as defined herein and x and y are selected from the group x=l, y=1 and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen to which they are attached, can optionally form a cyclic ring system. "Dialkylamino" refers to a -N(alkyl)2 group, where alkyl is as defined herein.
[0053] The term "aromatic" refers to a planar ring having a delocalized 71 -electron system containing 4n+2 π electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).
[0054] As used herein, the term "aryl" refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e an arylene group).
[0055] "Carboxy" refers to -CO2H. In some embodiments, carboxy moieties may be replaced with a "carboxylic acid bioisostere", which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic
Figure imgf000020_0001
acid include, but are not limited to, OH
Figure imgf000020_0002
and the like.
[0056] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated or partially unsaturated. In some embodiments, a cycloalkyl ring is fused with an aryl, heteroaryl, heterocycloalkyl, or a second cycloalkyl ring. In some embodiments, a cycloalkyl ring is a spirocyclic cycloalkyl ring. In some embodiments, cycloalkyl groups include groups having from 3 to 10 ring atoms. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (i.e., a cycloalkylene group).
[0057] The terms "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, or tricyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated. An V- containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group).
[0058] A "heterocycloalkyl" group or "heteroalicyclic" group refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. Heterocycloalkyls may be saturated or partially unsaturated. In some embodiments, a heterocycloalkyl ring is fused with an aryl, heteroaryl, cycloalkyl, or a second heterocycloalkyl ring. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In some embodiments, a heterocycloalkyl ring is a spirocyclic heterocycloalkyl ring. In some embodiments, a heterocycloalkyl ring is a bridged heterocycloalkyl ring. 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). Depending on the structure, a heterocycloalkyl group can be a monoradical or a diradical (i.e., a heterocycloalkylene group).
[0059] The term "halo" or, alternatively, "halogen" means fluoro, chloro, bromo and iodo.
[0060] The term "haloalky 1" refers to an alkyl group that is substituted with one or more halogens. The halogens may the same or they may be different. Non-limiting examples of haloalkyls include -CH2C1, -CF3, -CHF2, - CH2CF3, -CF2CF3, and the like.
[0061] The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyls include -CF3, -CHF2, -CH2F, - CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH3)3, and the like. Non-limiting examples of fluoroalkoxy groups, include - OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2, and the like.
[0062] The term "heteroalkyl" refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, - CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-NH-OCH3, -CH2-O- Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Excluding the number of heteroatoms, a "heteroalkyl" may have from 1 to 6 carbon atoms.
[0063] The term "oxo" refers to the =0 radical.
[0064] The term "bond" or "single bond" refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
[0065] The term "moiety" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
[0066] As used herein, the substituent "R" appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalky 1, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.
[0067] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.
[0068] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, - CN, alkyne, C -Galky lalkyne, halo, acyl, acyloxy, -CO2H, -COi-alkyl. nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g. -NH2, -NHR, -N(R)2), and the protected derivatives thereof. By way of example, an optional substituents may be LSRS, wherein each Ls is independently selected from a bond, - O-, -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -NH-, -NHC(O)-, -C(O)NH-, S(=O)2NH-, -NHS(=O)2, -OC(O)NH-, - NHC(O)O-, -(C1-C6 alkyl)-, or -(C2-C6alkenyl)-; and each Rs is independently selected from among H, ( C1-C6alkyI). (C3-C8cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C1-C6heteroalkyl. The protecting groups that may form the protective derivatives of the above substituents are found in sources such as Greene and Wuts, above.
[0069] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
[0070] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, tiifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
[0071] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, V, V-dibcnzvlcthylcncdiaminc. chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A-mcthy Iglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine. polyamine resins and the like. See Berge et al., supra.
[0072] The terms "polypeptide", "peptide" and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. As used herein the term "amino acid" refers to either natural and/or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics.
[0073] The terms "polynucleotide", "nucleotide", "nucleotide sequence", "nucleic acid" and "oligonucleotide" are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or noncoding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acid (PNA), Morpholino and locked nucleic acid (LNA), glycol nucleic acid (GNA), threose nucleic acid (TNA), 2’-fluoro, 2’-OMe, and phosphorothiolated DNA. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.
[0074] As used herein, "expression" refers to the process by which a polynucleotide is transcribed from a DNA template (such as into and mRNA or other RNA transcript) and/or the process by which a transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins. Transcripts and encoded polypeptides may be collectively referred to as "gene product." If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaiyotic cell.
[0075] The terms "subject," "individual," and "patient" are used interchangeably herein to refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.
[0076] The terms "therapeutic agent", "therapeutic capable agent" or "treatment agent" are used interchangeably and refer to a molecule or compound that confers some beneficial effect upon administration to a subject. The beneficial effect includes enablement of diagnostic determinations; amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or pathological condition.
[0077] 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 a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms under treatment. For prophylactic benefit, the compositions may be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject reporting one or more of the physiological symptoms of a disease, even though the disease, condition, or symptom may not have yet been manifested. Typically, prophylactic benefit includes reducing the incidence and/or worsening of one or more diseases, conditions, or symptoms under treatment (e.g. as between treated and untreated populations, or between treated and untreated states of a subject).
[0078] The term "effective amount" or "therapeutically effective amount" refers to the amount of an agent that is sufficient to effect beneficial or desired results. The therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. An effective amount of an active agent may be administered in a single dose or in multiple doses. A component may be described herein as having at least an effective amount, or at least an amount effective, such as that associated with a particular goal or purpose, such as any described herein. The term "effective amount" also applies to a dose that will provide an image for detection by an appropriate imaging method. The specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.
[0079] An "antigen" is a moiety or molecule that contains an epitope, and, as such, also specifically binds to an antibody.
[0080] An "antigen binding unit" may be whole or a fragment (or fragments) of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof. A full-length antibody may be, for example, a monoclonal, recombinant, chimeric, deimmunized, humanized and human antibody. Examples of a fragment of a full-length antibody may include, but are not limited to, variable heavy (VH), variable light (VL), a heavy chain found in camelids, such as camels, llamas, and alpacas (VHH or VHH), a heavy chain found in sharks (V-NAR domain), a single domain antibody (sdAb, i.e., "nanobody") that comprises a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and "r IgG" (or half antibody). Examples of modified fragments of antibodies may include, but are not limited to scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single chain diabodies, tandem diabodies (Tandab's), tandem di-scFv, tandem tri-scFv, minibodies (e.g., (VH-VL-CH3 )2, (scFv- CH3 )2, ((scFv)2-CH3 +CH3 ), ((scFv)2-CH3 ) or (scFv-CH3 -scFv)2), and multibodies (e.g., triabodies or tetrabodies).
[0081] The term "antibody" and "antibodies" encompass any antigen binding units, including without limitation: monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, and any other epitope-binding fragments.
[0082] The term “in vivo” refers to an event that takes place in a subject’s body.
[0083] The term “ex vivo” refers to an event that first takes place outside of the subject’s body for a subsequent in vivo application into a subject’s body. For example, an ex vivo preparation may involve preparation of cells outside of a subject’s body for the purpose of introduction of the prepared cells into the same or a different subject’s body. [0084] The term “in vitro” refers to an event that takes place outside of a subject’s body. For example, an in vitro assay encompasses any assay run outside of a subject’s body. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.
[0085] The term "Ras" or "RAS" refers to a protein in the Rat sarcoma (Ras) superfamily of small GTPases, such as in the Ras subfamily. The Ras superfamily includes, but is not limited to, the Ras subfamily, Rho subfamily, Rab subfamily, Rap subfamily, Arf subfamily, Ran subfamily, Rheb subfamily, RGK subfamily, Rit subfamily, Miro subfamily, and Unclassified subfamily. In some embodiments, a Ras protein is selected from the group consisting of KRAS (K-Ras or K-ras or Kras), HRAS (or H-Ras), NRAS (or N-Ras), MRAS (or M-Ras), ERAS (or E-Ras), RRAS2 (or R-Ras2), RALA (or RalA), RALB (or RalB), RIT1, and any combination thereof, such as from KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.
[0086] The terms "Mutant Ras" and "Ras mutant," as used interchangeably herein, refer to a Ras protein with one or more amino acid mutations, such as with respect to a common reference sequence such as a wild-type (WT) sequence. In some embodiments, a mutant Ras is selected from a mutant KRAS, mutant HRAS, mutant NRAS, mutant MRAS, mutant ERAS, mutant RRAS2, mutant RALA, mutant RALB, mutant RIT1, and any combination thereof, such as from a mutant KRAS, mutant HRAS, mutant NRAS, mutant RALA, mutant RALB, and any combination thereof. In some embodiments, a mutation can be an introduced mutation, a naturally occurring mutation, or a non-naturally occurring mutation. In some embodiments, a mutation can be a substitution (e.g., a substituted amino acid), insertion (e.g., addition of one or more amino acids), or deletion (e.g., removal of one or more amino acids). In some embodiments, two or more mutations can be consecutive, non-consecutive, or a combination thereof. In some embodiments, a mutation can be present at any position of Ras. In some embodiments, a mutation can be present at position 12, 13, 62, 92, 95, or any combination thereof of Ras relative to SEQ ID No. 1 when optimally aligned. In some embodiments, a mutant Ras may comprise about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more than 50 mutations. In some embodiments, a mutant Ras may comprise up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mutations. In some embodiments, the mutant Ras is about or up to about 500, 400, 300, 250, 240, 233, 230, 220, 219, 210, 208, 206, 204, 200, 195, 190, 189, 188, 187, 186, 185, 180, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 160, 155, 150, 125, 100, 90, 80, 70, 60, 50, or fewer than 50 amino acids in length. In some embodiments, an amino acid of a mutation is a proteinogenic, natural, standard, non-standard, non- canonical, essential, non-essential, or non-natural amino acid. In some embodiments, an amino acid of a mutation has a positively charged side chain, a negatively charged side chain, a polar uncharged side chain, a non-polar side chain, a hydrophobic side chain, a hydrophilic side chain, an aliphatic side chain, an aromatic side chain, a cyclic side chain, an acyclic side chain, a basic side chain, or an acidic side chain. In some embodiments, a mutation comprises a reactive moiety. In some embodiments, a substituted amino acid comprises a reactive moiety. In some embodiments, a mutant Ras can be further modified, such as by conjugation with a detectable label. In some embodiments, a mutant Ras is a full-length or truncated polypeptide. For example, a mutant Ras can be a truncated polypeptide comprising residues 1-169 or residues 11-183 (e.g., residues 11-183 of a mutant RALA or mutant RALB).
Compounds
[0087] The compounds of Formula (I’), (I), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (III’), or (III), or a pharmaceutically acceptable salt or solvate thereof, disclosed herein are SOS modulators and have a wide range of applications in therapeutics, diagnostics, and other biomedical research.
[0088] In one aspect, the disclosure provides a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000025_0001
wherein:
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
L1 is a bond or C1-6alkyl;
X and Y are selected from N(R2) and C(O), wherein one of X and Y is N(R2) and one of X and Y is C(O); Z1, Z2, and Z3 are each independently selected from N and C(R3a), wherein at least one of Z1, Z2, and Z3 is N;
R2 is selected from hydrogen, C1-6alkyl, alkenyl. C2-6alkynyI. C3 -10cycloalkyI. and C2-9heterocycloalkyl wherein C1-6alkyl, C2-6alkenyl . C1-9alkynyl, C3-10cy cloalky 1, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20a;
R3 is selected from halogen, CN, C1-6alkyl, C2-6alkeny 1, C2-6alkynyI. C3-14cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, N(R14)S(O)R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(O)N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R1S, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), CH2S(O) R15, -CH2S(O)N(R12)(R13), -CH2N(R12)S(O)(R13) and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6 alkenyl, C2-6alky ny I. C3-1 icycloalkyl. C2-9heterocycloalkyl, C6-10aryl, and C1-9hctcroaryI are optionally substituted with one, two, or three R20b; each R3a is independently selected from hydrogen, halogen, -CN, C1-9alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R1J, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2. •.heterocycloalkyl, and C1-9heteroary 1 are optionally substituted with one, two, or three R20c;
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C,. -cycloalky I. C2.
• hclerocycloalkyl. C6-10aryl, C1-9 heteroaryl. -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2.,alkenyl. C2-6alkynyl, C.. -cycloalkyI. C2.
• hclerocycloalkyl. C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkynyl. C2-6alkynyl, C3-7 cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryI. wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryI are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky I: or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky 1; each R15 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and Ci-whcteroary I. wherein C1-6alkyl, C2-6alkenyl, C C2-6alkynyl, C3-7 cycloalkyI, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R2°B; each R17 and each R17a are each independently selected from C1-6alkyl and C3-6 cycloalkyl, wherein Ci-6 alkyl and C3- 6cy cloalky 1 are optionally substituted with one, two or three of R20h; or R17 and R17a form a C2-9cy cloalky 1 ring; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, C1- 6alkyl, C2-6 alkenyl. C2-6alkynyl. CYiocycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalky . -CH2-C2- 9 hctcrocycloalkyl. C6-10aryl, -ClR-C3-10aryl, C1-9 ictcroary l. -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -
C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6 alkenyl. C2-6alkynyI. C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, and C1-9heteroary l are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6 haloalkyI.
Figure imgf000027_0001
alkoxy. Ci. ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cy cloalky I. C2- sheterocycloalkyl, C6-10aryl, and CiJielcroary k each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cy cloalky I. C2-
• heterocycloalkyl. C6-10aryl, and C1-9heteroaryl; each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; and each R25 is selected from C1-6 aIky 1, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C1-9heterocycloalkyl, C3-10aryl, and Ci. siheteroaryl.
[0089] In some embodiments is a compound of Formula (I’) having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000027_0002
Formula (I); wherein:
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
L1 is a bond or C1-6alkyl;
X and Y are selected from N(R2) and C(O), wherein one of X and Y is N(R2) and one of X and Y is C(O);
Z1, Z2, and Z3 are each independently selected from N and C(R3a), wherein at least one of Z1, Z2, and Z3 is N;
R2 is selected from hydrogen, C1-6alkyl, C2-6 alkenyl. C2-6alkynyl, and C3-cycloalkyl -wherein C1-6alkyl, CS- .alkeny I. C2-6alkynyl, and C3-10cy cloalky 1 are optionally substituted with one, two, or three R20a;
R3 is selected from halogen, C1-6alkyl, CYr, alkenyl. CY-,alky ny I. C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1- 9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), - CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, Cwalkynyl, C3-10 cycloalkyl, C2-9heterocy cloalky 1, C6-10aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R20b; each R3a is independently selected from hydrogen, halogen, -CN, C1-6alky 1, C2-6alkenyl, C2-6alkynyl, C3-10 cycloalkyl, C2-9heterocycloalkyl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R1S, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C -ocycloalkyl. C2-9heterocycloalkyl. and C1- 9heteroaryl are optionally substituted with one, two, or three R20c;
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C-,. -cycloalkyI. C2.
• heterocycloalkyl. C6-10aryl, C1-9heteroaryl. -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R13, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2.,,alkenyl. C2-6alkynyl, C-. -cycloalkyl, C2-9heterocycloalky . C3-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R2M; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2.<>heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky I: or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky 1; each R15 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C-,. -cycloalky 1, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6 alkenyl. C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; each R17 and each R17a are each independently selected from C1-6alkyl and C3-6 cycloalkyI. wherein C1-6alky 1 and C-,.
, cycloalkyl are optionally substituted with one, two or three of R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, Ci- ralkyl. C2., alkenyl. C2-6alkynyl, C3-10 cycloalkyl. -CH2- C3-10 cycloalkyl, C2-9heterocycloalkyl, -CH2-C2. sheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cy cloalky 1, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, and Ciohctcroary l are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C .„alkoxy. C1- 6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6 haloalky 1, C2-6alkenyl, C2-6alky nyl, C3-7 cycloalkyl, C2.
9, heterocycloalkyl. C6-10aryl, and C1-9heteroaryl; each R22 is independently selected from H, C1-6alkyl, C .„haloalky I. C2.,, alkenyl. C2-6alkynyl, C3-7 cloalkyI. C2. 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; and each R25 is selected from C1-6alkyl, C2-6 alkenyl. C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl.
[0090] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is a bond.
[0091] In some embodiments is a compound of Formula (I) having the structure of Formula (1-1), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000029_0001
Formula (1-1).
[0092] In some embodiments is a compound of Formula (I) having the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000029_0002
Formula (la).
[0093] In some embodiments is a compound of Formula (I) having the structure of Formula (lb) , or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000029_0003
Formula (lb). [0094] In some embodiments is a compound of Formula (I) having the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000030_0001
Formula (Ic).
[0095] In some embodiments is a compound of Formula (I) having the slnictu rc of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000030_0002
Formula (Id).
[0096] In some embodiments is a compound of Formula (I) having the structure of Formula (le), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000030_0003
Formula (le).
[0097] In some embodiments is a compound of Formula (I) having the slnictu re of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000030_0004
Formula (If).
[0098] In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from -OR12, -N(R12)(R13), -C(O)R15, - C(O)N(R12)(R13), -SR12, -SOR12, -SO2(R12)(R13), -SO2N(R12)(R13), -P(O)(R17)(R17a), C1-6alkyl, C3-10cycloalkyl, C2. sheterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-10cycloalkyl, C2-sheterocycloalkyl, C6-10aryl, and C . Jieteroary 1 are optionally substituted with one, two, or three R20b.
[0099] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from -C(O)R15, -C(O)N(R12)(R13), CS. sheterocycloalkyl, C3-10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), wherein R3 is selected from -C(O)R15. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (Id), (le) or (If), wherein R15 is C1-6heterocycloalkyl optionally substituted with one, two, or three R20g.
[00100] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (1), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is spirocyclic C2-s>heterocycloalkyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is fused C2- sheterocycloalkyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C6-10aryl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is fused C6-10aryl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C1-9heteroaryl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is fused C1-9heteroaryl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -C(O)N(R12)(R13).
[00101] In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R15 is C1-9heterocycloalkyl optionally substituted with one, two, or three R20g. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceuticalty acceptable salt or solvate thereof, wherein R15 is spirocyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R20g. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R15 is fused C2- shelerocycloalkyI optionally substituted with one, two, or three R20g.
[00102] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C1-6alkyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OR12. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -N(R12)(R13). In some embodiments is a compound of Formula (F), (I), (I- 1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. [00103] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is cyclopropyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is cyclobutyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is cyclopentyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is cyclohexyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is aziridinyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is azetidinyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is pyrrolidinyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is piperidinyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is piperizinyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is morpholinyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is oxetanyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is tetrahydrofuranyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is tetrahydropyranyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is pyridinyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is pyrazinyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is pyrimidinyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is pyridazinyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is phenyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is pyrazolyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is pyrrolyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is thiophenyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is thianyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is 1,3-imidazolyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is thiazolyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is oxepanyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is azepanyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is 1,4-dioxapanyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is 1,4-oxazepanyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is 2,6-diazaspiro[3.3]heptanyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is 2-oxa-6- azaspiro[3.3]heptanyl optionally substituted with one, two, or three R20b.
[00104] In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is G.i icycloalkyI. including C6-14cycloalkyI. C6-9cycloalkyl, C3-7cycloalkyl, C3-6cycloalkyl, C3-5cycloalkyk and C3-4cycloalkyl, each of which being optionally substituted with one, two, or three R20b. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is G, - icycloalkyI optionally substituted with one, two, or three R20b. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is G.ecycloalkyl optionally substituted with one, two, or three R20b. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is G. cycloalkyl optionally substituted with one, two, or three R20b. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is G.ecycloalkyl optionally substituted with one, two, or three R20b. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-5cycloalkyI optionally substituted with one, two, or three R20b. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-4cycloalkyl optionally substituted with one, two, or three R20b.
[00105] In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-14cycloalky k including C6-14cycloalkyl C6-9cycloalky k C3-7cycloalkyl, G.ecycloalkyI. C3-5cycloalkyk and C3-4cycloalkyI. each of which being substituted with one, two, or three R20b. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI substituted with one, two, or three R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-9cycloalkyl substituted with one, two, or three R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C .K'ycloalkyl substituted with one, two, or three R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (II), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3- 6, cycloalkyl substituted with one, two, or three R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-5cycloalkyl substituted with one, two, or three R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-4cycloalkyl substituted with one, two, or three R20b.
[00106] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C1-1 icycloalkyI. including C,-i icycloalkyI. Ce-gcycloalky 1, C3-7cycloalkyl, C3-6cycloalkyl, C3-5cycloalkyl, and C3-4cycloalkyl, each of which being optionally substituted with one R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloaIkyI optionally substituted with one R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-9 cycloalkyl optionally substituted with one R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-7 cycloalky I optionally substituted with one R20b. In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3- 6 cycloalkyl optionally substituted with one R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (II), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-5cycloalkyl optionally substituted with one R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C i. icycloalkyI optionally substituted with one R20b.
[00107] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-14cycloalkyI. including C6-14cycloalkyI. C6-9cycloalkyI. C3-7cycloalkyl, C3-6cycloalkyl, C3-5cycloalkyl, and C3-4cycloalkyl, each of which being optionally substituted with two R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI optionally substituted with two R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-9cycloalkyl optionally substituted with two R20b. In embodiments of a compound of Formula (I'), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-7cycloalkyl optionally substituted with two R20b. In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3- 6, cycloalkyl optionally substituted with one R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (II), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-5cycloalkyl optionally substituted with two R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-4cycloalkyl optionally substituted with two R20b. [00108] In each of the above embodiments, R20b is independently selected from amino, -CN, C1-9alkyl, C1.3 alkoxy, C1-9haloalkyl, -OH, -N(R24)C(O)R25, and -C(O)N(R22)(R23). In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is amino. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -CN. In some embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (II), or a pharmaceutically acceptable salt or solvate thereof, R20b is Ci-aalkyl. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is Ci.ialkoxy . In some embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is C 1 haloa Iky 1 In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is —OH. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -N(R24)C(O)R25. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -C(O)N(R22)(R23). In some embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is - NHC(O)R25. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -C(O)NH(R22). In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -NHC(O)R25 and R25 is C).<;hetcrocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C1-9alkyl, C1-6haloalkyl, C1-6alkoxy, C3-7cycloalkyI. C2-9heterocycloalkyl. C6-10aryl, and C1- 9heteroaryl. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -C(O)NH(R22) and R22 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -NHC(O)R25 and R25 is C2-5heterocycloalkyI optionally substituted with one C1-6alkyl. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -C(O)NH(R22) and R22 is C2-5heterocycloalkyI optionally substituted with one C1-6alkyl.
[00109] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI (including C6-14cycloalkyI. C6-9cycloalkyl, C3-7cycloalkyl, C3-6cycloalkyl, C3-5cycloalkyI. and C3-4cycloalkyl), optionally substituted with one, two, or three R20b that is amino. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (II), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI (including C6-14cycloalkyl, C6-9cycloalkyl, C3-7cycloalkyl. C3-6cycloalkyl, C3-5cycloalkyI, and C3-4cycloalkyl). optionally substituted with one, two, or three R20b that is -CN. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI (including G.i icycloalkyI. C6-9cycloalkyl, C3-7cycloalkyl, C3-6cycloalkyl. C3-5cycloalkyl, and C3-4cycloalkyl), optionally substituted with one, two, or three R20b that is C1-9alkyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI (including C6-14cycloalkyI. C6-9cycloalkyl. C3-4cycloalkyl, C3-6cycloalkyl. C3-5cycloalkyl, and C3-4cycloalkyl). optionally substituted with one, two, or three R20b that is C1-3alkoxy. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI (including C6-14 icycloalkyl, C6-9cycloalkyl. C3-7cycloalkyl. C3-6cycloalkyl. C3-5cycloalkyI, and C3-4cycloalkyl). optionally substituted with one, two, or three R20b that is C -.haloalky I. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI (including C6-14cycloalkyI. C6-9cycloalkyl, C3-7cycloalkyl, C3-6cycloalkyl, C3-5cycloalkyl, and C3-4cycloalkyl), optionally substituted with one, two, or three R20b that is -OH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI (including C6-14cycloalkyI. C6-9cycloalkyl, C3-7cycloalkyl, C3-6cycloalkyl, C3-5cycloalkyI, and C3-4cycloalkyl), optionally substituted with one, two, or three R20b that is oxo. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI (including C6-14cycloalkyI. C6-9cycloalkyl, C3-7cycloalkyl, C3-6cycloalkyl, C3-5cycloalkyI. and C3-4cycloalkyl), optionally substituted with one, two, or three R20b that is -N(R24)C(O)R25. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI (including C6-14cycloalkyI, G. scycloalkyl, C3-7cycloalkyl, C3-5cycloalkyI. C3-5cycloalkyI, and C3-4cycloalkyl). optionally substituted with one, two, or three R20b that is -NHC(O)R25. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI (including C6-14cycloalkyI, C6- 9icycloalkyI. C3-7cycloalkyl, C3-6 cycloalkyl, C3-5cycloalkyI. and C3-4cycloalkyl). optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2-9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalky I. C1-6alkoxy, G. -cycloalkyI. C2- sheterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI (including C6- 14cycloalkyl, C6-9cycloalkyl. C3-7cycloalkyl, C3-6cycloalkyl, C3-5cycloalkyI. and C3-4cycloalkyl). optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2-5heterocycloalkyI optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI (including C6-14cycloalkyI. C6-9cycloalkyl, Cs-7cycloalkyl, Cs-gcycloalkyl, C3-5cycloalkyI. and C3-4cycloalkyl), optionally substituted with one, two, or three R20b that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-1 4cycloalkyI (including G.1 icycloalkyI. C6-
9 cycloalkyl. C3-7cycloalkyl, C3-6cycloalkyl, C3-5cycloalkyI. and C3-4cycloalkyl), optionally substituted with one, two, or three R20b that is -C(O)NH(R22). In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is G,.i icycloalkyI (including C6-14cycloalkyl. C6-9cycloalkyl, G.-cycloalkyI. Cs^cycloalkyl, C3-5cycloalkyI. and C3-4cycloalkyl). optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C2-9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C2-6alkyl. In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-14cycloalkyI (including C6-14cycloalkyI. C6-9cycloalkyl, C3-7cycloalkyl. C3-6cycloalkyl, C3-5cycloalkyI. and C3-4cycloalkyl), optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C2-5heterocycloalkyI optionally substituted with one C1-6alkyl.
[00110] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is GGieterocycloalkyl. including C6-9heterocycloalkyI, C3- 7heterocycloalkyl, C3-6heterocycloalkyl, C5-6 heterocycloalkyl, C3-5heterocycloalkyl, C3-4heterocycloalkyl, each of which being optionally substituted with one, two, or three R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is Cg. gheterocycloalkyl optionally substituted with one, two, or three R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3- -heterocycloalkyI optionally substituted with one, two, or three R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3- gheterocycloalkyl optionally substituted with one, two, or three R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is Cs- e heterocycloalkyl optionally substituted with one, two, or three R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-5 heterocycloalkyl optionally substituted with one, two, or three R20b. In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3. iheterocycloalkyl optionally substituted with one, two, or three R20b.
[00111] In embodiments, each of the R3 described above including C6-9heterocycloalkyl, C3-7heterocycloalkyk C3- 6 heterocycloalkyI. C5-6 heterocycloalkyl, C3-5heterocycloalkyl. C3-4heterocycloalkyl, is optionally substitued with one R20b. In embodiments, each of the R3 described above, including C6-9heterocycloalkyl, C3-7hctcrocycloalky I. C3- gheterocycloalkyl, C5-6heterocycloalkyl , C3-5heterocycloalkyl, C3-4heterocycloalkyl, is optionally substituted with two R20b In embodiments, each of the R3 described above, including C6-9heterocycloalkyl, C . -heterocycloalky I. C3- 6 heterocycloalkyI. C5-6heterocycloalkyl , C3-5heterocycloalkyl, C3-4heterocycloalkyl. is optionally substituted with three R20b.
[00112] In each of the above embodiments, R20b is independently selected from amino, -CN, C1-9alkyl, C1-3 alkoxy, C1- 3 haloalky I. -OH, -N(R24)C(O)R25, and -C(O)N(R22)(R23). In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is amino. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -CN. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is Ci-aalkyl. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is C1-3 alkoxy . In some embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is C1-9haloalkyl. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is —OH. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -N(R24)C(O)R25. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -C(O)N(R22)(R23). In some embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is - NHC(O)R25. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -C(O)NH(R22). In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -NHC(O)R25 and R25 is C2-9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-7reycloalky I. C2-9heterocycloalkyI C6-10aryl, and C1- 9heteroaril In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -C(O)NH(R22) and R22 is Cj-sheterocycloalky 1 optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -NHC(O)R25 and R25 is Ci.shctcrocycloalkyI optionally substituted with one C1-6alkyl. In some embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R20b is -C(O)NH(R22) and R22 is C2-5heterocycloalkyI optionally substituted with one C1-6alkyl.
[00113] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-9heterocycloalkyl (including C6-9heterocycloalkyI. C3. iheterocycloalkyl. C3-6heterocycloalkyI. C5-6heterocycloalkyI, C3-5heterocycloalkyI and C3-4heterocycloalkyI , optionally substituted with one, two, or three R20b that is amino. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2- shcterocycloalkyI (including C6-9heterocycloalkyl, C3-7hctcrocycloalkyI. C .ehctcrocycloalkyl, Cs-eheterocycloalky 1, C ,.sheterocycloalkyl, and C,.|heterocycloalkyl), optionally substituted with one, two, or three R20b that is -CN. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is CGhctcrocycloalkyI (including C6-9heterocycloalkyl, G. iheterocycloalkyl. C’-ehetcrocycloalkyl, C5-6heterocycloalkyl, C, -iheterocycloalkyl. and G. iheterocycloalkyl). optionally substituted with one, two, orthree R20b that is Cijalkyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl, G. iheterocycloalkyl. G-<hcterocycloalkyI. C5-6heterocycloalkyl, G.sheterocycloalky I. and C3- ihctcrocycloalkyl), optionally substituted with one, two, or three R20b that is Cwalkoxy . In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-9helerocycloalkyI (including C6-9heterocycloalkyl, G^heterocycloalkyl, G.dtclerocycloalky I . C5. eheterocycloalkyl, G.-JictcrocycloalkyI. and G. iheterocycloalkyl). optionally substituted with one, two, or three R20b that is C -’.haloalky I. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-sheterocycloalkyl (including C6-9heterocycloalkyl, C3- 7heterocycloalkyl, C’,. iheterocycloalkyl. Cj-eheterocycloalkyl, G.sheicrocycloalkyk and C.. iheterocycloalkyl). optionally substituted with one, two, or three R20b that is -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2- sheterocycloalkyl (including C6-9heterocycloalkyl, G.-hctcrocycloalkyI. C3-6 heterocycloalkyl, Cs.,, heterocycloalky I. G.sheterocycloalkyI. and G. iheterocycloalkyl). optionally substituted with one, two, orthree R20b that is oxo. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-sheterocycloalkyl (including C6-9heterocycloalkyl, C3-7heterocycloalkyl, G-eheterocycloalkyl, C5-6heterocycloalkyl, G.-hctcrocycloalkyI. and G. ihctcrocvcloalkyl). optionally substituted with one, two, orthree R20b that is -N(R24)C(O)R25. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-sheterocycloalkyl (including C6-9heterocycloalkyl, G. iheterocycloalkyl. C3-6heterocycloalkyl, G-e heterocycloalkyl, C3- sheterocycloalkyI. and Ci- iheterocycloalkyl). optionally substituted with one, two, or three R20b that is -NHC(O)R25. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-sheterocycloalkyl (including C6-9heterocycloalkyl, C3-7heterocycloalkyl, C-,. iheterocycloalkyl. G.-hctcrocycloalkyI. Ci.dictcrocycloalkyI. and Ci. ihetcrocycloalkyl), optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, Ci-dialoalky I. C' R, alkoxy . Ci-cycloalky I. C2- Uictcrocycloalkyl. C3-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl, C3-7hctcrocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalky 1, and C3- ihctcrocycloalkyl), optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2- sheterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (F), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2- oheterocycloalkyl (including Cf,.<;heterocycloalkyI. C,.-hctcrocycloalkyI. C3-6 heterocycloalkyl, C5-6 heterocycloalky 1, Ci.sheterocycloalkyI. and C’,.|hcterocycloalkyl), optionally substituted with one, two, or three R20b that is - C(O)N(R22)(R23). In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl, C3- dielcrocycloalkyI. C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and Ci-ihelcrocycloalky 1), optionally substituted with one, two, or three R20b that is -C(O)NH(R22). In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2- sheterocycloalkyl (including C6-9heterocycloalkyl, C3-7hctcrocycloalkyI. C .dictcrocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C’,.|hctcrocycloalkyl), optionally substituted with one, two, or three R20b that is - C(O)NH(R22) and R22 is Cb- JielerocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-9heterocycloalkyl (including Ce- sheterocycloalkyl, C3-7heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalky 1, and C3- ■iheterocycloalkyl), optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C2- sheterocycloalkyl optionally substituted with one C1-6alkyl.
[00114] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl substituted with one, two, or three R20b. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide substituted with one, two, or three R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent 4λ2-thiomorpholine substituted with two R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is tetrahydro-2H-thiopyranyl 1,1-dioxide. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2-thiomorpholinyl substituted with two R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl substituted with one R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl substituted with one R20b. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl substituted with one R20b.
[00115] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-9heterocycloalkyl substituted with one methyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-9heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-7heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-6heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C5-6heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C5-6heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-4heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-7 heterocycloalkyI substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C|.-heicrocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C1-9hcicrocycloalkyI substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C5heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is CihctcrocycloalkyI substituted with one methyl, one ethyl, or one propyl. [00116] In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-9heterocycloalkyI substituted with one propyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-7heicrocycloalkyI substituted with one propyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C ..,, heterocycloalkyI substituted with one propyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C5- 6heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C5-6heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is Ch.iheterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C4-5heterocycloalkyI substituted with one propyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C5heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C4heterocycloalkyl substituted with one propyl.
[00117] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-9heterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3-7hcicrocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C4-7heterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C4- sheterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (II), or a pharmaceutically acceptable salt or solvate thereof, R3 is Cshcicrocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C4heterocycloalkyl substituted with one isopropyl.
[00118] In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-9heterocycloalkyI substituted with two oxo. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C2-7heterocycloalkyI substituted with two oxo. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C^heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C6-
9heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is Ch.-helerocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C1-6heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C5-6heterocycloalkyI substituted with two oxo. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C5-6heterocycloalkyI substituted with two oxo. In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C3- ihctcrocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C1-9heterocycloalkyI substituted with two oxo. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is Csheterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is C4heterocycloalkyl substituted with two oxo.
[00119] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is amino. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (II), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is -CN. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is C1-3 alkoxy. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is C1-9alkoxy. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is C .’, haloalky I. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is oxo. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is -N(R24)C(O)R25. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is -NHC(O)R25. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2-9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1- 6haloalky I. C1-6alkoxy, C3-7cycloalkyl. C2-9heterocycloalkyI. C6- 10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2-sheterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is - C(O)NH(R22). In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C2-9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la),
(lb), (Ic), (Id), (le), or (II), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C2-5heterocycloalkyI optionally substituted with one C1-6alkyl.
[00120] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R20b that is amino. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R20b that is -CN. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, orthree R20b that is Ci-jalkyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb),
(lc), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H- thiopyran 1, 1-dioxide, optionally substituted with one, two, orthree R20b that is C1-3 alkoxy. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is thianyl, optionally substituted with one, two, or three R20b that is C1-3 haloalky 1. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R20b that is -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R20b that is oxo. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20b that is -N(R24)C(O)R25. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20b that is -NHC(O)R25. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H- thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2- 9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1- 6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-7cycloalkyl, Cb.ehctcrocycloalkyl. C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (II), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2-5heterocycloalkyI optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20b that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H- thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20b that is -C(O)NH(R22). In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C2-9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is monovalent tetrahydro-2H- thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is Ck- shctcrocycloalkyI optionally substituted with one C1-6alkyl.
[00121] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2-thiomorphol i ny 1, optionally substituted with one, two, or three R20b that is amino. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2-thiomorpholiny 1, optionally substituted with one, two, or three R20b that is -CN. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20b that is C1-9alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20b that is Ci-’.alkoxy. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ.2- thiomorpholinyl, optionally substituted with one, two, or three R20b that is C1-3haloalkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20b that is -OH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20b that is oxo. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2-thiomorpholi ny 1, optionally substituted with one, two, or three R20b that is -N(R24)C(O)R25. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2-thiomorpholiny 1, optionally substituted with one, two, or three R20b that is -NHC(O)R25. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4 V-thiomorpholinyl, optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-9haloalky 1, C1-9alkoxy, C3-7cycloalkyI. C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (II), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2-thiomorpholiny 1, optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2-thiomoipholiny 1, optionally substituted with one, two, or three R20b that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id),
(le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20b that is -C(O)NH(R22). In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (II), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2- thiomorpholinyl, optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C2- sheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and Ci- ,,alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (II), or a pharmaceutically acceptable salt or solvate thereof, R3 is 4λ2-thiomorpholiny 1, optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl. [00122] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is amino. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is -CN. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is Ci-jalkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is C1.3 alkoxy. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is C . ,haloalkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is -OH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is oxo. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is -N(R24)C(O)R25. In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or
(lf), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is -NHC(O)R25. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C1-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-9haloalkyl, C1-9alkoxy, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is -C(O)NH(R22). In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id),
(le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C1-6heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (F), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperidinyl, optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl.
[00123] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is amino. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (II), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is -CN. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is Ci-jalkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is Ci-3 alkoxy. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is C1-9haloalkyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is oxo. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is -N(R24)C(O)R25. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or
(lf), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is -NHC(O)R25. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C1-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is -C(O)NH(R22). In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id),
(le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C1-6heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is piperazinyl, optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl.
[00124] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is amino. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is -CN. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is C1-9alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is Ci-3 alkoxy. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is C1-3haloalkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is -OH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or
(lf), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is oxo. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is -N(R24)C(O)R25. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id),
(le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is -NHC(O)R25. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6 haloalky 1, C1-6alkoxy, C3-7cycloalky I. C2- 9heterocycloalkyl, C3-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is -NHC(O)R25 and R25 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or
(lf), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is -C(O)NH(R22). In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C1-6heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is pyrrolidinyl, optionally substituted with one, two, or three R20b that is -C(O)NH(R22) and R22 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl.
[00125] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000047_0001
[00126] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000047_0002
[00127] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000048_0001
[00128] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000048_0002
[00129] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000049_0001
[00130] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000050_0001
[00131] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000050_0002
[00132] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000051_0001
[00133] In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000051_0002
[00134] In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000052_0001
[00135] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000052_0002
[00136] In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000053_0001
[00137] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000053_0002
[00138] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000054_0001
[00139] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000055_0001
[00140] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is
Figure imgf000056_0001
[00141] In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000056_0002
some embodiments of a compound of
Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, R3 is
Figure imgf000056_0003
some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (II), or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000056_0004
some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000056_0005
[00142] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a is selected from hydrogen, C1-6alkyl, C3- 10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-10cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a is selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a is C1-6alkyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a is hydrogen. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a is methyl.
[00143] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a 6-10 membered aryl ring optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is C2-9heterocycloalkyI optionally substituted with one, two, or three R20b, each R3a is hydrogen, R4 is hydrogen, and R5 is C1-6alkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is C2-9heterocycloalkyI optionally substituted with one, two, or three R20b, each R3a is hydrogen, R4 is hydrogen, and R5 is C1-6alkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is C2-9heterocycloalkyI selected from piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, wherein piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl are optionally substituted with one, two, or three R20b, each R3a is hydrogen, R4 is hydrogen, and R5 is C1-6alkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is C2-9heterocycloalkyI selected from piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, wherein piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl are optionally substituted with one, two, or three R20b, each R3a is hydrogen, R4 is hydrogen, R5 is C1-6alkyl, and each R10 is independently selected from halogen, C1-6alkyl, and C1-6haloalky 1. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is C2-9heterocycloalkyl selected from piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, wherein piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl are optionally substituted with one, two, or three R20b, each R3a is hydrogen, R4 is hydrogen, R5 is C1-6alkyl, each R10 is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, and each R20b is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is C2-9heterocycloalkyI selected from piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, wherein piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl are unsubstituted, each R3a is hydrogen, R4 is hydrogen, R5 is C1-6alkyl, and each R10 is independently selected from halogen, C1-9alkyl, and Ci-6 haloalky 1. [00144] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a 6-10 membered aryl ring optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is - N(R12)(R13) or -C(O)N(R12)(R13), R4 is hydrogen, and R5 is C1-6alkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is -N(R12)(R13) or -C(O)N(R12)(R13), each R3a is hydrogen, R4 is hydrogen, and R5 is C1-6alkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is -N(R12)(R13), each R3a is hydrogen, R4 is hydrogen, R5 is C1-6alkyl, R12 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20e, and R13 is hydrogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is -N(R12)(R13), each R3a is hydrogen, R4 is hydrogen, R5 is C1-6alkyl, each R10 is independently selected from halogen, C1-6alkyl, and C1-6 haloalky I. R12 is C2-9heterocycloalkyI optionally substituted with one, two, or three R20e, and R13 is hydrogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is -N(R12)(R13), each R3a is hydrogen, R4 is hydrogen, R5 is C1-6alkyl, each R10 is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, R12 is unsubstituted C2-9heterocycloalkyl, and R13 is hydrogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is -C(O)N(R12)(R13), each R3a is hydrogen, R4 is hydrogen, R5 is C1-6alkyl, and R12 and R13, together with the nitrogen to which they are attached, form a C1-6heterocycloalkyl ring optionally substituted with one, two, or three R20f. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is -C(O)N(R12)(R13), each R3a is hydrogen, R4 is hydrogen, R5 is C1-6alkyl, each R10 is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl, and R12 and R13, together with the nitrogen to which they are attached, form a Ci-'JielerocycloalkyI ring optionally substituted with one, two, or three R20f. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl optionally substituted with one or more R10, R2 is C1-6alkyl, R3 is -C(O)N(R12)(R13), each R3a is hydrogen, R4 is hydrogen, R5 is C1-6alkyl, each R10 is independently selected from halogen, C1-6alkyl, and Ci., haloalky I. and R12 and R13, together with the nitrogen to which they are attached, form an unsubstituted C1-9heterocycloalkyl ring.
[00145] In another aspect, the disclosure provides a compound of Formula (II’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000058_0001
Formula (II');
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
R2 is selected from hydrogen, C1-6alkyl, Ch-.alkeny I. C2-6alkynyl, and C3-10cycloalkyl wherein C1-6alkyl, C1-9alkenyl, C2-6alkynyl, and C3-10cycloalkyl are optionally substituted with one, two, or three R20a;
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R6 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl. C2-6alkynyl. C3-10cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C -sheteroaryk -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkenyl, C3-10cycloalkyl, C2-9heterocycloalkyI, C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b;
R7 is selected from halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, Ci- sheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), - CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein Ci-6alkyl, C2.6alkenyl, C2-6alkynyl, C,. iocycloalkyl. C2-9heterocycloalkyI. C6-10aryl, and C1-9heteroaryI are optionally substituted with one, two, or three R’Oc: each R10 is independently selected from halogen, -CN, C1-6alkyl, alkynyl, C3-7cycloalkyl, C2. sheterocycloalkyl, C6-10aryl, C1-9heteroaryI. -OR12, -SR12, -N( O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15 (O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, - )2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)
Figure imgf000059_0001
2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2.,, alkenyl, C2-6alkynyl, C3-7cycloalkyl. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl. C2-6alkynyl, C-,. -cycloalky 1, C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryI. whereinC1-9alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalky 1, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C1-9 haloalky 1; or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky 1; each R15 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C-,. -cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl. C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; each R17 and each R17a are each independently selected from C1-6alkyl and C3-6 cycloalkyI. wherein C1-6alkyl and C;. ecy cloalky 1 are optionally substituted with one, two or three of R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, Ci. ealkyl, C2., alkenyl. C2.(,alkynyl. C3-10cycloalkyl, -CH2- C3-10cycloalkyl, C2-9heterocycloalkyl. -CH2-C2. gheterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl. -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyI. C1-6alkoxy. C1- 6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6 haloalky 1, CL.,, alkenyl. C2-6alkynyl, C3-7 cy cloalky I. C2.
•.heterocycloalkyl. C6-10aryl, and C1-9heteroaryl; each R22 is independently selected from H, C1-6alkyl, C . ehaloalky 1, CL.,, alkenyl. C2-6alkynyl, CL.-cy cloalky I. C2.
•.heterocycloalkyl. C6-10aryl, and Cinheteroaiyk each R23 is independently selected from H and C1-6alky I: each R24 is independently selected from H and C1-6alkyl; each R25 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, CL.ecycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and Ci-
• hc ternary I: and p is 0, 1, or 2.
[00146] In some embodiments is a compound of Formula (II’) having the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000060_0001
Formula (II);
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
R2 is selected from hydrogen, C1-6alkyl, C2- 6 alkenyl. CL-ealky ny 1, and CL. i >cycloalkyl wherein C1-6alky 1, CL-, alkenyl. CL.f,alky ny 1, and C3-10cy cloalky 1 are optionally substituted with one, two, or three R20a;
R4 is selected from hydrogen, C1-6alky I. and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R6 is independently selected from halogen, -CN, C1-6alkyl, C2- 6 alkenyl. CL-ealky ny I. CL. ocycloalky 1, C2- •.hctcrocycloalkyl. C6-10aryl, C kictcroaryl. -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R13, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R13, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, CL- ocycloalkyl. C2-9heterocycloalkyl, Ce- waryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b;
R7 is selected from halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, CL.ghcicrocycloalkyI. C6-10aryl, Ci- sheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R13, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), - CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2.6alkenyl, C2-6alkynyl, CL- iocy cloalky 1, C2-9heterocycloalkyl, C6-10aryl, and Cikrc ternary I are optionally substituted with one, two, or three R20c; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, CL. -cycloalky I. C2. gheterocycloalkyl, C6-10aryl, Ci-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2.f, alkenyl. C2.(,alky ny I. C-. -cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R2M; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C-,. -cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryI. wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl. C3-7cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryI are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C .f, haloalky I: or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C .„haloalky 1; each R15 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9hcteroary k wherein C1-6alkyl, Ch-,, alkenyl. C2-6alkynyl, C . -cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9hcteroary I are optionally substituted with one, two, or three R2°B; each R17 and each R17a are each independently selected from C1-6alkyl and Cw, cycloalkyI. wherein C .fla 1 ky 1 and C-,. ecy cloalky 1 are optionally substituted with one, two or three of R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, Ci. ealkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2. sheterocycloalkyl, C6-10aryl, -CH2-C6-ioaryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, Ci- ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cy cloalky I. C2. gheterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cy cloalky I. C2. gheterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; each R25 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C’..-cycloalkyI. C2-9heterocycloalkyl, C3-10ary 1, and Ci- gheteroaryl; and p is 0, 1, or 2.
[00147] In some embodiments is a compound of Formula (II) having the structure of Formula (II- 1), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000062_0001
Formula (II-l).
[00148] In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from hydrogen, halogen, C1-9alkyl, C3-10cycloalkyl, C1-9heterocycloalky 1, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl. C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from hydrogen, halogen, and C1-6alkyl optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is hydrogen. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is hydrogen. In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.
[00149] In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from halogen, -OR12, -N(R12)(R13), -SR12, -SOR12, -SO2(R12)(R13), - SO2N(R12)(R13), -P(O)(R17)(R17a), C1-6alkyl, C3-10cycloalkyl, C2-9iheterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl. Cc-ioaryl, and Ci- sheteroaryl, wherein C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from -C(O)R15, -C(O)N(R12)(R13), C2- sheterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryI are optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), wherein R7 is selected from -C(O)R15. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (Id), (le) or (If), wherein R15 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20g.
[00150] In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is spirocyclic C2.<>heterocycloalkyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is fused C2-9heterocycloalkyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is C6-10aryl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II- 1 ), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is fused C6-10aryl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II- 1 ), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is C1-9heteroaryl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is fused C1-9heteroaryl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -C(O)N(R12)(R13).
[00151] In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R15 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20g. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R15 is spirocyclic C1-6heterocycloalkyl optionally substituted with one, two, or three R20g. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R15 is fused C2-9heterocycloalkyl optionally substituted with one, two, or three R20g.
[00152] In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is C1-6alky 1 optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -OR12. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -N(R12)(R13). In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is halogen.
[00153] In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is cyclopropyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is cyclobutyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is cyclopentyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is cyclohexyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is aziridinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is azetidinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is pyrrolidinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is piperidinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is piperizinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is morpholinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is oxetanyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II- 1 ), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is tetrahydroluranyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is tetrahydropyranyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II- 1 ), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is pyridinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is pyrazinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is pyrimidinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is pyridazinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is phenyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is pyrazolyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is pyrrolyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is thiophenyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is thianyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is 1,3 -imidazolyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is thiazolyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II- 1 ), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is oxepanyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is azepanyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is 1,4-dioxapanyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is 1,4-oxazepanyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is 2,6- diazaspiro[3.3]heptanyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is 2-oxa-6- azaspiro[3.3]heptanyl optionally substituted with one, two, or three R20c.
[00154] In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3.1 icvcloalkvl. including G5-1 icvcloalkvl. G,-<iCycioalky 1, Cg-jcycloalkyl, C3-6cycloalkyl, C3- scycloalkyl, and G. icvcloalkvl. each of which being optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is G,.1 icvcloalkvl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is GvicycloalkyI optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is G,. -cycloalkyI optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C1-6cycloalkyI optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is G. scycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-4cycloalkyl optionally substituted with one, two, or three R20c.
[00155] In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is Ci-ucy cloalky 1, including Ce-ucycloalkyl, Ce-icycloalkyl, G.-cycloalkyI. G.rcycloalky 1, C3. scycloalkyI. and G.icycloalkyl. each of which being substituted with one, two, or three R20c. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is G>.
1 icycloalkyl substituted with one, two, or three R20c. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C6-9cycloalkyl substituted with one, two, or three R20c. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is G.-cycloalkyI substituted with one, two, or three R20c. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3.6 cycloalkyl substituted with one, two, or three R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-5cycloalkyI substituted with one, two, or three R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-4cycloalkyl substituted with one, two, or three R20c.
[00156] In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3.1 icycloalkyl, including C6-14cycloalkyI. G,. ^cycloalkyI. G.-cycloalkyI. G.rcycloalky I. C3- scycloalkyl, and C3-4cycloalkyl. each of which being optionally substituted with one R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is Cs-
1 icycloalkyI optionally substituted with one R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is G.-cycloalkyI optionally substituted with one R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is G. -cycloalkyI optionally substituted with one R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is G.-cycloalkyI optionally substituted with one R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C .scycloalkyl optionally substituted with one R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-4cycloalkyl optionally substituted with one R20c.
[00157] In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3.1 icycloalkyl, including G-ucycloalkyl, G,. icycloalkyI. G.-cycloalkyl, G.-cycloalky I. G- scy cloalky 1, and Gi. icycloalkyI. each of which being optionally substituted with two R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is G>.
1 icycloalkyl optionally substituted with two R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is G.-cycloalkyl optionally substituted with two R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-7cycloalkyl optionally substituted with two R20c. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is Ci.ecycloalkyl optionally substituted with one R20c. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C .-scycloalkyl optionally substituted with two R20c. In embodiments of a compound of Formula (II’), (II), or (II- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R7 is C ,.icycloalkyl optionally substituted with two R20c.
[00158] In each of the above embodiments, R20c is independently selected from amino, -CN, C1-9alkyl, C1-9alkoxy, C1-9haloalkyl, -OH, -N(R24)C(O)R25, and -C(O)N(R22)(R23). In some embodiments of a compound of Formula (II'), (II), or (II- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R20c is amino. In some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R20c is -CN. In some embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R20c is C1-9alkyl. In some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R20c is C i-salkoxy . In some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R20c is Ci-ihaloalky 1. In some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R20c is --OH. In some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R20c is -N(R24)C(O)R25. In some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)N(R22)(R23). In some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R20c is - NHC(O)R25. In some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)NH(R22). In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -NHC(O)R25 and R25 is C1-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, Ci .ealkyl, C1-6haloalkyl, C1-6alkoxy, Ck.-cycloalkyl. C2-9heterocycloalkyl , C6-10aryl, and Ci.Jiclcroary I . In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)NH(R22) and R22 is Ci-'Jieterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -NHC(O)R25 and R25 is Cz-jheterocycloalkyl optionally substituted with one C1-6alkyl. In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)NH(R22) and R22 is Cj.JictcrocycloalkyI optionally substituted with one Ci- salkyl.
[00159] In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C6-14cycloalkyl (including C(,.| icycloalkyI. C6-9cycloalkyl, C-,. -cycloalkyl, C-.(, cycloalky I. Ca- scycloalkyI. and C\ icycloalkyI). optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is G,. i icycloalkyI (including C„.| icycloalkyI. C6-9cycloalkyl, Cy. -cycloalkyI. Ca-ecycloalkyl, Cy.scycloalkyl. and C . 4cycloalkyl), optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is Cg-i icycloalkyl (including Ce i icycloalkyI. Cs-scycloalkyl, C.. -cycloalkyI. C-.,, cycloalkyl. C-.scycloalkyI. and Csacycloalkyl), optionally substituted with one, two, or three R20c that is Ci-aalkyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is Ce-ncycloalkyl (including Ce-wcycloalkyl, G,. gcycloalkyl, C3-7 cycioalky I. Cs-scycloalkyl, C3-5cycloalkyl, and Gi-icy cloalky 1), optionally substituted with one, two, or three R20c that is Ci-aalkoxy. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is G-i icycloalkyl (including C6-14cycloalkyI. Ce-scycloalky 1, C3-7cycloalkyl, G-ecycloalkyl, Gi.scy cloalky 1, and C3-4cycloalkyl), optionally substituted with one, two, or three R20c that is C .’, haloalky I. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C6-14cycloalkyl (including G,-i icycloalkyl. C6-9cycloalkyl, C3-7cycloalkyl, G- 6 cycloalkyl, C .scy cloalky 1, and C3-4cycloalkyl), optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C6-14cycloalkyI (including Cs-i 4cycloalkyl, C6-9cycloalkyl, C3-7cycloalkyl, Ch-ecy cloalky 1, G-scycloalkyl, and C3-4cycloalkyl), optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is Ce-ucy cloalky 1 (including G,.1 icycloalkyI. G, -icycloalkyI. C3-7cycloalkyl, G-ecycloalkyl, G.scycloalkyl, and C3-4cycloalkyl). optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (II'), (II), or (II- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R7 is G-i icycloalkyl (including G.
1 icycloalkyl. G,.<;cycloalkyk C3-7cycloalkyl, G-ecycloalkyl, G-scycloalkyl, and C3-4cycloalkyl), optionally substituted with one, two, or three R20c that is -NHC(O)R25. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C,.| icycloalkyl (including G-i icycloalkyl. Ce-sicycloalkyl, G-cy cloalky 1. G.scycloalkyk G-scycloalkyl, and C3-4cycloalkyl). optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, G-salkyl, G-Galoalky 1. G-e alkoxy, Cs-scy cloalky 1, C2- sheterocycloalkyl, G-ioaryl, and C1-9heteroaryl. In embodiments of a compound of Formula (II'), (II), or (II-l), ora pharmaceutically acceptable salt or solvate thereof, R7 is G-i icycloalkyl (including G, - icycloalkyl. G-scycloalkyl, G-scycloalkyl, G-ecy cloalky 1, G.scycloalkyl. and C3-4cycloalkyl), optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is G-shclcrocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is G- 1 icycloalkyl (including C,,-i icycloalkyl. G,->.cycloalkyl. G-scycloalkyl, G-ecycloalkyl, G.scycloalkyk and G- 4cycloalkyl), optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is G-
1 icycloalkyI (including G-ucycloalkyl, G.scycloalkyk G-7Cycloalkyl, G-ecycloalkyl, G.scycloalkyk and G- 4cycloalkyl), optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is Ce- ucycloalkyl (including G-ucycloalkyl, G-scycloalkyl. G-7cycloalkyl, G-ecycloalkyl, C3-5cycloalkyl. and G- 4cycloalkyl), optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is G-Gctcrocycloalky 1 optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is Ce-ucycloalkyl (including G-ucycloalkyl, C6-9cycloalkyl, G-7Cycloalkyl, G-ecy cloalky 1, G-scycloalkyl, and G-4cycloalkyl), optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is G- sheterocycloalkyI optionally substituted with one G-ealkyl.
[00160] In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl, including C6-9heterocycloalkyl, G-7heterocycloalkyl, G- eheterocycloalkyl, G-e heterocycloalkyl, G-sheterocycloalkyl, G-4heterocycloalkyl, each of which being optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C6-9heterocycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (II'), (II), or (II- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-7heterocycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3- 6heterocy cloalky 1 optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C5-6heterocycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-5 heterocycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (II’), (II), or (II- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-4heterocycloalkyl optionally substituted with one, two, or three R20c.
[00161] In embodiments, each of the R7 described above including C6-9heterocycloalkyl, C3-7heterocycloalkyl. C3- 6heterocycloalkyI. C5-6heterocycloalkyl,C3-5heterocycloalkyl. C3-4heterocycloalkyl, is optionally substitued with one R20c. In embodiments, each of the R7 described above, including C6-9heterocycloalkyl, C3-7heterocycloalkyl, C3- 6heterocycloalkyI. C5-6heterocycloalkylC3-5heterocycloalkyl, C3-4heterocycloalkyl, is optionally substituted with two R20c. In embodiments, each of the R7 described above, including C6-9heterocycloalkyl. C3-7heterocycloalkyl, C3- 6heterocycloalkyI. C5-6heterocycloalkyl,C3-5heterocycloalkyl. C3-4heterocycloalkyl, is optionally substituted with three R20c.
[00162] In each of the above embodiments, R20c is independently selected from amino, -CN, C1-6alkyl, Ci.yilkoxy. C1-9haloalkyl, -OH, -N(R24)C(O)R25, and -C(O)N(R22)(R23). In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is amino. In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -CN. In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is Cualkyl. In some embodiments of a compound of Formula (II’), (II), or (II-l), ora pharmaceutically acceptable salt or solvate thereof, R20c is C i. ialkoxy . In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is C1.3 haloalky 1. In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is —OH. In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -N(R24)C(O)R25. In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)N(R22)(R23). In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -NHC(O)R25. In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)NH(R22). In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -NHC(O)R25 and R25 is C2- 9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C1- 6alkyl. C1-6haloalkyl, C1-6alkoxy, Cy.-cycloalkyI. Cx-Jictcrocycloalkyl. C6-10aryl, and C .Uieteroaryl. In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)NH(R22) and R22 is C2-9iheterocy cloalky 1 optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In some embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -NHC(O)R25 and R25 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl. In some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)NH(R22) and R22 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl.
[00163] In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl, C3-7heterocycloalkyl. C3-
6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl, C3- 7hetcrocycloalkyI. C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl (including Ce- sheterocycloalkyl, Ci-dictcrocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalky 1, and C3- 4heterocycloalkyl), optionally substituted with one, two, or three R20c that is C1-9alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2- 9heterocycloalkyl (including C6-9heterocycloalkyl, C3-7heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is C1-9alkoxy. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl, C3-7heterocycloalkyl. C3-6heterocycloalkyl, Cs- eheterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is C1-9haloalkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl, C3-7heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl). optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl, C3- 7heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and Ci. ihelerocycloalky I), optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl (including C6- 9heterocycloalkyl, C3-7heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and Cs- 4heterocycloalkyl), optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2- 9heterocycloalkyl (including C6-9heterocycloalkyl, C3-7heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is - NHC(O)R25. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl, C3-7heterocycloalkyl, Cs- eheterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, Cs-scycloalkyl, C2- sheterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl, Cs- sheterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is Cs-sheterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is Ch.Jictcrocycloalkyl (including C6-9heterocycloalkyl, C3-7heterocycloalky 1, C3-6heterocycloalkyl, C5-6heterocycloalkyl, Ci.dicterocycloalkyI. and Ci. iheterocycloalkyl). optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl (including C(1. sheterocycloalkyl, C3-7heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl and C.- ihctcrocycloalkyl), optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2- 4 heterocycloalkyI (including Ce-gheterocycloalkyl, C3-7heterocycloalkyI. C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl , optionally substituted with one, two, or three R20c that is - C(O)NH(R22) and R22 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6 alkyl. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl, C3- -hclcrocycloalkyI. C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2-9heterocycloalkyl optionally substituted with one C1-6alkyl.
[00164] In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl substituted with one, two, or three R20c. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H- thiopyran 1,1-dioxide substituted with one, two, or three R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent 4λ2-thiomorpholine substituted with two R20c. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is tetrahydro-2H-thiopyranyl 1,1-dioxide. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4k2-thiomorpholinyl substituted with two R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl substituted with one R20c. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl substituted with one R20c. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl substituted with one R20c.
[00165] In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl substituted with one methyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C6-9heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-7hetcrocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-6heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is Cs-JieterocycloalkyI substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C5-6heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-4heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-7hcicrocycloalkyI substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C4-7heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C4-5heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is CshctcrocycloalkyI substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is CiliclerocycloalkyI substituted with one methyl, one ethyl, or one propyl. [00166] In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C6-9heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-7heterocycloalkyI substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-6heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C5-6heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C5-6heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C >. iheterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C1-9hctcrocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is CshctcrocycloalkyI substituted with one propyl. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C4heterocycloalkyl substituted with one propyl. [00167] In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is Ci.-lieterocycloalky I substituted with one isopropyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C4-7heterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C4- sheterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C5heterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C4heterocycloalkyl substituted with one isopropyl.
[00168] In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-9heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C2-7heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C4-7heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C6-9heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-7heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-6heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C5-6heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C5-6heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C3-4heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is C1-9hctcrocycloalkyI substituted with two oxo. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C5heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is C ihcterocycloalkyI substituted with two oxo.
[00169] In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is C1-3alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is C ., alkoxy. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is C ., haloalky I. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is - N(R24)C(O)R25. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-7cycloalkyl. C2-9heterocycloalkyl. C6-10aryl, and Ci.Jictcroary I. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C'z-shctcrocycloalky I optionally substituted with one C1-6alkyl.
[00170] In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R20c that is C1-9alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R20c that is C1-9alkoxy. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is thianyl, optionally substituted with one, two, or three R20c that is Ci- .lialoalkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H-thiopyran 1,1- dioxide, optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H- thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R20c that is - NHC(O)R25. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalky 1, C1-6alkoxy, C3-7cycloalkyI. C2-9heterocycloalkyI, C6- 10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is CF-shctcrocycloalky 1 optionally substituted with one Ci. ealkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H- thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C1- 9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1- 6alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is monovalent tetrahydro-2H-thiopyran 1, 1-dioxide, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2-9heterocycloalkyl optionally substituted with one C1-6alkyl.
[00171] In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2-thiomorpholiny I. optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ 2- thiomorpholinyl, optionally substituted with one, two, or three R20c that is C1-9alkyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20c that is Ci- . alkoxy. In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20c that is C1-3haloalkyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2-thiomorpholiny 1, optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2 - thiomorpholinyl, optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20c that is - NHC(O)R25. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2-thiomorpholiny 1, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C1-9alkyl, C1-6haloalkyl, C1-6alkoxy, Ck. -cycloalkyl. Cz-pheterocycloalkyl, C6-10aryl, and C6-9heteroaryI. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2-thiomorpholiny I. optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2- 5heterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2-thiomorpholiny 1, optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2-thiomorpholiny 1, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is Cz-pheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2-5heterocycloalkyl optionally substituted with one Ci- ealkyl.
[00172] In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is C1-9alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is C .ialkoxy . In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is Ci-ihaloalkyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalky 1. C1-6alkoxy, C3-7cycloalkyl, C2- sheterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is CF-shcterocycloalkyI optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperidinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is Ci.shelerocycloalkyI optionally substituted with one Ci. ealkyl.
[00173] In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is C1-9alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is C ., alkoxy . In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is C1-3haloalkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25. In embodiments of a compound of Formula (II'), (II), or (II- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-<>heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-9haloalkyl, C1-9alkoxy, C3-7cycloalkyl, C2- oheterocycloalkyl, C6-10aryl, and Ci- shete roaryl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is piperazinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2-5heterocycloalkyl optionally substituted with one C1- 6alkyl.
[00174] In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is C1-9alkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is C1-3alkyl . In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is C1-9haloalkyl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, CiHialoalky I. C1-6alkoxy, C3- 7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof, R7 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2- sheterocycloalkyl optionally substituted with one C1-9alkyl.
[00175] In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000077_0001
[00176] In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000077_0002
[00177] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000078_0001
[00178] In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000078_0002
[00179] In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000079_0001
[00180] In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000080_0001
[00181] In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000080_0002
[00182] In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000081_0001
[00183] In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000081_0002
[00184] In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000082_0001
[00185] In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000082_0002
Figure imgf000082_0003
[00186] In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000083_0001
[00187] In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000083_0002
[00188] In some embodiments is a compound of Formula (II'), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000084_0001
[00189] In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000085_0001
[00190] In some embodiments is a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is
Figure imgf000086_0001
[00191] In some embodiments of a compound of Formula (II'), (II), or (II- 1 ), or a pharmaceutically acceptable salt
Figure imgf000086_0002
some embodiments of a compound of Formula (II’), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000086_0003
some embodiments of a compound of Formula (II’), (II), or (II-l), or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000086_0004
some embodiments of a compound of Formula (II'), (II), or (II- 1), or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000086_0005
[00192] In another aspect, the disclosure provides a compound of Formula (111’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000087_0001
Formula (in’);
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
R2 is selected from hydrogen, C1-6alkyl, C1-6alkeny 1, C2-6alkynyl, C3-10cycloalkyl-wherein C1-6alkyl, C2- 6 alkenyl. C2- 6alkynyl, and C3-10cycloalkyl are optionally substituted with one, two, or three R20a;
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R8 is independently selected from halogen, -CN, C1-6alkyl, C2- 6 alkenyl. CL-Lilky ny I. C . ocycloalky I. C2. sheterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R13, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C - ocycloalkyl. C2-9heterocycloalkyl. C6- 10aryl, and C1-9 heteroaryl are optionally substituted with one, two, or three R20b;
R9 is selected from C1-6alky 1, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl. C2-9heterocycloalkyl, C6-10aryl, C1- 9heteroaryl, -C(O)OR12, -C(O)R15, -S(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, and - S(O)2N(R12)(R13), wherein C1-6alkyl. C2-6 alkenyl. C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C1-9 heteroaryl. -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C . -cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9hcteroary I are optionally substituted with one, two, or three R2M; each R12 is independently selected from hydrogen, C1-6alkyl. C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl. and C1-6 haloalky 1; or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-9 haloalkyl: each R15 is independently selected C1-6alkyl, C2-6alkenyl, C1-6alky ny I. C-,. -cycloalkyI. C2-9heterocycloalkyl I. C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6alkenyl, C2-6alky nyl. C ,--cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; each R17 and each R17a are each independently selected from C|.(,alky I and C’,.(, cycloalkyI. wherein C1-6alkyl and C3- ecycloalkyl are optionally substituted with one, two or three of R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, Ci- ealkyl, C2-9alkenyl, Ci-ealkynyl. C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl. -CH2-C2- sheterocycloalkyl, C6-10aryl, -CHi-C3-10aryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, and Ci-Jictcroary l are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, Ci.„haloalky I. C1-6 alkoxy. Ci. ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C-.-cy cloalky I. C2. sheterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C-.-cy cloalky I. C2.
• heterocycloalkyl. C6-10aryl, and C1-9heteroaryl; each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; each R25 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C,. -cycloalky 1, C1-9heterocycloalkyl , C6-10aryl, and Ci. sheteroaryl; and p is 0, 1, or 2.
[00193] In some embodiments is a compound of Formula (III’) having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000088_0001
Formula (III);
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
R2 is selected from hydrogen, C1-6alky I. Ci.,, alkenyl. C2-6alkynyl, C-. ocy cloalky 1, -wherein C1-6alkyl, C2-6alkenyl, C2. ealkynyl, and C3-10cycloalkyl are optionally substituted with one, two, or three R20a;
R4 is selected from hydrogen, C1-6alky I. and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alky 1, and C1-6haloalkyl; each R8 is independently selected from halogen, -CN, C1-6alkyl, Ch.-alkcny I. C2-6alkynyl, C . ocycloalky 1. C2- sheterocycloalkyl, C6-10aryl, C .Uietcroaryl. -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R1J, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CHjC(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C -ncycloalkyl. C2-9heterocycloalkyl, Ce- waryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b;
R9 is selected from C1-9alkyl, C;. , alkenyl. C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, Ci. sheteroaryl, -C(O)OR12, -C(O)R15, -S(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R1J, and - S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C3-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2^alkenyl, C2-6alkynyl, Ch. -cycloalky 1, C2. •liclcrocycloalkyl. C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, Ch.,, alkenyl. C2-6alkynyl, Ch. -cycloalkyI. C2.<>heterocycloalkyl, C6-10aryl, and Ch-dieleroary I are optionally substituted with one, two, or three R20d; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, Ch. -cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9 ieteroary I. whereinC1-9alkyl, C2-6alkenyl, C2-6alkynyl, Ch, .-cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and Ch .,, haloalky 1; or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky 1; each R15 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Ch. -cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and Ci- <lictc roaryl, wherein C1-6alkyl, Ch.,, alkenyl. C2-6alkynyl, Ch. -cycloalkyl, C2.<>heterocycloalkyl, C6-10aryl, and C3-7hclcroary I are optionally substituted with one, two, or three R2°B; each R17 and each R17a are each independently selected from Ch -r, alky I and C3-6 cycloalkyl, wherein C1-6alkyl and C3- ecycloalkyl are optionally substituted with one, two or three of R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, Ci. , alkyl. Ch., alkenyl. C2.(,alkynyl. C-.iocycloalkyl. -CH2-C3-wcycloalkyl, Ch.Jieterocycloalkyl. -CH2-C2.
• hcterocycloalkyl. C6-10aryl, -CH2-C6-ioaryl, C1-9 hcleroary l. -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, Cwalkynyl, Ch-iocycloalkyl, -CEh-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, Cg-ioaryl, -CH2-C6-ioaryl, and Ci-Jieteroary I are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, Ch-„haloalky I. C1-6 alkoxy. Ci- ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6 haloalky I. C1-6alkeny 1, C2-6alkynyl, C3-7 cy cloalky I. C2-
<, heterocycloalkyl. C6-10aryl, and C1-9heteroaryl; each R22 is independently selected from H, C1-6alkyl, C1-6 haloalky 1, C1-6alkeny 1, C2-6alkynyl, C'-.-cy cloalky I. C2-
9 heterocycloalkyl, C6-10aryl, and Ci-rheteroaiy k each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; each R25 is selected from C1-6alkyl, C2-9alkeny 1, C2-6alkynyl, Ci.ecycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and Ci- gheteroaryl; and p is 0, 1, or 2.
[00194] In some embodiments is a compound of Formula (III) having the structure of Formula (III-l), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000090_0001
Formula (III-l).
[00195] In some embodiments is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen, C1-6alkyl, C3-10cycloalky 1, C2- sheterocycloalkyl, C6-10aryl, and C|.<lictcroary I. wherein C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C . Jieteroary I are optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen, C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9 ieteroary I. wherein C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen and C1-6alky I optionally substituted with one, two, or three R20b. In some embodiments is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.
[00196] In some embodiments is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is selected from C1-6alkyl, C3- wcycloalkyl, C1-9heterocycloalkyl, C6-10aryl, and Ci- 9heteroaryl, wherein C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is selected from C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c. [00197] In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is selected from C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- gheteroaryl, wherein C1-9alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl. C3-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), wherein R9 is selected from -C(O)R15. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (Id), (le) or (If), wherein R15 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20g.
[00198] In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is C1-6heterocycloalkyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is spirocyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is fused C2-9heterocycloalkyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is C6-10aryl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is fused C6-10aryl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is C1-9heteroaryl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is fused C1-9heteroaryl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is -C(O)N(R12)(R13).
[00199] In some embodiments is a compound of Formula (I), (1-1), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R15 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20g. In some embodiments is a compound of Formula (I), (1-1), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R15 is spirocyclic C2-9heterocycloalkyl optionally substituted with one, two, or three R20g. In some embodiments is a compound of Formula (I), (1-1), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R15 is fused CL-Jictcrocycloalkyl optionally substituted with one, two, or three R20g.
[00200] In some embodiments is a compound of Formula (I), (1-1), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is C1-6alkyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is cyclopropyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is cyclobutyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is cyclopentyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is cyclohexyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is aziridinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is azetidinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is pyrrolidinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is piperidinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is piperizinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is morpholinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is oxetanyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is tetrahydrofuranyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is tetrahydropyranyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is pyridinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is pyrazinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is pyrimidinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (HF), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is pyridazinyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (HF), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is phenyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (HF), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is pyrazolyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is pyrrolyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is thiophenyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is thianyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
1.3 -imidazolyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is thiazolyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is oxepanyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is azepanyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is 1,4-dioxapanyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
1.4-oxazepanyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is 2,6- diazaspiro[3.3]heptanyl optionally substituted with one, two, or three R20c. In some embodiments is a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is 2-oxa-6- azaspiro[3.3]heptanyl optionally substituted with one, two, or three R20c.
[00201] In embodiments of a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-14cycloalkyI. including C6-14cycloalkyl. C6-9 cycloalkyI. CF. cycloalky 1, C3-6cycloalkyl, C3-5cycloalkyl. and C3-4 cycloalkyl, each of which being optionally substituted with one, two, or three R20c In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-14cycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is Cs- gcycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C . icycloalkyI optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-6cycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-5cycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C.F.
4cycloalkyl optionally substituted with one, two, or three R20c.
[00202] In embodiments of a compound of Formula (III'), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-14cycloaIkyl. including C6-14cycloalkyl. C6-9cycloalkyl, C3-7cycloalkyl, C3-6cycloalkyl, C3-5cycloalkyl, and C3-4cycloalkyl, each of which being substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R9 is CF, - icycloalkyI substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-9cycloalkyl substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-7cycloalkyl substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3- cycloalkyl substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-5cycloalkyI substituted with one, two, or three R20c. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is CF,. icycloalkyl substituted with one, two, or three R20c.
[00203] In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is CF-i icycloalkyI. including CF-i icycloalkyI. CGcycloalkyI. CF.-cycloalkyl, CF,. icycloalky I. C3- scycloalkyl, and CF,. icycloalkyI. each of which being optionally substituted with one R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C,.
1 icycloalkyl optionally substituted with one R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-9cycloalkyl optionally substituted with one R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-7cycloalkyl optionally substituted with one R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is CF.,, cycloalkyI optionally substituted with one R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-5cycloalkyl optionally substituted with one R20c. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-4cycloalkyl optionally substituted with one R20c.
[00204] In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3.1 icycloalkyl, including C6-14cycloalkyI. C6-9cycloalkyl, C3-7 cycloalkyI, C3-6cycloalkyI. C3- 5cycloalkyl, and C3-4 cycloalkyI each of which being optionally substituted with two R20c. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is Cg.
1 icycloalkyl optionally substituted with two R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-9cycloalkyl optionally substituted with two R20c. In embodiments of a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R9 is C . -cycloalkyI optionally substituted with two R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-6 cycloalkyl optionally substituted with one R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-5cycloalkyl optionally substituted with two R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C-,. icycloalky I optionally substituted with two R20c.
[00205] In each of the above embodiments, R20c is independently selected from amino, -CN, C1-9alkyl, C1-9alkoxy, C|., haloalky I. -OH, -N(R24)C(O)R25, and -C(O)N(R22)(R23). In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is amino. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -CN. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is C1-9alkyl. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is C1-3alkoxy . In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is C1-3haloalkyl. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is --OH. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -N(R24)C(O)R25. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)N(R22)(R23). In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -NHC(O)R25. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)NH(R22). In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -NHC(O)R25 and R25 is C2-9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6 alkoxy, CF. -cycloalkyI. C2-9heterocycloalkyI. C6-10aryl, and C1-9heteroaryl. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)NH(R22) and R22 is C2-9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -NHC(O)R25 and R25 is C2-5heterocycloalkyI optionally substituted with one C1-6alkyl. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)NH(R22) and R22 is CGshctcrocycloalky I optionally substituted with one C1-6alkyl. [00206] In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-14cycloalkyI (including C6-14cycloalkyI. C6-9cycloalkyl, C3-7 cycloalkyI C3-6 cycloalkyI C3- 5cycloalkyI. and C3-4cycloalkyl), optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is Ce- 14cycloalkyI (including C6-14cycloalkyl, C6-9cycloalkyl. C3-7 cycloalkyI C3-6 cycloalkyI C3-5 cycloalkyI and C3- 4cycloalkyl), optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-14cycloalkyl (including C6-14cycloalkyl. C6-9cycloalkyl, C3-7 cycloalkyI. C3-6 cycloalkyI. C3-5 cycloalkyI. and C3-4 cycloalkyl), optionally substituted with one, two, or three R20c that is C1-9alkyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is G-i icycloalkyl (including Cg. i icycloalkyI. C6-9cycloalkyl C3-7cycloalkyl, C3-6 cycloalkyI C3-5 cycloalkyI and C3-4cycloalkyl), optionally substituted with one, two, or three R20c that is G-ialkoxy. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-14cycloalkyl (including G.i icycloalky I. G,. ecycloalkyI. C3-7 cycloalkyI. C3-6 cycloalkyI C3-5 cycloalkyI and C3-4cycloalkyl), optionally substituted with one, two, or three R20c that is G.. haloalky I. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-14cycloalkyl (including G, - icycloalkyl. G.ecycloalkyk C3-7cycloalkyl, C3-6 cycloalkyI G.scycloalkyl, and C3-4cycloalkyl). optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C'e-i icycloalkyI (including C6-14cycloalkyl. C6-9cycloalkyl. C3-7cycloalkyl, C3-6 cycloalkyI, C3- scycloalkyI. and C3 - icycloalkyl), optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is Cg. ucycloalkyl (including C6-14cycloalkyI. C6-9cycloalkyl. C3-7 cycloalkyI. C3-6 cycloalkyI C3-5cycloalkyl, and C3- 4cycloalkyl), optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is G- 1 icycloalkyI (including C6-14cycloalkyI. C6-9cycloalkyl. C3-7 cycloalkyI C3-6 cycloalkyI C3-5cycloalkyl and C3- icycloalkyl), optionally substituted with one, two, or three R20c that is -NHC(O)R25. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-14cycloalkyI (including G.i icycloalkyI. C6-9cycloalkyl, G. -cycloalkyI. C3-6 cycloalkyI G.scycloalkyk and C3-4cycloalkyl), optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-7 cycloalkyI, C1-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-14cycloalkyl (including G- 1 icycloalkyI. C6-9cycloalkyl, C3- 7cycloalkyl. C3-6 cycloalkyI C3-5cycloalkyl, and C3-4cycloalkyl). optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-5heterocycloalkyI optionally substituted with one G -ealky I. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-14cycloalkyI (includingC6-14cycloalkyl. C3-6 cycloalkyI Cs-scycloalky 1, C3- 6cycloalkyI. C3-5 cycloalkyI and C3-4cycloalkyl), optionally substituted with one, two, or three R20c that is - C(O)N(R22)(R23). In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is G-i icycloalky l (including C6-14cycloalkyl. C6-9cycloalkyl, C3-7 cycloalkyI C3- 6cycloalkyI. C3-5 cycloalkyI. and C3-4cycloalkyl), optionally substituted with one, two, or three R20c that is - C(O)NH(R22). In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-14cycloalkyl (including C6-14cycloalkyl. C6-9cycloalkyl, C3-7Cycloalkyl, C3- ecycloalkyl, C .scycloalkyl. and Csucycloalkyl), optionally substituted with one, two, or three R20c that is - C(O)NH(R22) and R22 is Ci-Jictcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-14cycloalkyl (including G,- icycloalkyL C6-9cycloalkyl, C3-7Cycloalkyl, Ci.ecy cloalky 1, Ci.scycloalkyI. and C3-4cycloalkyl), optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is Ck-sheterocycloalkyI optionally substituted with one C1-6alkyl.
[00207] In embodiments of a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is Ck-'JieicrocycloalkyI. including C6-9heterocycloalkyl, Ckdieterocycloalkyl, C3-
,, heterocycloalkyl, C5-6 heterocycloalkyl, Ci.dicterocycloalkyI. CM hctcrocy cloalky 1, each of which being optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-9heterocycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (III'), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R9 is Cs^heterocycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3. ijictcrocycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is Cs-r, heterocycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-5 heterocycloalkyl optionally substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is Ci.ihctcrocycloalkyI optionally substituted with one, two, or three R20c.
[00208] In embodiments, each of the R9 described above including C„.)heterocycloalkyl. G.-dicicrocycloalkyk C3- sheterocycloalkyl, C5.6 heterocycloalkyl, Cs.jheterocycloalkyl, C.ihclerocycloalky 1, is optionally substitued with one R20c. In embodiments, each of the R9 described above, including Ce-gheterocycloalkyl, Ci- hctcrocy cloalky 1, C3- „heterocycloalkyI. C5-6 heterocycloalkyl, Ci.dicterocycloalkyl. Cg-rheterocycloalkyl, is optionally substituted with two R20c. In embodiments, each of the R9 described above, including C6-9heterocycloalkyl, C3-7heterocycloalkyl, C3- nheterocycloalkyI. Cs-r, heterocycloalkyl, Cs-jheterocycloalkyl, C3-4heterocycloalkyl, is optionally substituted with three R20c.
[00209] In each of the above embodiments, R20c is independently selected from amino, -CN, Cj.ialky I. C1-9alkoxy, C1-9haloalkyk -OH, -N(R24)C(O)R25, and -C(O)N(R22)(R23). In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is amino. In some embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -CN. In some embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is Chalky 1. In some embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is C i.salkoxy . In some embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is Ci-, haloalky I. In some embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -OH. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -N(R24)C(O)R25. In some embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)N(R22)(R23). In some embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -NHC(O)R25. In some embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)NH(R22). In some embodiments of a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R20c is -NHC(O)R25 and R25 is Ch-UieterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-9haloalkyl, C1-6 alkoxy, Ch. -cycloalkyI. Cs-<, heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In some embodiments of a compound of Formula (III'), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)NH(R22) and R22 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In some embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R20c is -NHC(O)R25 and R2i is Cs-sheterocycloalkyl optionally substituted with one C1-6alkyl. In some embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R20c is -C(O)NH(R22) and R22 is Cs-sheterocycloalkyl optionally substituted with one C1-6alkyl.
[00210] In embodiments of a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyI (including C6-9heterocycloalkyI, C3-7heterocycloalkyI, C3.
,, heterocycloalkyl, C5-6heterocycloalkyI. C3-5heterocycloalkyI. and C3-4heterocycloalkyI), optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl. C3. -helerocycloalkyI. C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyI. and Csuheterocycloalky 1), optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyl (including C,,- sheterocycloalkyl, C3- -heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalky 1, and Cs- ■iheterocycloalkyl), optionally substituted with one, two, or three R20c that is C1-9alkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2- siheterocycloalkyl (including C6-9heterocycloalkyI. C3-7heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl. and C3-4heterocycloalkyI). optionally substituted with one, two, or three R20c that is C3-7.alkoxy. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyI (including C6-9heterocycloalkyI. C3-7heterocycloalkyI. C3-6heterocycloalkyl, C5- 6heterocycloalkyl, C3-5heterocycloalkyI, and C3-4heterocycloalkyI), optionally substituted with one, two, or three R20c that is C1-9haloalkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyl (including C6-9heterocycloalkyI. C3-7heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyI ). optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9 heterocycloalkyl (including C6-9heterocycloalkyl, C3- 7heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyI), optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyl (including C6- 9heterocycloalkyl, C3-7heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and Cs- iheterocycloalkyI), optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2- 9heterocycloalkyl (including C6-9heterocycloalkyl. C3-7heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is - NHC(O)R25. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl, C3-7heterocycloalkyl. C3- 6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1- 6 alkyl. C1-6haloalkyl, C1-6alkoxy, C3-7 cycloalkyl. C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl. C3. 7heterocycloalkyI. C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl. C3- 7heterocycloalkyl, C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyl (including C6-9heterocycloalkyl, C3- -hetcrocycloalkyl, C3-6heterocycloalkyl. C5-6heterocycloalkyl, C3- sheterocycloalkyl, and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is - C(O)NH(R22). In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyl (including Ce-gheterocycloalkyl, C3-7heterocycloalkyl, Cs- eheterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalkyl, and C3-4heterocycloalkyl), optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyl (including C6- 9heterocycloalkyl, C3-7heterocycloalkyl . C3-6heterocycloalkyl, C5-6heterocycloalkyl, C3-5heterocycloalky 1, and C3- 4heterocycloalkyl), optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2- 5heterocycloalkyl optionally substituted with one C1-6alkyl.
[00211] In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro-2H- thiopyran 1,1-dioxide substituted with one, two, or three R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent 4λ2 -thiomorpholine substituted with two R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is tetrahydro-2H-thiopyranyl 1,1-dioxide. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2-thiomorpholiny 1 substituted with two R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl substituted with one R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl substituted with one R20c. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl substituted with one R20c.
[00212] In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyl substituted with one methyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is Cs-sheterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-7heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C’,.(,hcicrocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R9 is Cs- JictcrocycloalkyI substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is Cs- sheterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C’,.|heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-7heterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is Cmheicrocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R9 is C1-9hcterocycloalkyI substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is Csheterocycloalkyl substituted with one methyl, one ethyl, or one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C4heterocycloalkyl substituted with one methyl, one ethyl, or one propyl.
[00213] In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-9heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C;.?heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-6heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is Cs-Jieterocycloalky I substituted with one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C5-6heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3. 4heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C4-5heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R9 is C5heterocycloalkyl substituted with one propyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C4heterocycloalkyl substituted with one propyl.
[00214] In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C1-6heterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-7heterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is C4-7heterocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R9 is C1-9heterocycloalkyI substituted with one isopropyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C-hctcrocycloalkyl substituted with one isopropyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C4heterocycloalkyl substituted with one isopropyl.
[00215] In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-9heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C2-7heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C4-7heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C6-9heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-7heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3 6heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C5-6heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is Cs.Jictcrocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C3-4heterocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C1-9heicrocycloalkyl substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C5heterocycloalkyI substituted with two oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is C4heterocycloalkyl substituted with two oxo.
[00216] In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is Ci.jalkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is C .’.alkoxy. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is Ci.
, haloalky I. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is - NHC(O)R25 and R25 is C1-9heterocy cloalky 1 optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-7cycloalkyI. C1-9heterocycloalkyl, Cg-ioaryl, and Ci- sheteroaryl. In embodiments of a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is Ci. sheterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is - C(O)NH(R22) and R22 is CF-sheterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C1-9heterocycloalkyl optionally substituted with one C1-6alkyl.
[00217] In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro-2H-thiopyran 1,1 -dioxide, optionally substituted with one, two, or three R20c that is C1-9alkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro -2H- thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20c that is C1-9alkoxy. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is thianyl, optionally substituted with one, two, or three R20c that is Ci- , haloalky I. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro -2H- thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (ID’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20c that is -NHC(O)R25. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro-2H-thiopyran 1, 1 -dioxide, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-7cycloalkyl, C2-9heterocycloalkyl. C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro-2H-thiopyran 1, 1 -dioxide, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-5heterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro- 2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20c that is - C(O)NH(R22) and R22 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is monovalent tetrahydro-2H-thiopyran 1,1-dioxide, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is Cj-sheterocycloalkyl optionally substituted with one C1-6alkyl.
[00218] In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2-thiomorpholiny 1, optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2- thiomorpholinyl, optionally substituted with one, two, or three R20c that is C1-9alkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4V-thiomorpholinyl, optionally substituted with one, two, or three R20c that is Ci.yilkoxy. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2-thiomorpholiny 1, optionally substituted with one, two, or three R20c that is C1- 3 haloalky I. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2-thiomorpholinyl. optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2-thiomorphol i ny 1, optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2-thiomorpholi ny 1, optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2-thiomorpholi ny I. optionally substituted with one, two, or three R20c that is -NHC(O)R25. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20c that is - NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-7cycloalkyl, C2-9heterocycloalkyl. C6-10aryl, and C1- 9heteroaryl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2-thiomorpholiny 1, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2-thiomorpholiny 1, optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2-thiomorpholiny 1, optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4λ2-thiomorpholinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is 4k2-thiomorpholinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is Ck-shetcrocycloalky I optionally substituted with one C1-6alkyl.
[00219] In embodiments of a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is C1-9alkyl. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is C ., alkoxy . In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is C1-3haloalkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1 -6aloalkyI. C1-6alkoxy, C3-7cycloalkyl, C2-9heterocycloalkyI. C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-5heterocycloalkyI optionally substituted with one C1-6alkyl. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2-9heterocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperidinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2- 5heterocycloalkyI optionally substituted with one C1-6alkyl.
[00220] In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is Ci-3alkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is C ., alkoxy . In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is C1-3haloalkyl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (ID’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R2i. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocy cloalky 1 optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C|.<alko\y , C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one Ci. ealkyl. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2-9hctcrocycloalkyI optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is piperazinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is CF- slielerocycloalkyI optionally substituted with one C1-6alkyl.
[00221] In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is amino. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -CN. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is Ci-3alkyl. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is Ci-3alkoxy . In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is Ci-, haloalky I. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -OH. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is oxo. In embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -N(R24)C(O)R25. In embodiments of a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalky 1, C1-6alkoxy, C3-7cycloalkyl, C1-6heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -NHC(O)R25 and R25 is C2-9heterocycloalkyl optionally substituted with one Ci- ealkyl. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -C(O)N(R22)(R23). In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22). In embodiments of a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is R20c that is optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl. In embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, R9 is pyrrolidinyl, optionally substituted with one, two, or three R20c that is -C(O)NH(R22) and R22 is C2- 5heterocycloalkyI optionally substituted with one C1-6alkyl.
[00222] In some embodiments is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000105_0001
[00223] In some embodiments is a compound of Formula (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000105_0002
[00224] In some embodiments is a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000106_0001
[00225] In some embodiments is a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000106_0002
[00226] In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000107_0001
[00227] In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000107_0002
[00228] In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000108_0001
[00229] In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000108_0002
[00230] In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000109_0001
[00231] In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000109_0002
[00232] In some embodiments is a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000110_0001
[00233] In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000110_0002
[00234] In some embodiments is a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000111_0001
[00235] In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000112_0001
[00236] In some embodiments is a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is
Figure imgf000113_0001
[00237] In some embodiments of a compound of Formula (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000113_0002
In some embodiments of a compound of Formula (III’), (III), or (III-
1), or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000113_0003
some embodiments of a compound of Formula (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, R9 is
Figure imgf000113_0004
In some embodiments of a compound of Formula (III'), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000113_0005
[00238] In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (II), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from C1-6alky 1 and C1-6haloalkyl. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CH3.
[00239] In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. [00240] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three R20a. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C1-6alkyl optionally substituted with one, two, or three R20a. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is unsubstituted C1-6alkyl. In some embodiments is a compound of (F), (I), (I- 1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments is a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R2 is C|. , alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one, two, or three R20a and R20a is C1-9heterocycloalkyl. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R2 is C2- sheterocycloalkyI optionally substituted with one, two, or three R20a and R20a is -N(R22)(R23) and R22 and R23 are independently selected from H and C1-6alkyl (e.g., methyl). In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R2 is -OR12, R12 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20e and R20e is C1-6alkyl (e.g., methyl, ethyl, or propyl). In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III'), (III), or (III-l), R2 is -OR12, R12 is C1-6alkyl optionally substituted with one, two, or three R20e, and R20e is CF- shctcrocycloalkyl optionally substituted with one, two, or three C1-6alkyl (e.g., methyl, ethyl, or propyl).
[00241] In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a 6-10 membered aryl ring substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl substituted with one or more R10. In some embodiments is a compound of Formula (F), (I), (I- 1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl substituted with one, two, or three R10. In some embodiments is a compound of Formula (F), (I), (I- 1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a 5-10 membered heteroaryl ring are substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a 5-10 membered heteroaryl ring are substituted with one, two, or three R10. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein each R10 is independently selected from halogen, C1-6alkyl, C3-7cycloalkyI. C2- 9heterocycloalkyI. C6-10aryl, C1-9heteroaryl, -OR12, and N(R12)(R13), wherein C1-6alkyl, C3-7cycloalkyI. C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein each R10 is independently selected from halogen, C|.,alky 1. and N(R12)(R13), wherein C1-6alky 1 is optionally substituted with one, two, or three R20d. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein each R10 is independently selected from halogen, C1-6alkyl, and N(R12)(R13), wherein C1-6alky I is substituted with one, two, or three R20d, and each R20d is halogen.
[00242] In embodiments, R20a, R20b, R20c, R20d, R20e, R2M, R20g, and R20h are each independently selected from halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkeny 1, C2-6alkynyl, C3-10cycloalkyl, CH2-C3-10cycloalkyl . C2. sheterocycloalkyl, -CH2-C1-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroar l. -OR21, -SR21, -N(R22)(R23), - C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), - N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-9alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, Ci- ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, - S(O)2N(R22)(R23), and -OC(O)R25.
[00243] In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III’), (III), or (III- 1), R20b is C1-6alkyl (e.g., methyl, ethyl, or propyl) optionally substituted with one, two, or three - N(R22)(R23) and R22 and R23 are independently selected from H and C|.,alkyl (e.g., methyl). In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20b is Ci. ealkyl (e g., methyl, ethyl, or propyl) optionally substituted with one, two, or three -OR21 and R21 is independently selected from H and C1-6alky. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1 ), (III’), (III), or (III- 1), R20b is selected from -CH2-C6-10aryl and -CN. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20b is selected from oxo and =NH. In embodiments of a compound of Formula (I’), (I), (I- 1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (DI’), (III), or (III-l), R20b is C2-9heterocycloalkyI. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20b is -C(O)R25 and R25 is Ci-6alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), R20b is -C(O)R25 and R25 is C2-6heterocycloalkyl optionally substituted with one, two, or three C1-6alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), R20b is C1-6alkyl optionally substituted with one, two, or three groups independently selected from oxo, - OR21, and -N(R22)(R23), R21 is H, and R22 and R23 are independently selected from H and C |.(, alkyl (e.g., methyl).
[00244] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), R20c is C1-6 alky 1 (e.g., methyl, ethyl, or propyl) optionally substituted with one, two, or three - N(R22)(R23) and R22 and R23 are independently selected from H and C|_, alkyl (e.g., methyl). In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20c is Ci- „alkyl (e g., methyl, ethyl, or propyl) optionally substituted with one, two, or three -OR21 and R21 is independently selected from H and C1-6alky. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), R20c selected from -CH2-C6-10aryl and -CN. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20c is selected from oxo and =NH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (nF), (III), or (III-l), R20c is C2-9heterocycloalkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20c is -C(O)R25 and R25 is C1-6alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), R20c is -C(O)R25 and R25 is C2-6hetcrocycloalkyl optionally substituted with one, two, or three C1-6alkyl. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), R20c is C 1-6 alkyl optionally substituted with one, two, or three groups independently selected from oxo, - OR21, and -N(R22)(R23), R21 is H, and R22 and R23 are independently selected from H and C1-6alky I (e.g., methyl). [00245] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III'), (III), or (III-l), wherein R1 is benzothiazolyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is 1 //-benzo [</|imidazoly 1 optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is benzo [c]thiophenyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (in), or (III-l), wherein R1 is benzo [b ]thiophenyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is indanyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is indenyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is tetrahnyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is coumaranyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is furanyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is thiophenyl optionally substituted with one or more R10 In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is oxazolyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is thiazolyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is 1H -indazolyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (ni’), (III), or (III-l), wherein R1 is imidazo[ 1 ,2-α]pyridinyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is pyrazolyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is l//-indolyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is pyridinyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (HI’), (III), or (III-l), wherein R1 is pyrimidinyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is pyrizinyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), wherein R1 is l//-imidazolyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (III), or (III-l), wherein R1 is 1,4-benzodioxanyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is 3,4-dihydrobenzo[l,4]oxazinyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (III), or (III-l), wherein R1 is benzo [b] |furany 1 optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (nF), (III), or (III-l), wherein R1 is benzo [c]furanyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is phenyl optionally substituted with one or more R10. In some embodiments is a compound of Formula (I'), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), wherein R1 is naphthalenyl optionally substituted with one or more R10.
[00246] In some embodiments is a compound of Formula (I'), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III’), (III), or (III-l), wherein R1 is (benzo[d][l,3]dioxol-4-yl, l,8a-dihydroimidazo[l,2-a]pyridin-8-yl, 1H- indazol-4-yl, lH-indazol-5-yl, lH-indazol-6-yl, lH-indazol-7-yl, lH-inden-4-yl, lH-inden-5-yl, lH-inden-6-yl, 1H- inden-7-yl, 2,3-dihydro-lH-inden-4-yl, 2,3 -dihydro- lH-inden-5-yl, 2,3-dihydrobenzo[b][l,4]dioxin-5-yl, 2,3- dihydrobenzo[b] [l,4]dioxin-6-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzoluran- 6-yl, 2,3-dihydrobenzofuran-7-yl, 3,4-dihydro-2H-benzo[b] [ 1,4] oxazin-5 -yl, 3,4-dihydro-2H-benzo[b] [l,4]oxazin- 6-yl, 3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl, 3,4-dihydro-2H-benzo[b][l,4]oxazin-8-yl, 4-(benzo[d][l,3]dioxol- 5-yl, 5,6,7,8-tetrahydronaphthalen-l-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, benzo [b]thiophen-4-yl, benzo [b]thiophen-5-yl, benzo [b]thiophen-6-yl, benzo[b]thiophen-7-yl, benzo[d]thiazol-4-yl, benzo [d]thiazol-5-yl, benzo [d]thiazol-6-yl, benzo [d]thiazol-7-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl, chroman-8-yl, furan-2-yl, furan-3-yl, imidazo[l,2-a]pyridin-5-yl, imidazo[l,2-a]pyridin-6-yl, imidazo[l,2-a]pyridin-7-yl, naphthalen-l-yl, naphthalen-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, or thiophen-3-yl, any of which is optionally substituted with one or more R10.
[00247] In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-
Figure imgf000117_0001
[00248] In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III’), (III), or (III-l), wherein R1 is
Figure imgf000118_0001
[00249] In some embodiments is a compound of Formula (I'), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-
1), (III’), (III), or (III-l), wherein R1 is
Figure imgf000118_0002
Figure imgf000118_0003
wherein each R2M is as described herein.
[00251] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (III), or (III-l), R20d is C1-6alkyl optionally substituted with one, two, or three groups independently selected from halogen and -OR21. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (I!!’), (III), or (III-l), R20d is C1-6alkyl optionally substituted with one, two, or three groups independently selected from halogen and -OH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20d is C1-6alkyl optionally substituted with one, two, or three groups independently selected from F and -OH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20d is C1-6alkyl optionally substituted with one - OH. In embodiments of a compound of Formula (I'), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20d is C1-6alkyl optionally substituted with one, two, or three F.
[00252] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), R20d is Ci.ialkyl optionally substituted with one, two, or three groups independently selected from halogen and -OR21. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (ni’), (III), or (III-l), R20d is C1-3alkyI optionally substituted with one, two, or three groups independently selected from halogen and -OH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), R20d is Ci.mlkyl optionally substituted with one, two, or three groups independently selected from F and -OH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III- 1 ), R20'1 is Ci-,al ky 1 substituted with one, two, or three groups independently selected from halogen and -OR21. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R2M is Ci-3alkyl substituted with one, two, or three groups independently selected from halogen and -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R20d is Ci.3alkyl substituted with one, two, or three groups independently selected from F and -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III'), (III), or (III-l), R20d is Ci-3alkyl substituted with one -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III'), (III), or (III-l), R20d is Ci-3alkyl substituted with one, two, or three F.
[00253] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III'), (III), or (III-l), R20d is isopropyl optionally substituted with one, two, or three groups independently selected from halogen and -OR21. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (IH’), (III), or (III-l), R20d is isopropyl optionally substituted with one, two, or three groups independently selected from halogen and -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb),
(lc), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20d is isopropyl optionally substituted with one, two, or three groups independently selected from F and -OH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), R20d is isopropyl substituted with one, two, or three groups independently selected from halogen and -OR21. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R20d is isopropyl substituted with one, two, or three groups independently selected from halogen and -OH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20d is isopropyl substituted with one, two, or three groups independently selected from F and -OH. In embodiments of a compound of Formula (I’), (I), (1-1),
(la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R20d is isopropyl substituted with one -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R20d is isopropyl substituted with one, two, or three F.
[00254] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III'), (III), or (III-l), R20d is ethyl optionally substituted with one, two, or three groups independently selected from halogen and -OR21. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R20d is ethyl optionally substituted with one, two, or three groups independently selected from halogen and -OH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R20d is ethyl optionally substituted with one, two, or three groups independently selected from F and -OH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic),
(ld), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20d is ethyl substituted with one, two, or three groups independently selected from halogen and -OR21. In embodiments of a compound of Formula (I’), (I), (1-1), (la),
(lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R20d is ethyl substituted with one, two, or three groups independently selected from halogen and -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20d is ethyl substituted with one, two, or three groups independently selected from F and -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III- 1), R20d is ethyl substituted with one -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (HI’), (III), or (III-l), R20d is ethyl substituted with one, two, or three F.
[00255] In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R20d is methyl optionally substituted with one, two, or three groups independently selected from halogen and -OR21. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R20d is methyl optionally substituted with one, two, or three groups independently selected from halogen and -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20d is methyl optionally substituted with one, two, or three groups independently selected from F and -OH. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R20d is methyl substituted with one, two, or three groups independently selected from halogen and -OR21. In embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R20d is methyl substituted with one, two, or three groups independently selected from halogen and -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R20d is methyl substituted with one, two, or three groups independently selected from F and -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III'), (III), or (III-l), R20d is methyl substituted with one -OH. In embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R2M is methyl substituted with one, two, or three F.
[00256] In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III’), (III), or (III-l), wherein R1 is
Figure imgf000120_0001
[00257] In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III’), (III), or (III-l), wherein R1 is
Figure imgf000120_0002
[00258] In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-
Figure imgf000121_0001
. In some embodiments of a compound of Formula (I’), (I), (1-1),
Figure imgf000121_0007
Figure imgf000121_0002
In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If),
Figure imgf000121_0003
n some embodiments of a compound of Formula
Figure imgf000121_0004
some embodiments of a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III'),
Figure imgf000121_0005
some embodiments of a compound of Formula (I’), (I), (1-1), (la),
Figure imgf000121_0008
Figure imgf000121_0006
. In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If),
Figure imgf000122_0001
In some embodiments of a compound of Formula
Figure imgf000122_0005
, , , , , , , , ,
Figure imgf000122_0002
some embodiments of a compound of Formula
Figure imgf000122_0006
Figure imgf000122_0003
In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb),
Figure imgf000122_0004
some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III-l), R1 is
Figure imgf000123_0001
In some embodiments of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If),
Figure imgf000123_0002
. In some embodiments of a compound of Formula
Figure imgf000123_0003
[00260] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (III), or (III-l), wherein R1 is
Figure imgf000124_0001
[00261] In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III’), (III), or (III-l), wherein R1 is
[00262] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II 1), (HI’), (III), or (III-l), wherein R1 is
Figure imgf000126_0001
[00263] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (HI’), (III), or (III-l), wherein R1 is
Figure imgf000127_0001
[00264] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (HI), or (III-l), wherein R1 is
Figure imgf000128_0001
, or
[00265] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (HI’), (III), or (III-l), wherein R1 is
Figure imgf000129_0001
[00266] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (III), or (III-l), wherein R1 is
Figure imgf000130_0001
[00267] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III'), (III), or (III-l), wherein R1 is
Figure imgf000131_0001
[00268] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (III), or (III-l), wherein R1 is
Figure imgf000132_0001
[00269] In some embodiments is a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (III), or (III-l), wherein R1 is
Figure imgf000133_0001
[00271] In some embodiments is a compound of Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-
1), (III’), (III), or (III-l), wherein R1 is
Figure imgf000134_0001
R3 is cyclopentyl, cyclohexyl, pyrrolyl, pyrrolidinyl, piperidyl, pyridyl, phenyl, pyrazolyl, tetrahydropyridinyl, dihydropyridinyl. -O-pyrrolidinyl, -O-tetrahydrofuranyl, -O-piperidinyl, or thianyl, wherein the cyclopentyl, cyclohexyl, pyrrolyl, pyrrolidinyl, piperidyl, pyridyl, phenyl, pyrazolyl, tetrahydropyridinyl, dihydropyridinyl. -O- pyrrolidinyl, -O-tetrahydrofuranyl, -O-piperidinyl, or thianyl is optionally substituted with one, two, or three R20b. [00274] In some embodiments is a compound of Formula (I), (1-1), (la), (lb), (Ic), (Id), (le), or (If), wherein R1 is
Figure imgf000135_0001
and
R3 is cyclopentyl, cyclohexyl, pyrrolyl, pyrrolidinyl, piperidyl, pyridyl, phenyl, pyrazolyl, tetrahydropyridinyl, dihydropyridinyl. -O-pyrrolidinyl, -O-tetrahydrofuranyl, -O-piperidinyl, or thianyl, wherein the cyclopentyl, cyclohexyl, pyrrolyl, pyrrolidinyl, piperidyl, pyridyl, phenyl, pyrazolyl, tetrahydropyridinyl, dihydropyridinyl. -O- pyrrolidinyl, -O-tetrahydrofuranyl, -O-piperidinyl, or thianyl is optionally substituted with one, two, or three R20b.
Figure imgf000135_0002
Figure imgf000135_0003
Figure imgf000136_0001
[00276] In some embodiments is a compound of Formula (II’), (II), or (II-l), wherein R1 is
Figure imgf000136_0002
R7 is cyclopentyl, cyclohexyl, pyrrolyl, pyrrolidinyl, piperidyl, pyridyl, phenyl, pyrazolyl, tetrahydropyridinyl, dihydropyridinyl. -O-pyrrolidinyl, -O-tetrahydrofuranyl, -O-piperidinyl, or thianyl, wherein the cyclopentyl, cyclohexyl, pyrrolyl, pyrrolidinyl, piperidyl, pyridyl, phenyl, pyrazolyl, tetrahydropyridinyl, dihydropyridinyl. -O- pyrrolidinyl, -O-tetrahydrofuranyl, -O-piperidinyl, or thianyl is optionally substituted with one, two, or three R20c. [00277] In some embodiments is a compound of Formula (II’), (II), or (II-l), wherein R1 is
Figure imgf000137_0001
and
R7 is cyclopentyl, cyclohexyl, pyrrolyl, pyrrolidinyl, piperidyl, pyridyl, phenyl, pyrazolyl, tetrahydropyridinyl, dihydropyridinyl. -O-pyrrolidinyl, -O-tetrahydrofuranyl, -O-piperidinyl, or thianyl, wherein the cyclopentyl, cyclohexyl, pyrrolyl, pyrrolidinyl, piperidyl, pyridyl, phenyl, pyrazolyl, tetrahydropyridinyl, dihydropyridinyl. -O- pyrrolidinyl, -O-tetrahydrofuranyl, -O-piperidinyl, or thianyl is optionally substituted with one, two, or three R20c. [00278] In some embodiments is a compound of Formula (II’), (II), or (II-l), wherein R1 is
Figure imgf000137_0002
Figure imgf000138_0001
[00279] In some embodiments is a compound of Formula (III ), (III), or (III-l), wherein R1 is
Figure imgf000138_0002
R9 is cyclopentyl, cyclohexyl, pyrrolyl, pyrrolidinyl, piperidyl, pyridyl, phenyl, pyrazolyl, tetrahydropyridinyl, dihydropyridinyl, or thianyl, wherein the cyclopentyl, cyclohexyl, pyrrolyl, pyrrolidinyl, piperidyl, pyridyl, phenyl, pyrazolyl, tetrahydropyridinyl, dihydropyridinyl, or thianyl is optionally substituted with one, two, or three R20c. [00280] In some embodiments is a compound of Formula (III’), (III), or (III-l), wherein R1 is
Figure imgf000139_0001
and
R9 is cyclopentyl, cyclohexyl, pyrrolyl, pyrrolidinyl, piperidyl, pyridyl, phenyl, pyrazolyl, tetrahydropyridinyl, dihydropyridinyl, or thianyl, wherein the cyclopentyl, cyclohexyl, pyrrolyl, pyrrolidinyl, piperidyl, pyridyl, phenyl, pyrazolyl, tetrahydropyridinyl, dihydropyridinyl, or thianyl is optionally substituted with one, two, or three R20c.
Figure imgf000139_0002
R9 is
Figure imgf000139_0003
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
or a pharmaceutically acceptable salt or solvate thereof.
[00283] In some embodiments is a compound selected from:
Figure imgf000146_0002
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000160_0002
Further Forms of Compounds Disclosed Herein
Isomers
[00284] Furthermore, 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, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. 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 optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. 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 (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boihng 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, by any practical means that does not result in racemization.
Labeled compounds
[00285] 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 are incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2H, 3H, 13C, 14C, 15N, 17O, 180, 31P, 32P, 35S, 18F, and 36C1, respectively. Compounds described herein, and pharmaceutically acceptable salts, esters, 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 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, 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 compounds, pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative thereof is prepared by any suitable method.
[00286] 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
[00287] 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. [00288] In some embodiments, the compounds described herein possess acidic or basic groups and therefore 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 described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
Solvates
[00289] In some embodiments, the compounds described herein exist as solvates. In some embodiments are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.
[00290] 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 are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein 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.
[00291] In an aspect is provided a compound having the formula A-LAB -B wherein
A is a monovalent form of a compound described herein;
LAB is a covalent linker bonded to A and B; and
B is a monovalent form of a degradation enhancer.
[00292] A "degradation enhancer" is a compound capable of binding a ubiquitin ligase protein (e g., E3 ubiquitin ligase protein) or a compound capable of binding a protein that is capable of binding to a ubiquitin hgase protein to form a protein complex capable of conjugating a ubiquitin protein to a target protein. In embodiments, the degradation enhancer is capable of binding to an E3 ubiquitin ligase protein or a protein complex comprising an E3 ubiquitin ligase protein. In embodiments, the degradation enhancer is capable of binding to an E2 ubiquitin- conjugating enzyme. In embodiments, the degradation enhancer is capable of binding to a protein complex comprising an E2 ubiquitin-conjugating enzyme and an E3 ubiquitin ligase protein.
[00293] In embodiments, the degradation enhancer is capable of binding a protein selected from E3A, mdm2, APC, EDD1, SOCS/BC-box/eloBC/CUL5/RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HER5, HERC6, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2 , STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHL (von-Hippel- Lindau ubiquitin ligase), WWP1, WWP2, Parkin, MKRN1, CMA (chaperon-mediated autophage), SCFb-TRCP (Skip-Cullin-F box (Beta-TRCP) ubiquitin complex), b-TRCP (b-transducing repeat-containing protein), cIAPl (cellular inhibitor of apoptosis protein 1), APC/C (anaphase-promoting complex/cyclosome), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL4CRBN) ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, S0CS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, S0CS6, FBXO4, FBXO31, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885. [00294] In embodiments, the degradation enhancer is capable of binding a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2L1, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.
[00295] In embodiments, the degradation enhancer is a compound described in Ishida and Ciulli, SLAS Discovery 2021, Vol. 25(4) 484-502, which is incorporated by reference in its entirety for any purpose, for example VH032, VH101, VH298, thalidomide, bestatin, methyl bestatin, nutlin, idasanutlin, bardoxolone, bardoxolone methyl, indisulam (E7070), E7820, chloroquinoxaline sulfonamide (CQS), nimbolide, KB02, ASTX660, lenalidomide, or pomalidomide.
[00296] In embodiments, the degradation enhancer is a compound described in US20180050021, WO2016146985, WO2018189554, WO2018119441, W02018140809, WO2018119448, WO2018119357, WO2018118598, W02018102067, WO201898280, WO201889736, W0201881530, W0201871606, WO201864589, WO201852949, WO2017223452, WO2017204445, WO2017197055, WO2017197046, W02017180417, WO2017176958, WO201711371, WO2018226542, WO2018223909, WO2018189554, WO2016169989, WO2016146985, CN105085620B, CN106543185B, US10040804, US9938302, US10144745, US10145848, US9938264, US9632089, US9821068, US9758522, US9500653, US9765019, US8507488, US8299057, US20180298027, US20180215731, US20170065719, US20170037004, US20160272639, US20150291562, or US20140356322, which are incorporated by reference in their entirety for any purpose.
[00297] In embodiments LAB is -LAB1-LAB2-LAB3-LAB4-LAB5-;
LAB1 LAB2 LA B3 LAB4 and L AB5 independently a bond, -O-, -N(R14)-, -C(O)-, -N(R14)C(O)-, -C(O)N(R14)-, -S-, - S(O)2-, -S(O)-, -S(O)2N(R14)-, -S(O)N(R14)-, -N(R14)S(O)-, -N(R14)S(O)2-, C1-6alkylene, (-O-C1-6alkyl)z-, (-C6- 6alkyl-O)z-, C2-6alkenylene, C2-6alkynylene, C1-6 haloalky Icnc. C3-12cycloalkylene, C1-11heterocycloalkylene, C6- 12arylene, or C1-11heteroarylene, wherein C1-6alkylene, C2-6alkenylene, C2-6alkynylene, C1-6haloalkylene, C3- 12cycloalkylene, C1-11heterocycloalkylene, C6-12arylene, or C1-11heteroarylene, are optionally substituted with one, two, or three R20j; wherein each C1-6alkyl of (-O-C1-6alkyl)z- and (-C1-6alkyl-O)z- is optionally substituted with one, two, or three R20j; z is independently an integer from 0 to 10; each R12 is independently selected from hydrogen, C1-6alkyl. C2-6alkenyl, C2-6alky nyl, C3-6cycloalkyl, -CH2-C3- ecycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl. and C1-9heteroaryl, wherein C1-9alkyl, C2-6alkeny 1, C2-9alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9 heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, C1-6alkyl. and C1-6 haloalkyI: or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20e; each R14 is independently selected from hydrogen, C1-6alkyl. and C1-6 haloalky I: each R15 is independently selected C1-6alkyl, C2-6alkenyl. C2-6alkynyl, C3-6CycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20f; each R20d, R20e, R20f, and R20j are each independently selected from halogen, -CN, C1-6alkyl, C2-6 alkenyl. C2-6alkynyl, C3-6 cycloalkyl. -CH2-C3-6 cycloalkyl, C1-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C3-10aryl, -CH2-C1-9heteroaryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6 cycloalkyl, -CH2-C3-6Cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2- C6-10aryl. -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, Ci.„haloalky I. alkoxy. Ci. ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C1-6alkeny 1, C2-6alkynyl, C3-6cycloalkyI. C2-
• lielcrocycloalkyl. C6-10aryl, and C1-9heteroaryl; each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkeny 1, C2-6alkynyl, C .f,cy cloalky I. C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; and each R25 is selected from C1-6alkyl, C2- 6 alkenyl. C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C3-10ary 1, and Ci. •.heteroaryk
[00298] In embodiments, LAB is -(O-C2alkyl)z- and z is an integer from 1 to 10.
[00299] In embodiments, LAB is -(C2alkyl-O-)z- and z is an integer from 1 to 10.
[00300] In embodiments, LAB is -(CH2)zz1LAB2(CH2O)zz2-, wherein LAB2 is a bond, a 5 or 6 membered heterocycloalkylene or hetero arylene, phenylene, -(C2- C4)alkynylene, -SO2- or -NH-; and zz1 and zz2 are independently an integer from 0 to 10.
[00301] In embodiments, LAB is -(CH2)zz1(CH2O)zz2-, wherein zzl and zz2 are each independently an integer from 0 to 10.
[00302] In embodiments, LAB is a PEG linker (e.g., divalent linker of 1 to 10 ethylene glycol subunits).
[00303] In embodiments, B is a monovalent form of a compound selected from
Figure imgf000164_0001
Figure imgf000165_0001
Synthesis of Compounds
[00304] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary.
[00305] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma- Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.
[00306] In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. In some embodiments, the following synthetic methods may be utilized.
General synthetic method for Formula (la)
Figure imgf000166_0001
General synthetic method for Formula (Id)
Figure imgf000167_0001
General synthetic method for Formula (II)
Figure imgf000168_0001
[00307] In some embodiments, the compounds of the present invention exhibit one or more functional characteristics disclosed herein. For example, a subject compound is capable of reducing Ras signaling output. In some instances, a subject compound is capable of disrupting Ras-SOS interaction, including disrupting interaction or binding between a mutant Kras (e.g., Kras G12C) and S0S1, or between a wildtype Kras and S0S1, thereby reducing Ras signaling output. In some embodiments, a subject compound binds specifically to a SOS protein, including SOS1. In some embodiments, the IC50 of a subject compound (including those shown in Table 1) for a SOS protein is less than about less than about 5 uM, less than about 1 uM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5nM, less than about lOOpM, or less than about 50 pM, as measured in an in vitro assay known in the art or exemplified herein.
[00308] A reduction in Ras signaling output can be evidenced by one or more members of the following: (i) an increase in steady state level of GDP-bound Ras protein; (ii) a reduction of phosphorylated AKTs473, (iii) a reduction of phosphorylated ERKT202/y204, (iv) a reduction of phosphorylated S6S235/236, (v) reduction (e.g., inhibition) of cell growth of Ras-driven tumor cells (e.g., those derived from a tumor cell line disclosed herein), and (vi) an interference or disruption of the interaction or binding between a SOS protein (e.g., SOS 1) with a Ras protein such as a wildtype or a mutant Ras. In some cases, the reduction in Ras signaling output can be evidenced by two, three, four, five, or all of (i)-(vi) above. [00309] It shall be understood that different aspects of the invention can be appreciated individually, collectively, or in combination with each other. Various aspects of the invention described herein may be applied to any of the particular applications disclosed herein. The compositions of matter including compounds of any formulae disclosed herein in the composition section of the present disclosure may be utilized in the method section including methods of use and production disclosed herein, or vice versa.
Methods
[00310] In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (ni’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a solid tumor or a hematological cancer. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a solid tumor. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (F), (I), (I- 1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II- 1), (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from prostate cancer, brain cancer, colon cancer, rectal cancer, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, cancer of the small intestine, cancer of the esophagus, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers, combinations of said cancers, and metastatic lesions of said cancers. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (F), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (in), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematological cancer. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (HI-1), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematological cancer selected from one or more of chronic lymphocytic leukemia (CLL), acute leukemias, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T-cell acute lymphoid leukemia (T-ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and preleukemia. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l ), (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is one or more cancers selected from the group consisting of chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), B cell acute lymphoblastic leukemia (B-ALL), and/or acute lymphoblastic leukemia (ALL).
[00311] Any of the treatment methods disclosed herein can be administered alone or in combination or in conjunction with another therapy or another agent. By "combination" it is meant to include (a) formulating a subject composition containing a subject compound together with another agent, and (b) using the subject composition separate from the another agent as an overall treatment regimen. By "conjunction" it is meant that the another therapy or agent is administered either simultaneously, concurrently or sequentially with a subject composition comprising a compound disclosed herein, with no specific time limits, wherein such conjunctive administration provides a therapeutic effect.
[00312] In some embodiment, a subject treatment method is combined with surgery, cellular therapy, chemotherapy, radiation, and/or immunosuppressive agents. Additionally, compositions of the present disclosure can be combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, immunostimulants, and combinations thereof.
[00313] In one embodiment, a subject treatment method is combined with a chemotherapeutic agent.
[00314] Exemplary chemotherapeutic agents include an anthracycline (e.g., doxorubicin (e.g., liposomal doxorubicin)), a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine), an alkylating agent (e.g., cyclophosphamide, decarbazine, melphalan, ifosfamide, temozolomide), an immune cell antibody (e g., alemtuzamab, gemtuzumab, rituximab, ofatumumab, tositumomab, brentuximab), an antimetabolite (including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)), a TNFR glucocorticoid induced TNFR related protein (GITR) agonist, a proteasome inhibitor (e.g., aclacinomycin A, gliotoxin or bortezomib), an immunomodulator such as thalidomide or a thalidomide derivative (e.g., lenalidomide). Additional chemotherapeutic agents contemplated for use in combination include busulfan (Myleran®), busulfan injection (Busulfex®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), mitoxantrone (Novantrone®), Gemtuzumab Ozogamicin (Mylotarg®), anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), dexamethasone, docetaxel (Taxotere®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), ifosfamide (II'EX®), irinotecan (Camptosar®), L -asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6 -mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6- thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).
[00315] Anti-cancer agents of particular interest for combinations with a compound of the present invention include: anthracy clines; alkylating agents; antimetabolites; drugs that inhibit either the calcium dependent phosphatase calcineurin or the p70S6 kinase FK506) or inhibit the p70S6 kinase; mTOR inhibitors; immunomodulators; anthracy clines; vinca alkaloids; proteosome inhibitors; GITR agonists; protein tyrosine phosphatase inhibitors; a CDK4 kinase inhibitor; a BTK inhibitor; a MKN kinase inhibitor; a DGK kinase inhibitor; or an oncolytic virus.
[00316] Exemplary antimetabolites include, without limitation, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors): methotrexate (Rheumatrex®, Trexall®), 5-fluorouracil (Adrucil®, Efudex®, Fluoroplex®), floxuridine (FUDF®), cytarabine (Cytosar-U®, Tarabine PFS), 6-mercaptopurine (Puri-Nethol®)), 6 -thioguanine (Thioguanine Tabloid®), fludarabine phosphate (Fludara®), pentostatin (Nipent®), pemetrexed (Alimta®), raltitrexed (Tomudex®), cladribine (Leustatin®), clofarabine (Clofarex®, Clolar®), azacitidine (Vidaza®), decitabine and gemcitabine (Gemzar®). Preferred antimetabolites include, cytarabine, clofarabine and fludarabine. [00317] Exemplary alkylating agents include, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman (Amedel®, Vercyte®), triethylenemelamine (Kernel®, Hexalen®, Hexastat®), triethylenethiophosphoramine, Temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and Dacarbazine (DTIC-Dome®). Additional exemplary alkylating agents include, without limitation, Oxaliplatin (Eloxatin®); Temozolomide (Temodar® and Temodal®); Dactinomycin (also known as actinomycin-D, Cosmegen®);
Melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan (Busulfex® and Myleran®); Carboplatin (Paraplatin®); Lomustine (also known as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® and Platinol®-AQ); Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® and Neosar®); Dacarbazine (also known as DTIC, DIC and imidazole carboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine (Matulane®); Mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, Mustargen®); Streptozocin (Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSP A, Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and Bendamustine HC1 (Treanda®).
[00318] In an aspect, compositions provided herein can be administered in combination with radiotherapy such as radiation. Whole body radiation may be administered at 12 Gy. A radiation dose may comprise a cumulative dose of 12 Gy to the whole body, including healthy tissues. A radiation dose may comprise from 5 Gy to 20 Gy. A radiation dose may be 5 Gy, 6 Gy, 7 Gy, 8 Gy, 9 Gy, 10 Gy, 11 Gy, 12, Gy, 13 Gy, 14 Gy, 15 Gy, 16 Gy, 17 Gy, 18 Gy, 19 Gy, or up to 20 Gy. Radiation may be whole body radiation or partial body radiation. In the case that radiation is whole body radiation it may be uniform or not uniform. For example, when radiation may not be uniform, narrower regions of a body such as the neck may receive a higher dose than broader regions such as the hips. [00319] Where desirable, an immunosuppressive agent can be used in conjunction with a subject treatment method. Exemplary immunosuppressive agents include but are not limited to cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3 antibodies (e.g., muromonab, otelixizumab) or other antibody therapies, cytoxin, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation, peptide vaccine, and any combination thereof. In accordance with the presently disclosed subject matter, the above-described various methods can comprise administering at least one immunomodulatory agent. In certain embodiments, the at least one immunomodulatory agent is selected from the group consisting of immunostimulatory agents, checkpoint immune blockade agents (e.g., blockade agents or inhibitors of immune checkpoint genes, such as, for example, PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs and CD39), radiation therapy agents, chemotherapy agents, and combinations thereof. In some embodiments, the immunostimulatory agents are selected from the group consisting of IL-12, an agonist costimulatory monoclonal antibody, and combinations thereof. In one embodiment, the immunostimulatoiy agent is IL-12. In some embodiments, the agonist costimulatory monoclonal antibody is selected from the group consisting of an anti-4-lBB antibody (e.g., urelumab, PF-05082566), an anti-OX40 antibody (pogalizumab, tavolixizumab, PF-04518600), an anti-ICOS antibody (BMS986226, MEDI-570, GSK3359609, 1TX- 2011), and combinations thereof. In one embodiment, the agonist costimulatory monoclonal antibody is an anti-4-1 BB antibody. In some embodiments, the checkpoint immune blockade agents are selected from the group consisting of anti-PD-Ll antibodies (atezolizumab, avelumab, durvalumab, BMS-936559), anti-CTLA-4 antibodies (e.g., tremelimumab, ipilimumab), anti-PD-1 antibodies (e g., pembrolizumab, nivolumab), anti-LAG3 antibodies (e.g., C9B7W, 410C9), anti-B7-H3 antibodies (e.g., DS-5573a), anti-TIM3 antibodies (e.g., F38-2E2), and combinations thereof. In one embodiment, the checkpoint immune blockade agent is an anti-PD-Ll antibody. In some cases, a compound of the present disclosure can be administered to a subject in conjunction with (e.g., before, simultaneously or following) bone marrow transplantation, T cell ablative therapy using either chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH. In some cases, expanded cells can be administered before or following surgery. Alternatively, compositions comprising a compound described herein can be administered with immunostimulants.
Immuno stimulants can be vaccines, colony stimulating agents, interferons, interleukins, viruses, antigens, co stimulatory agents, immunogenicity agents, immunomodulators, or immunotherapeutic agents. An immuno stimulant can be a cytokine such as an interleukin. One or more cytokines can be introduced with modified cells provided herein. Cytokines can be utilized to boost function of modified T lymphocytes (including adoptively transferred tumor-specific cytotoxic T lymphocytes) to expand within a tumor microenvironment. In some cases, IL-2 can be used to facilitate expansion of the modified cells described herein. Cytokines such as IL- 15 can also be employed. Other relevant cytokines in the field of immunotherapy can also be utilized, such as IL-2, IL-7, IL-12, IL-15, IL-21, or any combination thereof. An interleukin can be IL-2, or aldesleukin. Aldesleukin can be administered in low dose or high dose. A high dose aldesleukin regimen can involve administering aldesleukin intravenously every 8 hours, as tolerated, for up to about 14 doses at about 0.037 mg/kg (600,000 lU/kg). An immuno stimulant (e.g., aldesleukin) can be administered within 24 hours after a cellular administration. An immuno stimulant (e.g., aldesleukin) can be administered in as an infusion over about 15 minutes about every 8 hours for up to about 4 days after a cellular infusion. An immuno stimulant (e.g., aldesleukin) can be administered at a dose from about 100,000 lU/kg, 200,000 lU/kg, 300,000 lU/kg, 400,000 lU/kg, 500,000 lU/kg, 600,000 lU/kg, 700,000 lU/kg, 800,000 lU/kg, 900,000 lU/kg, or up to about 1,000,000 lU/kg. In some cases, aldesleukin can be administered at a dose from about 100,000 lU/kg to 300,000 lU/kg, from 300,000 lU/kg to 500,000 lU/kg, from 500,000 lU/kg to 700,000 lU/kg, from 700,000 lU/kg to about 1,000,000 lU/kg.
[00320] In some other embodiments, any of the compounds herein that is capable of modulating a SOS protein (e.g., S0S1) to reduce Ras signaling output may be administered in combination or in conjunction with one or more pharmacologically active agents including but not limited to: (l)an inhibitor of MEK (e g., MEK1, MEK2) or of mutants thereof (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib, AZD6244); (2) an inhibitor of epidermal growth factor receptor (EGFR) and/or of mutants thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab panitumumab, osimertinib, olmutinib, EGF-816); (3) an immunotherapeutic agent (e.g., checkpoint immune blockade agents, as disclosed herein); (4) a taxane (e.g., paclitaxel, docetaxel); (5) an anti-metabolite (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5 -fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine); (6) an inhibitor of FGFR1 and/or FGFR2 and/or FGFR3 and/or of mutants thereof (e.g., nintedanib); (7) a mitotic kinase inhibitor (e.g., a CDK4/6 inhibitor, such as, for example, palbociclib, ribociclib, abemaciclib); (8) an anti-angiogenic drug (e g., an anti-VEGF antibody, such as, for example, bevacizumab); (9) a topoisomerase inhibitor (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone); (10) a platinum-containing compound (e.g. cisplatin, oxaliplatin, carboplatin); (11) an inhibitor of ALK and/or of mutants thereof (e g. crizotinib, alectinib, entrectinib, brigatinib); (12) an inhibitor of c-MET and/or of mutants thereof (e g., K252a, SU11274, PHA665752, PF2341066); (13) an inhibitor of BCR-ABL and/or of mutants thereof (e.g., imatinib, dasatinib, nilotinib); (14) an inhibitor of ErbB2 (Her2) and/or of mutants thereof (e.g., afatinib, lapatinib, trastuzumab, pertuzumab); (15) an inhibitor of AXL and/or of mutants thereof (e.g., R428, amuvatinib, XL-880); (16) an inhibitor of NTRK1 and/or of mutants thereof (e.g., Merestinib); (17) an inhibitor of RET and/or of mutants thereof (e g., BLU-667, Lenvatinib); (18) an inhibitor of A-Raf, B-Raf (e.g., Sorafenib, Vemurafenib, Debrafenib, Encorafenib) and/or C-Raf and/or of mutants thereof (RAF-709, LY-3009120); (19) an inhibitor of ERK and/or of mutants thereof (e.g., ulixertinib); (20) an MDM2 inhibitor (e.g., HDM-201 , NVP-CGM097, RG-71 12, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115); (21) an inhibitor of mTOR (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus); (22) an inhibitor of BET (e.g., I-BET 151, 1-BET 762, OTX-015, TEN- 010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645); (23) an inhibitor of IGF1/2 and/or of IGF1-R (e.g., xentuzumab, MEDI-573); (24) an inhibitor of CDK9 (e.g., DRB, flavopiridol, CR8, AZD 5438, purvalanol B, AT7519, dinaciclib, SNS-032); (25) an inhibitor of famesyl transferase (e.g., tipifamib); (26) an inhibitor of SHIP pathway including SHIP2 inhibitor (e.g., 6-(4-amino-4-methylpiperidin-l-yl)- 3-(2,3-dichlorophenyl)pyrazin-2-amine), as well as SHIP1 inhibitors; (27) an inhibitor of SRC (e.g., dasatinib); (28) an inhibitor of JAK (e.g.. lofacil i nib ); (29) a PARP inhibitor (e.g. Olaparib, Rucaparib, Niraparib, Talazoparib), (30) a BTK inhibitor (e.g. Ibrutinib, Acalabrutinib, Zanubrutinib), (31) a ROS1 inhibitor (e.g., entrectinib), (32) an inhibitor of FLT3, HD AC, VEGFR, PDGFR, LCK, Bcr-Abl or AKT, (33) an inhibitor of Krasl2C mutant (e.g., including but not limited to AMG510, MRTX849, and any covalent inhibitors binding to the cysteine residue 12 of Kras, the structures of these compounds are publicly known)(e.g., an inhibitor of Ras G12C as described in US20180334454, US20190144444, US20150239900, US10246424, US20180086753, WO2018143315, WO2018206539, W020191107519, W02019141250, W02019150305, US9862701, US20170197945, US20180086753, US10144724, US20190055211, US20190092767, US20180127396, US20180273523, US10280172, US20180319775, US20180273515, US20180282307, US20180282308, W02019051291, WO2019213526, WO2019213516, WO2019217691, WO2019241157, WO2019217307, W02020047192,
WO2017087528, W02018218070, WO2018218069, W02018218071, W02020027083, W02020027084, WO2019215203, WO2019155399, W02020035031, W02014160200, WO2018195349, W02018112240, WO2019204442, WO2019204449, W02019104505, WO2016179558, WO2016176338, W02020050890, W02020097537, WO2020177629, WO2020221239, WO2021023247, WO2020259573, WO2021027943, W02020132071, WO2020163598, WO2020163594, W02021000885, W02021081212, WO2021083167, WO2021031952, W02020239077, W02021027911, WO2021084765, W02021107160, W02021106231, WO2021086833, WO2020259513, WO2021127404, WO2021121371, W02021121330, WO2021126816, W02021120045, WO2021124222, W02021120890, WO2021121367, WO201126799, W02021126120, WO2021108683, WO2021108682, W02021104431, WO2021109737, WO2021113595, WO2021118877, WO2021119343, WO2020132597, WO2021091956, WO2021091967, WO2021088458, WO2020238791, W02021000885, WO2021023154, WO2021088938, WO2021078312, WO2021086833, WO2021085653, WO2021084765, WO2021088458, WO 2021023247, WO2021142252, WO2021141628, WO2021139748, W02021150613, WO2021147965, WO2021152149, WO2021154929, W02021158071, WO2021144716, WO2020233592, WO2021163477, WO2021163434, WO2021147967, WO2021165453, WO2021165456, WO2021165452, WO20211168193, WO2021173524, W02020033413, WO2021173923, WO2021170684, WO2021169990, WO2021173902, WO2020239123, WO2021177721, WQO2021178741, WO2021178720, WO2021185233, WO2021190467, or related patents and applications, each of which is incorporated by reference in its entirety), (34) a SHC inhibitor (e.g., PP2, AID371185), (35) a GAB inhibitor (e.g, GAB-0001), (36) a GRB inhibitor, (37) a PI-3 kinase inhibitor (e.g., Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, NVP-BEZ235-AN), (38) a MARPK inhibitor, (39) CDK4/6 (e.g., palbociclib, ribociclib, abemaciclib), or (40) MAPK inhibitor (e.g., VX-745, VX-702, RO-4402257, SCIO-469, BIRB-796, SD-0006, PH- 797804, AMG-548, LY2228820, SB-681323, GW-856553, RWJ67657, BCT-197) , or (41) an inhibitor of SHP pathway including SHP2 inhibitor (e.g., 6-(4-amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazin-2-
Figure imgf000174_0001
1,
Figure imgf000175_0001
and RMC-4550 ( ), as well as SHP1 inhibitors; or (42) an inhibitor of a wildtype KRas or a Kras mutant (e.g., Kras G12D including a compound described in W02021041671, WO2021108683, WO2021091967, W02021107160, W02021081212, WO2021118877, or W02021150613; KRas G12C, KRas G12D, KRas G12S, KRas G12V, KRas G13D, KRas G13C, or KRas G13V). Inhibitors of any of the exemplary targets are applicable to the corresponding mutant targets having one or more mutations therein. In some embodiments, any of the compounds herein that is capable of inhibiting a SOS protein (e.g., S0S1) to reduce Ras signaling output may be administered in combination or in conjunction with one or more checkpoint immune blockade agents (e.g., anti-PD-1 and/or anti-PD-Ll antibody, anti-CLTA-4 antibody).
[00321] In combination therapy, a compound provided herein and other anti-cancer agent(s) may be administered either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
[00322] In some embodiments, a compound of the present disclosure and the other anti-cancer agent(s) are generally administered sequentially in any order by infusion or orally. The dosing regimen may vary depending upon the stage of the disease, physical fitness of the patient, safety profiles of the individual drugs, and tolerance of the individual drugs, as well as other criteria well-known to the attending physician and medical practitioner(s) administering the combination. The compound of the present invention and other anti-cancer agent(s) may be administered within minutes of each other, hours, days, or even weeks apart depending upon the particular cycle being used for treatment. In addition, the cycle could include administration of one drug more often than the other during the treatment cycle and at different doses per administration of the drug.
[00323] An antibiotic can be administered to a subject as part of a therapeutic regime. An antibiotic can be administered at a therapeutically effective dose. An antibiotic can kill or inhibit growth of bacteria. An antibiotic can be a broad spectrum antibiotic that can target a wide range of bacteria. Broad spectrum antibiotics, either a 3 or 4th generation, can be cephalosporin or a quinolone. An antibiotic can also be a narrow spectrum antibiotic that can target specific types of bacteria. An antibiotic can target abacterial cell wall such as penicillins and cephalosporins. An antibiotic can target a cellular membrane such as polymyxins. An antibiotic can interfere with essential bacterial enzymes such as antibiotics: rifamycins, lipiarmycins, quinolones, and sulfonamides. An antibiotic can also be a protein synthesis inhibitor such as macrolides, lincosamides, and tetracyclines. An antibiotic can also be a cychc lipopeptide such as daptomycin, glycylcyclines such as tigecycline, oxazohdiones such as linezolid, and lipiarmycins such as fidaxomicin. In some cases, an antibiotic can be 1st generation, 2nd generation, 3 rd generation, 4th generation, or 5th generation. A first-generation antibiotic can have a narrow spectrum. Examples of 1st generation antibiotics can be penicillins (Penicillin G or Penicillin V), Cephalosporins (Cephazolin, Cephalothin, Cephapirin, Cephalethin, Cephradin, or Cephadroxin). In some cases, an antibiotic can be 2nd generation. 2nd generation antibiotics can be a penicillin (Amoxicillin or Ampicillin), Cephalosporin (Cefuroxime, Cephamandole, Cephoxitin, Cephaclor, Cephrozil, Loracarbef). In some cases, an antibiotic can be 3 rd generation. A 3 rd generation antibiotic can be penicillin (carbenicillin and ticarcillin) or cephalosporin (Cephixime, Cephtriaxone, Cephotaxime, Cephtizoxime, and Cephtazidime). An antibiotic can also be a 4th generation antibiotic. A 4th generation antibiotic can be Cephipime. An antibiotic can also be 5th generation. 5th generation antibiotics can be Cephtaroline or Cephtobiprole.
[00324] In some cases, an anti-viral agent may be administered as part of a treatment regime. In some cases, a herpes vims prophylaxis can be administered to a subject as part of a treatment regime. A herpes virus prophylaxis can be valacyclovir (Valtrex). Valtrex can be used orally to prevent the occurrence of herpes virus infections in subjects with positive HSV serology. It can be supplied in 500 mg tablets. Valacyclovir can be administered at a therapeutically effective amount.
[00325] In some cases, a treatment regime may be dosed according to a body weight of a subject. In subjects who are determined obese (BMI > 35) a practical weight may need to be utilized. BMI is calculated by: BMI = weight (kg)/ [height (m)] 2.
[00326] Body weight may be calculated for men as 50 kg+2.3* (number of inches over 60 inches) or for women 45.5kg + 2.3 (number of inches over 60 inches). An adjusted body weight may be calculated for subjects who are more than 20% of their ideal body weight. An adjusted body weight may be the sum of an ideal body weight + (0.4 x (Actual body weight - ideal body weight)). In some cases, a body surface area may be utilized to calculate a dosage. A body surface area (BSA) may be calculated by: BSA (m2) —/Height (cm) *Weight (kg)/3600.
[00327] In some embodiments is a method of reducing Ras signaling output, comprising contacting a SOS protein (e.g., S0S1) with an effective amount of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (III), or (III- 1 ), or a pharmaceutically acceptable salt or solvate thereof, thereby reducing the Ras signaling output. In some embodiments is a method of reducing Ras signaling output, comprising contacting a SOS protein (e g., S0S1) with an effective amount of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (ni’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein said the compound inhibits the SOS 1 protein activity or disrupt interaction or binding between a SOS 1 protein and a Ras protein. In some embodiments, a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III- 1) inhibits SOS1 or disrupts interaction or binding between SOS1 and one or more of the following: a K-Ras protein including wildtype and any mutant thereof. In some embodiments, a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l) inhibits S0S1 activity or disrupts interaction or binding between SOS 1 and one or more of the following: K-RasG12D mutant and K- RasG12V mutant.
[00328] In some embodiments, provided is a method of reducing Ras signaling output in a cell by contacting the cell with a compound of the present disclosure. A reduction in Ras signaling can be evidenced by one or more members of the following: (i) an increase in steady state level of GDP-bound Ras protein; (ii) a reduction of phosphorylated AKTs473, (iii) a reduction of phosphorylated ERKT202/y204, (iv) a reduction of phosphorylated S6S235/236, (v) reduction (e.g., inhibition) of cell growth of Ras-driven tumor cells (e.g., those derived from a tumor cell line disclosed herein), and (vi) an interference or disruption of the interaction or binding between a SOS protein (e g., SOS1) with a Ras protein such as a wildtype or a mutant Ras. In some cases, the reduction in Ras signaling output can be evidenced by two, three, four , five or all of (i)-(vi) above. In some embodiments, the reduction any one or more of (i)-(vi) canbe 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8- fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800- fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000-fold, or more as compared to control untreated with a subject compound. A reduction in cell growth can be demonstrated with the use of tumor cells or cell lines. A tumor cell line can be derived from a tumor in one or more tissues, e.g., pancreas, lung, ovary, biliary tract, intestine (e.g., small intestine, large intestine (i.e. colon)), endometrium, stomach, hematopoietic tissue (e.g., lymphoid tissue), etc. Examples of the tumor cell line with a K-Ras mutation may include, but are not limited to, A549 (e.g., K-Ras G12S), AGS (e.g., K-Ras G12D), ASPC1 (e.g., K-Ras G12D), Calu-6 (e.g., K-Ras Q61K), CFPAC-1 (e.g., K-Ras G12V), CL40 (e.g., K-Ras G12D), COLO678 (e.g., K-Ras G12D), COR-L23 (e.g., K-Ras G12V), DAN-G (e.g., K-Ras G12V), GP2D (e.g., K-Ras G12D), GSU (e.g., K-Ras G12F), HCT116 (e.g., K-Ras G13D), HEC1A (e.g., K-Ras G12D), HEC1B (e.g., K-Ras G12F), HEC50B (e.g., K-Ras G12F), HEYA8 (e.g., K- Ras G12D or G13D), HP AC (e g., K-Ras G12D), HPAFII (e.g., K-Ras G12D), HUCCT1 (e.g., K-Ras G12D), KARPAS620 (e.g., K-Ras G13D), KOPN8 (e.g., K-Ras G13D), KP-3 (e.g., K-Ras G12V), KP-4 (e.g, K-Ras G12D), L3.3 (e.g, K-Ras G12D), LoVo (e.g, K-Ras G13D), LS180 (e.g, K-Ras G12D), LS513 (e.g, K-Ras G12D), MCAS (e.g, K-Ras G12D), NB4 (e.g, K-Ras A18D), NCI-H1355 (e.g, K-Ras G13C), NCI-H1573 (e.g, K-Ras G12A), NCI-H1944 (e.g, K-Ras G13D), NCI-H2009 (e.g, K-Ras G12A), NCI-H441 (e.g, K-Ras G12V), NCI-H747 (e.g, K-Ras G13D), NOMO-1 (e.g, K-Ras G12D), OV7 (e.g, K-Ras G12D), PANC0203 (e.g, K-Ras G12D), PANC0403 (e.g, K-Ras G12D), PANC0504 (e.g, K-Ras G12D), PANC0813 (e.g, K-Ras G12D), PANCI (e.g, K-Ras G12D), Panc-10.05 (e g, K-Ras G12D), PaTu-8902 (e.g, K-Ras GUV), PK1 (e.g, K-Ras G12D), PK45H (e.g, K-Ras G12D), PK59 (e.g, K-Ras G12D), SK-CO-1 (e g, K-Ras GUV), SKLU1 (e.g, K-Ras G12D), SKM-1 (e.g, K-Ras KI 17N), SNU1 (e.g, K-Ras GUD), SNU1O33 (e.g, K-Ras G12D), SNU1197 (e.g, K-Ras G12D), SNU407 (e.g, K-Ras GUD), SNU410 (e.g, K-Ras GUD), SNU601 (e.g, K-Ras GUD), SNU61 (e.g, K- Ras GUD), SNU8 (e.g, K-Ras GUD), SNU869 (e.g, K-Ras GUD), SNU-C2A (e.g, K-Ras GUD), SU.86.86 (e.g, K-Ras GUD), SUIT2 (e.g, K-Ras GUD), SW1990 (e.g, K-Ras GUD), SW403 (e.g, K-Ras GUV), SW480 (e.g, K-Ras GUV), SW620 (e.g, K-Ras GUV), SW948 (e.g, K-Ras Q61L), T3M10 (e.g, K-Ras GUD), TCC- PAN2 (e g, K-Ras G12R), TGBC11TKB (e g, K-Ras GUD), and MIA Pa-Ca (e g, MIA Pa-Ca 2 (e g, K-Ras G12Q).
[00329] In some embodiments is a SOS protein (e.g, SOS1) bound by a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II- 1), (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof, wherein interaction of SOS 1 protein with a Ras protein is reduced as compared to a SOS 1 protein unbound to said compound.
Pharmaceutical compositions and methods of administration
[00330] The compounds of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II'), (II), (II-l), (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, described herein are administered to subjects in a biologically compatible form suitable for administration to treat or prevent diseases, disorders or conditions. Administration of the compounds described herein can be in any pharmacological form including a therapeutically effective amount of a compound of Formula (I’), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III- 1), or a pharmaceutically acceptable salt or solvate thereof, alone or in combination with a pharmaceutically acceptable carrier.
[00331] In certain embodiments, the compounds described herein are administered as a pure chemical. In other embodiments, the compounds described herein are 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, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
[00332] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable excipients. The excipient(s) (or carriers)) is acceptable or suitable if the excipient is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
[00333] In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (T), (I), (1-1), (la), (lb), (Ic), (Id), (le), (If), (II’), (II), (II-l), (III’), (III), or (III-l), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (1-1), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (le), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (If), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (II’), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (II-l), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (III’), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (III-l), or a pharmaceutically acceptable salt or solvate thereof.
[00334] In some embodiments of the methods described herein, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ.
[00335] In some embodiments of the methods described herein, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water hquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.
[00336] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
[00337] In some embodiments of the methods described herein, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
[00338] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatly oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium caiboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
[00339] Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
EXAMPLES
[00340] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
[00341] As used herein, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:
ACN or MeCN acetonitrile
AcOH acetic acid
Ac acetyl
BINAP 2,2'-bis(diphenylphosphino)-l,l'-binaphthalene
Bn benzyl
BOC or Boc tert-buty 1 carbamate i-Bu Ao-butyl t-Bu tert-butyl
DCM dichloromethane (CH2CI2)
DIBAL-H diisobutylaluminum hydride
DIPEA or DIEA diisopropylethylamine
DMAP 4-(\, \-dimcthylamino)pyndinc
DME 1 ,2-dimethoxy ethane
DMF \', \'-diincthylforinamidc
DMA V, Y-dimethylacetamide
DMSO dimethylsulfoxide
Dppf or dppf 1 , 1 '-bis(dipheny lphosphino)ferrocene
EDC or EDCI 7V-(3-dimethylaminopropyl)-7V'-ethylcarbodiimide hydrochloride eq equivalent(s)
Et ethyl
Et2O diethyl ether
EtOH ethanol
EtOAc ethyl acetate HPLC high performance liquid chromatography
KHMDS potassium bis(trimethylsilyl)amide
NaHMDS sodium bis(trimethylsilyl)amide
LiHMDS lithium bis(trimethylsilyl)amide
LAH lithium aluminum anhydride
LCMS liquid chromatography mass spectrometry
Me methyl
MeOH methanol
MS mass spectroscopy
Ms mesyl
NMR nuclear magnetic resonance
Ph phenyl iPr/i-Pr Ao-propyl
RP-HPLC reverse-phase high-pressure liquid chromatography rt room temperature
TBS fert-butyldimethylsilyl
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl
TsOH/p-TsOH p-toluenesulfonic acid
Example 1: Compound Synthesis:
Compound 101: Synthesis of 4-((l-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6,7- dimethoxyquinazolin-2(lH)-one
Figure imgf000181_0001
compound 101
2-chloro-N-(l-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6,7-dimethoxyquinazolin-4-amine [00342] To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (200 mg, 0.77 mmol) in THF (10 mL) was added l-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethan-l-amine (200 mg, 0.77 mmol) and DIEA (1 mL). The resulting mixture was stirred at 80 °C overnight under nitrogen. The mixture was then cooled to room temperature, poured into water and extracted with EtOAc. The extracts were combined and washed with brine, dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography to obtain 2-chloro-N-(l-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)- 6,7-dimethoxyquinazolin-4-amine. ESI-MS m/z: 483.2 [M+H]+.
4-((l-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6,7-dimethoxyquinazolin-2(lH)-one [00343] 2-chloro-N-(l-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6,7-dimethoxyquinazohn-4- amine (142 mg) in HOAc (5 mL) was stirred at 70 °C for 12h. The solvent was removed under reduced pressure. The mixture was poured into sat. aqueous Na2CO3 solution and extracted with EtOAc. The extracts were combined and washed with brine, and dried over sodium sulfate. It was filtered and solvent was removed under reduced pressure to give a crude residue which was purified by silica gel column chromatography to obtain 4-((l-(5-(2- ((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6,7-dimethoxyquinazolin-2(lH)-one. ESI-MS m/z: 465.2 [M+H]+. 1HNMR (400MHz, DMSO-d6) δ 8.58 (1H, d, J = 9.2 Hz), 7.91 (1 H, brs), 7.78 (1H, s), 7.50-7.47 (4H, m),7.15 (2H, s), 6.77 (1H, s), 5.98-5.91 (1H, m), 4.32-4.30 (2H, brs), 3.87 (3H, s), 3.86 (3 H, s), 2.56-2.56 (6H, brs), 1.76 (3H, d, J = 6.8 Hz).
Compound 102: Synthesis of 4-((l-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6,7- dimethoxy-l-methylquinazolin-2(lH)-one
Figure imgf000182_0001
[00344] A solution of 4-((l-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6,7- dimethoxyquinazolin-2(lH)-one (25 mg, 0.05 mmol) in DMF (2 mL) was cooled to 0 °C. To the resulting mixture was added NaH (6 mg, 0.15 mmol). The mixture was stirred at 0 °C for Ih, followed by the addition of methyl iodide (7 mg, 0.05 mmol). The resulting mixture was stirred at 0 °C for Ih and quenched with water. The reaction mixture was then poured into water and extracted with EtOAc. The extracts were combined, washed with brine, dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure to give a crude residue which was purified by silica gel column chromatography to obtain the desired product. ESI-MS m/z: 479.2 [M+H]+. 1HNMR (400MHz, CD3OD) δ 7.68 (IH, s), 7.55-7.57 (IH, m), 7.42-7.46 (3H, m), 7.13 (1 H, dd, J = 0.8 Hz, J = 3.6 Hz), 6.99 (I H, d, J = 3.6 Hz), 6.89 (1 H, s), 6.01 ( 1 H, m), 4.11 ( 2H, m), 4.01 ( 3 H, s), 3.93 (3 H, s), 3.64 ( 3 H, s), 2.50 ( 6H, s), 1.80 ( 3 H, d, J = 6.4 Hz).
Compound 105: Synthesis of 4-((l-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6,7- dimethoxy-2-methylphthalazin-l(2H)-one
Figure imgf000183_0001
compound 105
4-chloro-6,7-dimethoxy-2-methylphthalazin-l(2H)-one
[00345] To a solution of 5, 6-dimethoxyisobenzofuran-l, 3-dione (50 mg, 0.24 mmol) in water (10 mL) were added 2,2,2-trifluoroacetic acid (0.5 mL) and tert-butyl 2-methylhydrazine-l-carboxylate (35 mg, 0.24 mmol). The resulting mixture was heated at 100°C and stirred for 15 minutes. The mixture was then stirred overnight at room temperature. The mixture was then extracted by ethyl acetate (60 mLx2 ). The combined organic solution was washed with brine, dried over Na2SO4, and filtered. The solvent was removed under reduced pressure to provide a crude residue which was purified by flash chromatography on silica gel to afford 4-chloro-6,7-dimethoxy-2- methylphthalazin-l(2H)-one as a white solid. ESI-MS m/z: 254.05 [M+H]+.
4-((l-(5-(2-((dimethylamino)niethyl)phenyl)thiophen-2-yl)ethyl)amino)-6,7-dimethoxy-2-methylphthalazin- l(2H)-one
[00346] To a solution of 4-chloro-6,7-dimethoxy-2-methylphthalazin-l(2H)-one (50 mg, 0.20 mmol) in toluene (10 mL) were added l-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethan-l-amine (51 mg, 0.20 mmol), Pdiidbaf (18 mg, 0.02 mmol ) Ru-phos (9.2 mg, 0.02 mmol) and t-BuONa (56 mg, 0.6 mmol) under argon. The resulting mixture was heated at 105°C and stirred overnight. The reaction mixture was cooled to room temperature and ethyl acetate (60 mL) was added. The mixture was extracted with EtOAc and the combined organic solution was washed with brine, dried over NibSO i. and filtered. The solvent was removed under reduced pressure to provide a crude residue which was purified by prep-TLC to afford 4-((l-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2- yl)ethyl)amino)-6,7-dimethoxy-2-methylphthalazin-l(2H)-one as a white solid. ESI-MS m/z: 478.20 [M+H]+;
1HNMR (400MHz, CD3OD) 87.61 (1H, s), 7.49 (1H, s), 7.43-7.42 (1H, m), 7.33-7.29 (3H, m), 7.00 (1H, d, J = 3.6 Hz), 6.87 (1H, d, J = 3.6 Hz), 5.39-5.36 1H, m), 3.92 (3H, s), 3.91 (2H, s), 3.88 (3H, s), 3.60 (3H, s), 2.31 (6H, s), 1.66 (3H, d, J = 6.8 Hz).
Compound 107: Synthesis of (R)-l-((l-(3-(difluoroniethyl)-2-fluorophenyl)ethyl)amino)-3-methyl-7-(l- methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyridazin-4(3H)-one
Figure imgf000184_0001
6-chloro-4-(ethoxycarbonyl)nicotinic acid
[00347] To a solution of 6-chloronicotinic acid (5 g, 31.8 mol) in anhydrous THF (50 mL) was added n-BuLi (2.5 M in hexane, 25 mL, 62 mol) dropwise for 30 mins at -78 °C, and then the mixture was stirred at 0°C for Ih. Chloroformate (6.7 mL, 62 mol) was added at -78 °C, and then the mixture was stirred at 0°C for an additional Ih. The mixture was quenched with saturated aq. NH4CI. The mixture was concentrated in vacuo and the residue was partitioned with 10% HC1 and EtOAc. The organic layer was washed with brine, dried over Na, SO 4, concentrated in vacuo. The crude residue was purified by reverse phase column to afford 6-chloro-4-(ethoxycarbonyl)nicotinic acid. ESI-MS m/z: 230.01 [M+H]+.
Ethyl 2-chloro-5-(chlorocarbonyl)isomcotinate
[00348] To a solution of 6-chloro-4-(ethoxycarbonyl)nicotinic acid (500 mg, 2.2 mmol) inDCM (5 mL) was added freshly distilled thionyl chloride (5 mL) and the mixture was heated to reflux for 2h. The mixture was then cooled to room temperature and evaporated under vacuum to dryness. The crude ethyl 2-chloro-5- (chlorocarbonyl)isonicotinate was used directly for the next step without purification.
Ethyl 5-(2-(tert-butoxycarbonyl)-l-methylhydrazine-l-carbonyl)-2-chloroisonicotinate
[00349] A solution of above ethyl 2-chloro-5-(chlorocarbonyl)isonicotinate in DCM (10 mL) was cooled to 0°C. To this cooled solution, tert-butyl 2-methylhydrazine-l-carboxylate (300 mg, 2.5 mmol) inDCM (10 mL) was added slowly followed by solution of EbN (2 mL). The reaction mixture stirred for Ih. The reaction mixture was quenched with saturated aqueous NaCl solution and the reaction mixture was diluted with water and EtOAc. The organic layer was washed with brine and dried over Na,SO 1. filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel to afford ethyl 5-(2-(tert-butoxycarbonyl)-l-methylhydrazine- l-carbonyl)-2-chloroisonicotinate. ESLMS m/z: 358.1 [M+H]+.
7-chloro-3-methyl-2T3-dihydropyrido [3, 4-d]pyridazine-l, 4-dione
[00350] Ethyl 5-(2-(tert-butoxycarbonyl)-l-methylhydrazine-l-carbonyl)-2-chloroisonicotinate (400 mg, 1.2 mmol) in TFA (10 mL) was heated to reflux for 2h. The mixture was then cooled to room temperature and evaporated under vacuum to dryness. The crude residue was purified by reverse phase column to afford 7-chloro-3-methyl-2,3- dihydropyrido[3,4-d]pyridazine-l, 4-dione. ESI-MS m/z: 212.8 [M+H]+.
3-methyl-7-(l-methyl-lH-pyrazol-4-yl)~23-dihydropyrido[3,4-d]pyridazine-l, 4-dione
[00351] 7-chloro-3-methyl-2,3-dihydropyrido[3,4-d]pyridazine-l, 4-dione (200 mg, 0.95 mmol), l-metbyl-4- (4,4,5,5-tetamethyl-[l,3,2]dioxaboiolan-2-yl)-lH-pyrazole (24 mg, 1.2 eq), K2CO3 (1.8 mg, 3 eq) and Pd(PPh3)4 (2 mg, 0.043 mmol) in dioxane (5 ml,) were reacted at 110 °C under microwave for lb. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to provide
3-metby1-7-( ! -methyl- lH-pyrazo1-4-yl)-2,3-dihydropyrido[3,4-d]py ridazine- 1 ,4-dione. ESI-MS m/z: 258.2 [M+H]+. l-chloro-3-methyl-7-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyridazin-4(3H)-one
[00352] To a solution of 3-methyl-7-( 1 -methyl-lH-pyrazol-4-yl)-2,3-dihydropy'rido[3,4-d]pyridazine- 1 ,4-dione (210 mg, 0.8 mmol) in freshly distilled thionyl chloride (5 mL) was added DMF (1 mL) and the mixture was heated to reflux for 2h. The mixture was then cooled to room temperature and evaporated under vacuum to dryness. The residue was diluted with DCM (20 mL) and was quenched with saturated aqueous NaHCOa solution. The organic layer was washed with brine, dried over Na3SOi. filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel to afford l-chloro-3-methyl-7-(l-methyl-lH-pyrazol-
4-yl)pyrido[3,4-d]pyridazin-4(3H)-one. ESI-MS m/z: 276.0 [M+H]+.
(R)-l-((l-(3-(difluoromethyl)-2-fhiorophenyl)ethyl)amino)-3-methyl-7-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4- d]pyridazin-4(3H)-one
[00353] l-chloro-3-methyl-7-(l-methyl-lH-pyrazol-4-yl)pyrido[3,4-d]pyridazin-4(3H)-one (50 mg, 0.2 mmol), (R)-l-(3-(difluoromeihyl)~2-fluorophenyl)ethan~l -amine (1 10 mg, 1.2 eq), t-BuOK(0.8 mg, 3 eq) and RuPhos 3 rd generation precatalyst (1 mg, 0.05 mmol) in DMF (5 mL) were reacted at 120 °C under microwave for 4h. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase column to afford (R)-l-((l-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-methyl-7-(l-methyl-lH-pyrazol-4- yl)pyrido[3,4-d]pyridazin-4(3H)-one. ESI-MS m/z: 429.0 [M+H]+.
Compound 108: (R)-l-((l-(3-(difluoromethyl)-2-fluorophenyl) ethyl)amino)-7-(4-isopropylpiperazin-l-yl)-3- methylpy rido [3 ,4-d] py ridazin-4(3H)-one
Figure imgf000185_0001
7-(4-sopropylpiperazine-l-yl)-3-metfayL23"dihydropyrkkj[3,4-d]pyridazine-l,4-di(jrie
[00354] 7-chloro-3-methyl-2,3-dihydropyrido[3,4-d]pyridazine-l, 4-dione (200 mg, 0,95 mmol), 1- isopropylpiperazine ( 18 mg, 1.5 eq), K2CO3 (5,5 mg, 3 eq) in DMF (8 mL) were reacted at 120 'C for 2h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to provide 7-(4-isopropylpiperazin-l-yl)-3-methyl1-2,3-dihydropyiido[3,4-d]pyridazme-l,4-dione.
ESI-MS m/z: 304.1 [M+H]+. l-chloro-7-(4-isopropylpiperazin-l-yl)-3-methylpyrido[3,4-d]pyridazm-4(3H)-one
[00355] To a solution of 7-(4-isoproj^lpipet^zin-l-y!)-3-methyl-2,3-dibydropyrido[3,4-d]pj'ridazine-l,4-dione (180 mg, 0.6 mmol) in freshly distilled thionyl chloride (5 mL) was added DMF (1 mL) and the mixture was heated to reflux for 2h. The mixture was then cooled to room temperature and evaporated under vacuum to dryness. The residue was diluted with DCM (20 mL) and was quenched with saturated aqueous NaHCOi solution. The organic layer was washed with brine and dried over Na^SO i. filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel to afford l-chloro-7-(4-isopropylpiperazin-l-yl)-3- methylpyrido[3,4-d]pyridazin-4(3H)-one. ESI-MS m/z: 322.02 [M+H]+.
(R)-l-((l-(3-(difluoromethyl)-2-fluorophenyl) ethyl)amino)-7-(4-isopropylpiperazin-l-yl)-3-methylpyrido[3,4- d]pyridazin-4(3H)-one
[00356] l-chloro-7-(4-isopropylpiperazin-l-yl)-3-methylpyrido[3,4-d]pyridazin-4(3H)-one (80 mg, 0.25 mmol), (R)- 1 -(3-(difluoromethyl)-2-fluoropheny1)ethan-l-amine ( 100 mg, 1 2 eq), t-BuOK (0.3 mg, 3 eq) and RuPhos 3rd generation precatalyst (1 mg, 0.05 mmol) in DMF (5 ml..) were reacted at 120 °C under microwave for 4b. The reaction was filtered to remove insoluble and the filtrate was concentrated in vacuo. The residue was purified by reverse phase column to afford (R)-l-((l-(3-(difluoromethyl)-2-fluorophenyl) ethyl)amino)-7-(4-isopropylpiperazin- l-yl)-3-methylpyrido[3,4-d]pyridazin-4(3H)-one. ESI-MS m/z: 475.2 [M+H]+.
[00357] The Compounds in Table 1 below were synthesized in the same or a similar maimer as described for the preceding compounds above.
Table 1
Figure imgf000186_0001
Figure imgf000187_0001
Example 2: Ras sequence
[00358] Human K-Ras4b (SEQ ID NO. 1):
1 MTEYKLVWG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET 51 CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI
101 KRVKDSEDVP MVLVGNKCDL PSRTVDTKQA QDLARSYGIP FIETS AKTRQ
151 GVDDAFYTLV REIRKHKEKM SKDGKKKKKK SKTKCVIM
[00359] Human SOS1 (SEQ ID NO. 3):
1 MQAQQLPYEF FSEENAPKWR GLLVPALKKV QGQVHPTLES NDDALQYVEE 51 LILQLLNMLC QAQPRSASDV EERVQKSFPH PIDKWAIADA QSAIEKRKRR 101 NPLSLPVEKI HPLLKEVLGY KIDHQVSVYI VAVLEYISAD ILKLVGNYVR 151 NIRHYEITKQ DIKVAMCADK VLMDMFHQDV EDINILSLTD EEPSTSGEQT 201 YYDLVKAFMA EIRQYIRELN LIIKVFREPF VSNSKLFSAN DVENII'SRIV 251 DIHELSVKLL GHIEDTVEMT DEGSPHPLVG SCFEDLAEEL AFDPYESYAR 301 DILRPGFHDR FLSQLSKPGA ALYLQSIGEG FKEAVQYVLP RLLLAPVYHC 351 LHYFELLKQL EEKSEDQEDK ECLKQAITAL LNVQSGMEKI CSKSLAKRRL 401 SESACRFYSQ QMKGKQLAIK KMNEIQKNID GWEGKDIGQC CNEFIMEGTL 451 TRVGAKHERH II'LFDGLMIC CKSNHGQPRL PGASNAEYRL KEKFFMRKVQ 501 INDKDDTNEY KHAFEIILKD ENSVII'SAKS AEEKNNWMAA LISLQYRSTL 551 ERMLDVTMLQ EEKEEQMRLP SADVYRFAEP DSEENIII'EE NMQPKAGIPI 601 KAGTVIKLI ERLTYHMYAD PNFVRTFLTT YRSFCKPQEL LSLIIERFEI 651 PEPEPTEADR IAIENGDQPL SAELKRFRKE YIQPVQLRVL NVCRHWVEHH 701 FYDFERDAYL LQRMEEFIGT VRGKAMKKWV ESITKIIQRK KIARDNGPGH 751 NITFQSSPPT VEWHISRPGH IETFDLLTLH PIEIARQLTL LESDLYRAVQ 801 PSELVGSVWT KEDKEINSPN LLKMIRHTTN LTLWFEKCIV ETENLEERVA 851 VVSRIIEILQ VFQELNNFNG VLEVVSAMNS SPVYRLDHTF EQIPSRQKKI 901 LEEAHELSED HYKKYLAKLR SINPPCVPFF GIYLTNILKT EEGNPEVLKR 951 HGKELINFSK RRKVAEITGE IQQYQNQPYC LRVESDIKRF FENLNPMGNS 1001 MEKEFTDYLF NKSLEIEPRN PKPLPRFPKK YSYPLKSPGV RPSNPRPGTM 1051 RHPTPLQQEP RKISYSRIPE SETESTASAP NSPRTPLTPP PASGASSTTD 1101 VCSVFDSDHS SPFHSSNDTV FIQVTLPHGP RSASVSSISL TKGTDEVPVP 1151 PPVPPRRRPE SAPAESSPSK IMSKHLDSPP AIPPRQPTSK AYSPRYSISD 1201 RTSISDPPES PPLLPPREPV RTPDVFSSSP LHLQPPPLGK KSDHGNAFFP 1251 NSPSPFTPPP PQTPSPHGTR RHLPSPPLTQ EVDLHSIAGP PVPPRQSTSQ 1301 HIPKLPPKTY KREHTHPSMH RDGPPLLENA HSS
[00360] Human S0S2 (SEQ ID NO. 5):
1 MQQAPQPYEF FSEENSPKWR GLLVS ALRKV QEQVHPTLSA NEESLYYIEE 51 LII'QLLNKLC MAQPRTVQDV EERVQKTFPH PIDKWAIADA QSAIEKRKRR 101 NPLLLPVDKI HPSLKEVLGY KVDYHVSLYI VAVLEYISAD ILKLAGNYVF 151 NIRHYEISQQ DIKVSMCADK VLMDMFDQDD IGLVSLCEDE PSSSGELNYY 201 DLVRTEIAEE RQYLRELNMI IKVFREAFLS DRKLFKPSDI EKII'SNISDI 251 HELTVKLLGL IEDTVEMTDE SSPHPLAGSC FEDLAEEQAF DPYETLSQDI 301 LSPEFHEHFN KLMARPAVAL HFQSIADGFK EAVRYVLPRL MLVPVYHCWH 351 YFELLKQLKA CSEEQEDREC LNQAITALMN LQGSMDRIYK QYSPRRRPGD
401 PVCPFYSHQL RSKHL AIKKM NEIQKNIDGW EGKDIGQCCN EFIMEGPLTR 451 IGAKHERHII' LFDGLMISCK PNHGQTRLPG YSSAEYRLKE KFVMRKIQIC 501 DKEDTCEHKH AFELVSKDEN SIII'AAKSAE EKNNWMAALI SLHYRSTLDR 551 MLDSVLLKEE NEQPLRLPSP EVYRFVVKDS EENIVFEDNL QSRSGIPIIK 601 GGTVVKLIER LTYHMYADPN FVRTFLTTYR SFCKPQELLS LLIERFEIPE 651 PEPTDADKLA IEKGEQPISA DLKRFRKEYV QPVQLRILNV FRHWVEHHFY 701 DFERDLELLE RLESFISSVR GKAMKKWVES IAKIIRRKKQ AQANGVSHNI 751 TFESPPPPIE WHISKPGQFE TFDLMTLHPI EIARQLTLLE SDLYRKVQPS 801 ELVGSVWTKE DKEINSPNLL KMIRHTTNLT LWFEKCIVEA ENFEERVAVL 851 SRIIEILQVF QDLNNFNGVL EIVSAVNSVS VYRLDHTFEA LQERKRKILD 901 EAVELSQDHF KKYLVKLKSI NPPCVPFFGI YLTNILKTEE GNNDFLKKKG 951 KDLINFSKRR KVAEITGEIQ QYQNQPYCLR IEPDMRRFFE NLNPMGSASE 1001 KEFTDYLFNK SLEIEPRNCK QPPRFPRKST FSLKSPGIRP NTGRHGSTSG 1051 TLRGHPTPLE REPCKISFSR IAETELESTV SAPTSPNTPS TPPVSASSDL 1101 SVFLDVDLNS SCGSNSII'AP VLLPHSKSFF SSCGSLHKLS EEPLIPPPLP 1151 PRKKFDHDAS NSKGNMKSDD DPPAIPPRQP PPPKVKPRVP VPTGAFDGPL 1201 HSPPPPPPRD PLPDTPPPVP LRPPEHFINC PFNLQPPPLG HLHRDSDWLR 1251 DISTCPNSPS TPPSTPSPRV PRRCYVLSSS QNNLAHPPAP PVPPRQNSSP 1301 HLPKLPPKTY KRELSHPPLY RLPLLENAET PQ
Example 3: Protein expression
[00361] DNA expression constructs encoding one or more protein sequences of interest (e.g., Kras fragments thereof, mutant variants thereof, etc.) and its corresponding DNA sequences are optimized for expression in E. coh and synthesized by, for example, the GeneArt Technology at Life Technologies. In some cases, the protein sequences of interest are fused with a tag (e.g., glutathione S-transferase (GST), histidine (His), or any other affinity tags) to facilitate recombinant expression and purification of the protein of interest. Such tag can be cleaved subsequent to purification. Alternatively, such tag may remain intact to the protein of interest and may not interfere with activities (e.g., target binding and/or phosphorylation) of the protein of interest
[00362] A resulting expression construct is additionally encoded with (i) att-site sequences at the 5'and 3' ends for subcloning into various destination vectors using, for example, the Gateway Technology, as well as (ii) a Tobacco Etch Virus (TEV) protease site for proteolytic cleavage of one or more tag sequences. The applied destination vectors can be a pET vector series from Novagen (e.g., with ampicillin resistance gene), which provides an N- terminal fusion of a GST-tag to the integrated gene of interest and/or a pET vector series (e g., with ampicillin resistance gene), which provides a N-terminal fusion of a HIS-tag to the integrated gene. To generate the final expression vectors, the expression construct of the protein of interest is cloned into any of the applied destination vectors. The expression vectors are transformed into E. coli strain, e.g., BL21 (DE3). Cultivation of the transformed strains for expression is performed in 10 L and 1 L fermenter. The cultures are grown, for example, in Terrific Broth media (MP Biomedicals, Kat. #1 13045032) with 200 ug/mL ampicillin at a temperature of 37 °C to a density of 0.6 (OD600), shifted to a temperature of ~27 °C (for K-Ras expression vectors) induced for expression with 100 mM IPTG, and further cultivated for 24 hours. After cultivation, the transformed E. coli cells are harvested by centrifugation and the resulting pellet is suspended in a lysis buffer, as provided below, and lysed by passing three-times through a high pressure device. The lysate is centrifuged (49000g, 45 min, 4 °C) and the supernatant is used for further purification.
Example 4: Ras protein Purification
[00363] A Ras (e.g., K-Ras wildtype or a mutant such as K-Ras G12D, K-Ras G12V or K-RasG12C) construct or a variant thereof is tagged with GST. E. coli culture from a 10L fermenter is lysed in lysis buffer (50mM Tris HCI 7.5, 500mM NaCI,l rnM DTT, 0,5% CHAPS, Complete Protease Inhibitor Cocktail-(Roche)). As a first chromatography step, the centrifuged lysate is incubated with 50mL Glutathione Agarose 4B (Macherey -Nagel; 745500.100) in a spinner flask (16 h, 10'0). The Glutathione Agarose 4B loaded with protein is transferred to a chromatography column connected to a chromatography system, e.g., an Akta chromatography system. The column is washed with wash buffer (50mM Tris HCI 7.5, 500mM NaCI, 1 mM DTT) and the bound protein is eluted with elution buffer (50mM Tris HCI 7.5, 500mM NaCI, 1 mM DTT, 15mM Glutathione). The main fractions of the elution peak (monitored by OD280) is pooled. For further purification by size-exclusion chromatography, the above eluate volume is applied to a column Superdex 200 HR prep grade (GE Healthcare) and the resulting peak fractions of the eluted fusion protein is collected. Native mass spectrometry analyses of the final purified protein construct can be performed to assess its homogeneous load with GDP.
Example 5: SOS purification
[00364] A SOS construct or a variant thereof is HislO-tagged. E. coli cultures is induced in a fermenter, harvested, and lysed in lysis buffer, for example, in 25mM Tris HCI 7.5, 500mM NaCI, 20mM Imidazol, Complete EDTA-free (Roche)). For immobilized metal ion affinity chromatography (IMAC), the centrifuged lysate (50 000 xg, 45 min, 40) is incubated with 30mL Ni-NTA (Macherey-Nagel; #745400.100) in a spinner flask (16 h, 40) and subsequently transferred to a chromatography column connected to a chromatography system, e.g., an Akta chromatography system. The column is rinsed with wash buffer, e g., in 25mM Tris HCI 7.5, 500mM NaCI, 20mM Imidazol and the bound protein is eluted with a linear gradient (0-100%) of elution buffer (25mM Tris HCI 7.5, 500mM NaCI, 300mM Imidazol). The main fractions of the elution peak (monitored by OD280) containing homogenous HislO- hSOS is pooled.
Example 6: Ras-SOS interaction assay
[00365] The ability of any compound of the present disclosure to reduce a Ras protein signaling output by, e g., interfering or disrupting interaction (or binding) between SOS 1 and a Ras protein can be assessed in vitro. For example, the equilibrium interaction of human SOS1 (hSOSl) with human wildtype Kras or K-Ras mutant (e.g., hK-Ras G12C mutant, or hK-RasG12C) can be assessed as a proxy or an indication for a subject compound’s ability to inhibit SOS. Detection of such interaction is achieved by measuring homogenous time-resolved fluorescence resonance energy transfer (HTRF) from (i) a fluorescence resonance energy transfer (FRET) donor (e.g., antiGST- Europium) that is bound to GST-tagged K-RasG12C to (ii) a FRET acceptor (e.g., anti-6His-XL665) bound to a His-tagged hSOSl .
[00366] The assay buffer can contain 5 mM HEPES pH 7.4, 150 mM NaCI, 10 mM EDTA, 1 mM DTT, 0.05% BSA, 0.0025% (v/v) Igepal and 100 mM KF. A Ras working solution is prepared in assay buffer containing typically 10 nM of the protein construct (e.g., GST-tagged hK-RasG12C) and 2 nM of the FRET donor (e.g., antiGST-Eu(K) from Cisbio, France). A S0S1 working solution is prepared in assay buffer containing typically lOnM of the protein construct (e g., His-hSOSl) and 10 nM of the FRET acceptor (e.g., anti-6His-XL665 from Cisbio, France). An inhibitor control solution is prepared in assay buffer containing 10 nM of the FRET acceptor without the S0S1 protein.
[00367] A fixed volume of DMSO with or without test compound is transferred into a 384-well plate. Ras working solution is added to all wells of the test plate. S0S1 working solution is added to all wells except for those that were subsequently filled the inhibitor control solution. After a 60 min incubation, the fluorescence is measured with a MIOOOPro plate reader (Tecan) using HTRF detection (excitation 337nm, emission 1 : 620nm, emission 2: 665nm). Compounds are tested in duplicates at different concentrations (for example, 10 pM, 2.5 μM. 0.63 pM, 0.16 pM, 0.04 pM, 0.01 pM test compound). The ratiometric data (i.e., emission 2 divided by emission 1) is used to calculate IC50 values against S0S1 using GraphPad Prism (GraphPad software).
[00368] Table 2 below shows the resulting IC50 values of the compounds exemplified in Table 1 against SOS1 using the Ras-SOS interaction assay.
Table 2
Figure imgf000191_0001
where ‘+++’ means IC50 < 1.0 pM; where ‘++’ means 1.0 pM < IC50 < 5.0 pM.
Example 7: ERK phosphoiylation assay
[00369] The ability of a compound disclosed herein to inhibit or reduce Ras signaling output can be evidenced by a reduction in the level of phosphorylated ERK (Phospho-ERK) in a compound treated cell as compared to a control. NCI-H358 cells (ATCC CRL-5807) expressing K-Ras G12C is grown in RPMI medium supplemented with 10% fetal bovine serum, penicillin/streptomycin and 10 mM HEPES. Cells are plated in poly-D-Lysine coated 96-well plates at a concentration of 50,000 cells/well and allowed to attach for 8-12 hours. Following, diluted solutions of the multifunctional inhibitor compounds are added to the cell culture at a final concentration of 0.5% DMSO. After 3 hours, the medium is removed, a 150 pL of 4% formaldehyde is added, and the plates is incubated for 20 minutes. The plates can be washed with PBS, and permeabilized using 150 pL of ice cold 100% methanol for 10 minutes. Non-specific antibody binding to the plates is blocked using 100 pL Licor Blocking Buffer (Li-Cor Biotechnology, Lincoln Nebr.) for 1 hour at room temperature. Positive control samples and samples lacking cells can be processed in parallel with test samples as standards.
[00370] The amount Phospho-ERK can be determined using an antibody specific for the phosphorylated form of ERK and compared to the amount of a housekeeping protein, such as GAPDH. Examples of the primary antibodies used for detection are as follows: Phospho-ERK (Cell Signaling cs9101) diluted 1:500 and GAPDH (Millipore MAB374) diluted 1:5000 in Licor block+0.05% Tween 20. The plates are incubated for 2 hours at room temperature. The plates are washed with PBS+0.05% Tween 20. Examples of the secondary antibodies used to visualize the primary antibodies are as follows: Anti-rabbit-680 diluted 1:1000 and Anti-mouse-800 diluted 1: 1000 in Licor Block+0.05% Tween 20 and incubated for 1 hour at room temperature. The plates are washed with PBS+0.05% Tween 20. A 100 pL aliquot of PBS are added to each well and the plates can be read on aplate reader, such as a LICOR AERIUS plate reader. The pERK(Thr202/Tyr204) signal is normalized with the GAPDH signal, and percent of DMSO control values can be calculated.
Example 8: Ras-SOS cellular assay [00371] The ability of any compound of the present disclosure to inhibit a Ras protein signalling can be demonstrated by inhibiting growth of a given Kras mutant cells.
Growth of cells with K-Ras G12C mutation
[00372] MIA PaCa-2 (ATCC CRL-1420) and NCI-H1792 (ATCC CRL-5895) cell lines comprise a G12C mutation and can be used to assess Ras cellular signaling in vitro, e.g., in response to a subject inhibitor compounds of the present disclosure. This cellular assay can also be used to discern selective inhibition of a subject compounds against certain types of Kras mutants, e.g., more potent inhibition against KrasG12D relative to KrasG12C mutant, by using MIA PaCa-2 (G12C driven tumor cell line) as a comparison. MIA PaCa-2 culture medium is prepared with DMEM/Ham's F12 (e.g., with stable Glutamine, 10% FCS, and 2.5% Horse Serum. NCI-H1792 culture medium is prepared with RPMI 1640 (e.g., with stable Glutamine) and 10% FCS.
[00373] On a first day (e g., Day 1), Softagar (Select Agar, Invitrogen, 3% in ddHjO autoclaved) is boiled and tempered at 48 °C. Appropriate culture medium (i.e. , medium) is tempered to 37 °C. Agar (3%) is diluted 1:5 in medium (=0.6%) and 50 ml/well plated into 96 well plates (Coming, #3904), then incubated at room temperature for agar solidification. A 3% agar is diluted to 0.25% in medium (1:12 dilution) and tempered at 42 °C. Cells are trypsinized, counted, and tempered at 37 °C. The cells (e.g., MIA PaCa-2 at about 125-150 cells, NCI-H1792 at about 1000 cells) are resuspended in 100 mL 0.25% Agar and plated, followed by incubation at room temperature for agar solidification. The wells are overlaid with 50 mL of the medium. Sister wells in a separate plate are plated for time zero determination. All plates are incubated overnight at 37 °C and 5% CO2.
[00374] On a second day (e.g., Day 2), time zero values are measured. A 40 mL volume of Cell Titer 96 Aqueous Solution (Promega) is added to each well and incubated in the dark at 37 °C and 5% CO2. Absorption can be measured at 490 nm and reference wavelength 660 nm. DMSO-prediluted test compounds are added to wells of interest, e.g., with HP Dispenser, to one or more desired concentrations (e.g., a final DMSO concentration of 0.3%). [00375] On a third day (e g., Day 10), absorption by wells treated with the test compounds and control wells are measured with, for example, Cell Titer 96 AQueous and analyzed in comparison to the time zero measurements. The IC50 values are determined using the four parameter fit. The resulting IC50 value is a measurement of the ability of the compounds herein to reduce cell growth of Ras-driven cells (e g., tumor cell lines) in vitro and/or in vivo.
Example 9: In vivo Ras inhibition
[00376] The in vivo reduction in Ras signaling output by a compound of the present disclosure is determined in a mouse tumor xenograft model.
[00377] Xenograft with K-Ras G12C mutation
[00378] In an example, tumor xenografts are established by administration of tumor cells with K-Ras G12C mutation (e.g., MIA PaCa-2 cells) into mice, e.g., injection of the tumor cells into the right flanks of female BomTacNMRI-Foxnlnu mice with an age between 6 to 8 weeks.
[00379] In case of the subcutaneous (s.c.) MIA PaCa-2 xenograft mouse models, MIA PaCa-2 cells are grown in cell culture flasks in appropriate medium. Cultures are incubated at 37 °C and 5 % CO2 in a humidified atmosphere, with medium change or subcultivation performed 2-3 times a week. For injection, the cultured tumor cells are mixed with PBS including 5% FCS and Matrigel in a 1:1 ratio. About 1x10E7 cells in a volume of 100 pL is injected s.c. in each mouse to establish tumors. Mice are randomized into treatment groups of 7-10 mice, once tumors reach a desirable size (e.g., between about 86 to about 170 mm3, or between about 115 to about 170 mm3). Treatment with the multifunctional inhibitor compounds or controls (e.g., vehicle control) may start on the day of randomization and can be continued until end of the study (e.g., 22 days). The test samples are administered intragastrically using a gavage needle at an application volume of 10 mL/kg in a volume of 10 mL/kg per mouse daily twice with a 6 h difference. In some cases, the test compounds are dissolved in 0.5 % DMSO (or 0.5% and 0.5 % Natrosol) in sterile PBS.
[00380] Mice are housed under standardized conditions at 21.5 ± 1.5 °C and 55 ± 10% humidity. Standardized irradiated diet and autoclaved tap water is provided ad libitum. In some cases, tags (e g., ear tags, microchips implanted subcutaneously under isoflurane anesthesia) are used to identify each mouse. The tumor diameter is measured two or three times a week with a caliper. The volume of each tumor (in mm3) is calculated according to the formula "tumor volume = (π * length * width2) / 6." To monitor side effects of treatment, mice are inspected daily for abnormalities and body weight is determined, e.g., daily. Animals are sacrificed at the end of the study. Animals with necrotic tumors or tumor sizes exceeding 1500 mm3 are sacrificed early during the study for ethical reasons.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000194_0001
Formula (F); wherein:
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
L1 is a bond or C1-6alkyl;
X and Y are selected from N(R2) and C(O), wherein one of X and Y is N(R2) and one of X and Y is C(O);
Z1, Z2, and Z3 are each independently selected from N and C(R3a), wherein at least one of Z1, Z2, and Z3 is N;
R2 is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl. and C2-9heterocycloalky 1 wherein C1-6alkyl, C2-6alkeny 1, C2-6 alky ny L C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20a;
R3 is selected from halogen, CN, C1-6alkyl, C2-6alkenyl, Ch- alkynyl , Cs-ircycloalkyl, C2-9heterocycloalky 1, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, N(R14)S(O)R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(O)N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), CH2S(O) R15, -CH2S(O)N(R12)(R13), -CH2N(R12)S(O)(R13) and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-1 icycloalkyl. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b; each R3a is independently selected from hydrogen, halogen, -CN, C1-6alky I. C2-6alkenyl, C2-6alkynyl, C3-10cycloalky 1, C2-9heterocycloalkyl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R13, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, CY, alkenyl. C2-6alkynyl, C3-10cycloalky 1, C2.
• hctcrocycloalkyI. and C1-9heteroaryl are optionally substituted with one, two, or three R20c;
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 7cycloalky I. C2- 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl. -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6 alkenyl, C2-6alkynyI. C3-7cycloalkyI. C2. 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkyny 1, C3-7cycloalkyl C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl. wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-9alkyl, and C1-9 ialoalky 1; or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and Ci- 6 haloalky 1; each R15 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C3-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; each R17 and each R17a are each independently selected from C1-6alkyl and C3-6 cycloalkyl, wherein C|.,,alky I and C3- 6cycloalkyl are optionally substituted with one, two or three of R20h; or R17 and R17a form a C2-9cycloalky I ring; each R20a, R20b, R20c, R2M, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2. 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6 alkoxy. C1- 6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C-.-cy cloalky 1, C2.
9 heterocycloalkyl C6-10aryl, and C1-9heteroaryl; each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C-.-cy cloalky 1. C2.
• hctcrocycloalkyk C6-10aryl, and C1-9heteroaryl: each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; and each R25 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and Ci- •.hcteroaryl.
2. The compound of claim 1 having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000196_0001
Formula (I); wherein:
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
L1 is a bond or C1-6alkyl;
X and Y are selected from N(R2) and C(O), wherein one of X and Y is N(R2) and one of X and Y is C(O);
Z1, Z2, and Z3 are each independently selected from N and C(R3a), wherein at least one of Z1, Z2, and Z3 is N;
R2 is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyI. wherein C1-6alkyl, C2-6alkenyl, C2- ealkyny 1, and C3-10cycloalkyl are optionally substituted with one, two, or three R20a;
R3 is selected from halogen, C1-6alkyl, C2-6alkeny 1, C2-6alkynyl. C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1- 9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR13, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), - CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2.6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b; each R3a is independently selected from hydrogen, halogen, -CN, C1-6alkyI. C2-6alkenyl, C2-6 alkynyI. C3-10cycloalky 1, C2-9heterocycloalkyl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR13, -N(R14)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R13, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R13, -CH2S(O)2R13, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl. C2-6alkynyl. C3-10cycloalkyl, CYsheterocycloalky 1, and Ci- sheteroaryl are optionally substituted with one, two, or three R’Oc:
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R3 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, CY -cycloalky I. C2.
• heterocycloalkyl. C6-10aryl, C1-9heteroaryl. -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R13, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R13, -S(O)2R13, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R13, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl. C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C-,. -cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9 hetcroaryI. whereinC1-9alkyl, C2-6alkenyI. C2-6alkynyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryI are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalky 1; each R15 is independently selected C1-6alkyl, C2-6alkenyl, C1-6alkynyl, C3-7cycloalkyI. C1-9heterocycloalky 1, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6alkenyl, C2-6alkynyl, C3-7cycloalkyI, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; each R17 and each R17a are each independently selected from C1-6alkyl and C3-6 cycloalkyl, wherein C1-6alkyl and C3- ecy cloalky 1 are optionally substituted with one, two or three of R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, Ci. ealkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -Clfe-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- • heterocycloalkyl. C6-10aryl, -CH2-C6-10aryl, C1-9 heteroary l. -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C1-9heterocycloalkyl, -CH2- Cz-'dieterocycloalkyI. C6-10aryl, -CH2-C3-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, Ci- ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cy cloalky I. C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cy cloalky I. C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaiy k each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; and each R25 is selected from C1-6alkyl, C2-, alkenyl. C2-6alkynyl, C3-7cycloalkyl, C1-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl.
3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is a bond.
4. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (la):
Figure imgf000197_0001
Formula (la). The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (lb):
Figure imgf000198_0001
Formula (lb). The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ic):
Figure imgf000198_0002
Formula (Ic). The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Id):
Figure imgf000198_0003
Formula (Id). The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (le):
Figure imgf000198_0004
Formula (le). The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (If):
Figure imgf000199_0001
Formula (If). The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from -OR12, -N(R12)(R13), -C(O)R15, -C(O)N(R12)(R13), -SR12, -SOR12, -SO2(R12)(R13), - SO2N(R12)(R13), -P(O)(R17)(R17a), C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci- sheteroaryl, wherein C1-6alkyl, C . ocycloalkyl. C2-9heterocycloalkyI. C6-10aryl, and C1-9heteroaryl are optionally substituted withone, two, or three R20b. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from -C(O)R15, -C(O)N(R12)(R13), C2-9heterocycloalkyl. C6-10aryl, and C1-9heteroaryl, wherein C2. 9heterocycloalkyl . C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from -C(O)R15. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein R15 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20g. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C2.<>heterocycloalkyl optionally substituted with one, two, or three R20b. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C6-10aryl optionally substituted with one, two, or three R20b. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C1-9heteroaryl optionally substituted with one, two, or three R20b. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -C(O)N(R12)(R13). The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3a is independently selected from hydrogen, halogen, C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl, wherein C1-6alkyl, C3-10cycloalkyI. C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3a is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3a is hydrogen. A compound of Formula (II’), or a pharmaceutically acceptable salt or solvate thereof: Formula (II');
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
R2 is selected from hydrogen, C1-6alkyl, C2-6alkeny 1, C2-6alky nyl, C3-14cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkcny I. C2-6 alkynyl. C3-14cycloalkyI. and C2-9 heterocycloalkyl are optionally substituted with one, two, or three R20a;
R4 is selected from hydrogen, C1-6alkyl, and C1-6 haloalky 1;
R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R6 is independently selected from halogen, -CN, C1-6alkyl, C2-9alkeny 1, C2-6alkyny 1, C3-10cycloalkyl. C2. 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R1J, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), CH2N(R12)S(O)2(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2- 6 alkenyl. C2-6alkynyI. C3-10cycloalkyl C2. sheterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b;
R7 is selected from halogen, CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Cs-iacycloalkyl, C2-9heterocycloalkyl, C3-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, N(R14)S(O)R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(O)N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), CH2S(O) R15, -CH2S(O)N(R12)(R13), -CH2N(R12)S(O)(R13) and -P(O)(R17)(R17a), wherein C1-6alkyl, C2- 6alkenyl, C2-6 alky ny 1, C3-14 cycloalkyl. C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryl are optionally substituted with one, two, or three R20c; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2^alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2. sheterocycloalkyl, C6-10aryl, C1-9 heteroaryk -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R1J, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2., alkenyl. C2-6alkynyl, C3-7cycloalkyI. C2. 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12 is independently selected from hydrogen, C1-9alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, CL,, -cycloalky 1, C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroary 1. wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl. C3-7cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9 ictcroary 1 are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky I: or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky I: each R15 is independently selected C1-6alkyl, C2-6alkenyl. C2-6alky ny 1, C3- 7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl. C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; each R17 and each R17a are each independently selected from C1-6alkyl and C3- 6cycloalkyI. wherein C1-6alky 1 and C-,. rcycloalkyl are optionally substituted with one, two or three of R20h; or R17 and R17a form a C2-9cycloalkyI ring; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, Ci- ealkyl, C2-6alkenyk C2-6alkynyl, C3-10cycloalkyl. -CH2- C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- sheterocycloalkyl, C6-10aryl, -CH2-C6-ioaryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2- C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, and Ci-;hctcroaiy I are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalky I. C1-6 alkoxy. C1- 6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2- 9 heterocycloalkyl. C6-10aryl, and C1-9heteroaryl each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2.
9 heterocycloalkyl. C6-10aryl, and C1-9heteroaryl each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; each R25 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl; and p is 0, 1, or 2.
22. The compound of claim 21 having the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000201_0001
Formula (II);
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10; R2 is selected from hydrogen, C1-6alkyl, C1-6alkeny 1, C2-6alkynyl, and C3-10cycloalkyl-wherein C1-6alkyl, C2-6alkeny 1, C2-6alkynyl, and C3-10cy cloalky 1 are optionally substituted with one, two, or three R20a;
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alkyl, and C1-6 haloalky 1; each R6 is independently selected from halogen, -CN, C1-6alky I. C2-6 alkenyl. C2-6alkynyI. C3-10cycloalkyI. C2. sheterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyk C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b;
R7 is selected from halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1- 9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), - CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2^alkenyl, C2-6alkynyl, C3-7cycloalky I. C2- gheterocycloalkyl, C6-10aryl, C1.9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R13, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C . cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9hcteroary I are optionally substituted with one, two, or three R20d; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C-,. -cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9 hctcroary I. wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9 ielcroary I are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky I: or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky I: each R15 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6 alkenyl. C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R2°B; each R17 and each R17a are each independently selected from C1-6alkyl and C3-6cycloalkyl. wherein C1-6alky I and C3- 6 cycloalkyI are optionally substituted with one, two or three of R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, Ci- 6alkyl, C2., alkenyl. C2-6alkynyl, C3-10cycloalkyl. -CH2-C3-10cycloalkyl, Cwheterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1.9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl. C3-10cycloalkyl, -CH2- C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2.<;lictcrocycloalkyl. C6-10aryl, -CHi-C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalky I. C .„alkoxy. Ci- ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyI. C2.
• heterocycloalkyl. C6-10aryl, and C1-9heteroaryl each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C-.-cy cloalkyI. C2.
• hctcrocycloalkyl. C6-10aryl, and C1-9heteroaryl each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; each R25 is selected from C1-6alkyl, C2- , alkenyl. C2-6alkynyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1- 9 hctcroaryk and p is 0, 1, or 2.
23. The compound of claim 21 or claim 22, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from halogen, -OR12, -N(R12)(R13), -SR12, -SOR12, -SO2(R12)(R13), -SO2N(R12)(R13), - P(O)(R17)(R17a), C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci.'ihcteroaryl. wherein Ci- ealkyl, C’.. i ecy cloalky 1, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c.
24. The compound of claim 23, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from C1-6alkyl, C3-10cycloalkyl, C2.<;liclcrocycloalky 1, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2. 10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R20c.
25. The compound of any one of claims 21-24, or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-10cycloalkyk C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted withone, two, or three R20b.
26. The compound of any one of claims 21-25, or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl.
27. The compound of any one of claims 21-24, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
28. A compound of Formula (III’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000203_0001
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
R2 is selected from hydrogen, C1-6alkyl, C2-6 alkenyl. C2-6alkynyl. C . icycloalkyI. and C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C-,.| icycloalkyI. and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20a;
R4 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R8 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C . ocycloalky I. C2-
• heterocycloalkyl. C6-10aryl, C1-9 heteroaryl -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R13, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R13, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2., alkenyl. C2-6alkynyl, C3-10cycloalky 1, C2.
• heterocycloalkyl. C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b;
R9 is selected from CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C . icycloalkyI. C2-9heterocycloalkyl, C6-10aryl, Ci- sheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), - N(R14)C(O)OR15, -N(R14)S(O)2R15, N(R14)S(O)R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), -S(O)N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R13, -CH2S(O)2R13, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), CH2S(O) R15, -CH2S(O)N(R12)(R13), -CH2N(R12)S(O)(R13) and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C’,-i icycloalkyl. C2-9heterocycloalkyl, C6-10aryl, and Ci-)heteroary I are optionally substituted with one, two, or three R20c; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci. cycloalkyl, C2. 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R13, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R13, -S(O)2R13, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R13, -CH2S(O)2N(R12)(R13), - CH2N(R12)S(O)2(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl. C2-6alkynyl, Ci. cydoalkvk C2. sheterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, CL,. -cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryI. wherein C1-6alkyl, C2-6 alkenyl, C2-6alkynyl, C3-7 cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9 ieleroary I are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C .,,alky I. and C1-6haloalkyl; or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C .f,alky I. and C1-6haloalkyl; each R13 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C,. -cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9hctcroaiy k wherein C1-6alkyl, CL-,, alkenyl. C2-6alkynyl, C3-7 cycloalkyl. C2-9heterocycloalkyl, C6-10aryl, and C|.<licteroary I are optionally substituted with one, two, or three R20g; each R17 and each R17a are each independently selected from Ci .ealkyl and Cw, cycloalkyl. wherein C1-6alkyl and C3. ecycloalkyl are optionally substituted with one, two or three of R20h; or R17 and R17a form a C2-9cycloalky 1 ring; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, C3- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CHj-C6-10aryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-s>heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, and Ci-Jieteroary 1 are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalky I. C .„alkoxy. Ci- 6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cy cloalky 1. C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R22 is independently selected from H, C1-6alkyl, C1-6haloalkyl, Cj.,, alkenyl. C2-6alkynyl, C3-7 cy cloalky 1. C2- 9 heterocycloalkyl. C6-10aryl, and Ci-<>heteroaryl; each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; each R25 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C1-9heterocycloalkyl, C6-10aryl, and Ci- • hctcroaiy l: and p is 0, 1, or 2.
29. The compound of claim 28 having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000205_0001
Formula (III);
R1 is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R10;
R2 is selected from hydrogen, C1-6alkyI. C2-6alkeny 1, C2-6alkynyl, and C3-10cycloalkyl wherein C1-6alkyI. C2-6alkenyl C2-6alkynyl, and C3-10cy cloalky 1 are optionally substituted with one, two, or three R20a;
R4 is selected from hydrogen, C1-6 alky 1, and C1-6 haloalky 1;
R5 is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R8 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalky 1. C2- 9heterocycloalkyl, C6-10aryl, C1-9 heteroaryl -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, Ce- waryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b;
R9 is selected from Ci-ealkyl. C2-6alkenyl, Chalkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, Ci- sheteroaryl, -C(O)OR12, -C(O)R15, -S(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, and - S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; each R10 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C,. -cycloalky I. C2.
• heterocycloalkyl. C6-10aryl, C1-9heteroaryl. -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R13, -S(O)2N(R12)(R13), - S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R13, -CH2S(O)2N(R12)(R13), and -P(O)(R17)(R17a), wherein C1-6alkyl, C2-,,alkenyl. C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9hcteroary I are optionally substituted with one, two, or three R20d; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalky I. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20e; each R13 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky I: or R12 and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20f; each R14 is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalky 1; each R13 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkynyl. C2-6alkynyl, C3-7 cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, and C1-9hcteroary I are optionally substituted with one, two, or three R20g; each R17 and each R17a are each independently selected from C1-6alkyl and C3-6 cycloalkyl, wherein C1-6alkyl and C3- ecycloalkyl are optionally substituted with one, two or three of R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R20h are each independently selected from halogen, oxo, -CN, Ci. ealkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl. -CH2- C3-10cycloalkyl, C2-9heterocycloalkyl. -CH2-C2. ghcterocycloalkyl. C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR23, - N(R24)C(O)R25, -N(R24)S(O)2R23, -C(O)R23, -S(O)2R23, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R23, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl. C6-10aryl, -CH2-C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalky I. C1-6alkyl . Ci- ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R23, -N(R24)S(O)2R25, -C(O)R23, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21 is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7 cy cloalky I. C2.
• hctcrocycloalkyl. C6-10aryl, and C1-9heteroaryl each R22 is independently selected from H, C1-6alkyl, C1-6 haloalky I. C1-6alkeny 1, C2-6alkynyl, C'-.-cy cloalky I. C2- 9 heterocycloalkyl. C6-10aryl, and C1-9heteroaryl; each R23 is independently selected from H and C1-6alkyl; each R24 is independently selected from H and C1-6alkyl; each R25 is selected from C1-6alkyl, C2-6alkenyl. C2-6alkynyl, C’,. -cycloalkyI. C2-9heterocycloalkyl. C3-10aryl, and C1- 9heteroaryl; and p is 0, 1, or 2.
30. The compound of claim 28 or claim 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is selected from C1-6alkyl, C1-10cycloalkyl, C2-9heterocycloalkyl. C6-10aryl, and C1-9heteroaryl. wherein C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c.
31. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is selected from C2-9heterocycloalkyl, C6-10ary 1, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three R20c.
32. The compound of any one of claims 28-31, or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen, C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-10cycloalkyl. C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroary 1 are optionally substituted with one, two, or three R20b.
33. The compound of any one of claims 28-32, or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen and unsubstituted C1-6alkyl.
34. The compound of any one of claims 28-31, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from C1-6alkyl and C1-6haloalkyl.
36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CH3.
37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen.
38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three R20a.
39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C1-6alkyl optionally substituted with one, two, or three R20a.
40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is unsubstituted C1-6alkyl.
41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3.
42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is - hydrogen.
43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a 6-10 membered aryl ring substituted with one or more R10. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl substituted with one or more R10. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is phenyl substituted with one, two, or three R10. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a 5-10 membered heteroaryl ring are substituted with one or more R10. The compound of claim 46, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a 5-10 membered heteroaryl ring are substituted with one, two, or three R10. The compound of any one of claims 43-47, or a pharmaceutically acceptable salt or solvate thereof, wherein each R10 is independently selected from halogen, C1-6alkyl, C3-7cycloalkyI. C2-9heterocycloalkyl, C6-10aryl, C1- 9heteroaryl, -OR12, and N(R12)(R13), wherein C1-6alkyl, C3-7 cy cloalky 1, C2-9heterocycloalkyl. C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three R20d. The compound of any one of claims 43-48, or a pharmaceutically acceptable salt or solvate thereof, wherein each R10 is independently selected from halogen, C1-6alkyl, and N(R12)(R13), wherein C1-6alkyl is optionally substituted with one, two, or three R20d. The compound of any one of claims 43-49, or a pharmaceutically acceptable salt or solvate thereof, wherein each R10 is independently selected from halogen, C1-6alkyl, and N(R12)(R13), wherein C1-6alkyl is substituted with one, two, or three R20d, and each R20d is halogen. A compound selected from:
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
or a pharmaceutically acceptable salt or solvate thereof. A pharmaceutical composition comprising a compound of any one of claims 1-51, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-51, or a pharmaceutically acceptable salt or solvate thereof. The method of claim 53, wherein the cancer is a solid tumor or a hematological cancer. The method of claim 53, wherein the subject is administered with an additional agent or therapy. A method of reducing Ras signaling output, comprising contacting a S0S1 protein with an effective amount of a compound of any one of claims 1-51, or a pharmaceutically acceptable salt or solvate thereof, thereby reducing the Ras signaling output. The method of claim 56, wherein the compound disrupts interaction between a Ras protein and S0S1. The method of claim 57, wherein the Ras protein is a wildtype K-Ras or a mutant K-Ras. A method of inhibiting cell growth, comprising administering a cell expressing S0S1 with an effective amount of a compound of any one of claims 1-51, or a pharmaceutically acceptable salt or solvate thereof, thereby inhibiting growth of said cells. The method of claim 59 further comprising administering the cell an additional agent. The method of claim 60, wherein the additional agent is an inhibitor against one or more targets selected from the group of: MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, FGFR4, mitotic kinase, topoisomerase, ALK, c-MET, ErbB2, AXL, NTRK1, RET, A-Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF1/2, IGF1-R, CDK9, SHC, GAB, GRB, PI3-kinase, MAPK, SHIP1, SHIP2, SHP1, SHP2, SRC, JAK, PARP, BTK, FLT3, HD AC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, wildtype KRas, KRas mutant (e.g., KrasG12C, KRas G12D, KRas G12S, KRas G12V, KRas G13D, KRas G13C, or KRas G13V), ROS1, CDK4/6, and a mutant of the one or more target thereof. The method of claim 60, wherein the additional agent is a chemotherapeutic agent, a radioactive agent, or an immune modulator. A SOS 1 protein bound by a compound of any one of claims 1 -51 , or a pharmaceutically acceptable salt or solvate thereof, wherein interaction of the S0S1 protein with a Ras protein is reduced as compared to a SOS1 protein unbound to said compound.
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WO2024075070A3 (en) * 2022-10-07 2024-05-23 제일약품주식회사 Novel bicyclic heterocyclyl compounds and use thereof

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