EP4355751A1 - Fused heteroaryl compounds useful as anticancer agents - Google Patents

Fused heteroaryl compounds useful as anticancer agents

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Publication number
EP4355751A1
EP4355751A1 EP22740705.3A EP22740705A EP4355751A1 EP 4355751 A1 EP4355751 A1 EP 4355751A1 EP 22740705 A EP22740705 A EP 22740705A EP 4355751 A1 EP4355751 A1 EP 4355751A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
alkyl
ioaryl
compound
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22740705.3A
Other languages
German (de)
French (fr)
Inventor
Liansheng Li
Xiuwen Zhu
Pingda Ren
Yi Liu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kumquat Biosciences Inc
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Kumquat Biosciences Inc
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Filing date
Publication date
Application filed by Kumquat Biosciences Inc filed Critical Kumquat Biosciences Inc
Publication of EP4355751A1 publication Critical patent/EP4355751A1/en
Pending legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Cancer e.g., tumor, neoplasm, metastases
  • K-Ras Kirsten Ras oncogene
  • PD AC pancreatic ductal adenocarcinoma
  • 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 draggable target.
  • such therapeutic approach is still limiting, as the G12C mutation in Ras has a low prevalence rate (e.g., about 3% in PD AC) as compared to other known Ras mutations.
  • 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.
  • W is C(O), S(O), or S(0) 2 ;
  • V is C(R 17 ) and J is C(R 16 ), or V is C(R 17 ) and J is N, or J is C(R 17 ) and V is C(R 16 ), or J is C(R 17 ) and V is N;
  • R 10 is -L 7 -R 7 ;
  • L 7 is a bond, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, - N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein Ci-Cealkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, are optionally substituted with one, two, or three R 20a ; R 7 is a 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl, wherein the 3-12 membered nitrogen containing heterocyclo
  • R 4 is optionally an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein), wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 20a ;
  • R 6 is -L 2 -R 5 ; each L 2 is independently selected from a bond, Ci-Cealkyl, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, - S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, -OCON(R 14 )-, -N(R 14 )C(0)0-, and - N(R 14 )C(0)N(R 14 )-; each R 5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
  • R 8 is selected from halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 12 , -SR 12 , -N(H)(R 12 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0) 2 R 15 , -
  • R 17 is -lA-R 19 ;
  • L 1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R 14 )-, -C(0)-, -N(R 14 )C(0)-, -
  • ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 201 ; or R lf and R lg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R 201 ;
  • R lc is selected from hydrogen, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 201 R 19 is selected from a C3-i2cycloalkyl (e.g., monocyclic, bicyclic, or polycyclic), C2-iiheterocycloalkyl (e.g., monocyclic, bicyclic, or polycyclic), C6-i2aryl (e.g., monocyclic, bicyclic, or polycyclic), and C2-i2heteroaryl (e
  • R 16 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0)
  • Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 20d ;
  • R 12a is selected from Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6 -ioaryl, -CH 2 -G5-ioaryl, -CH 2 -Ci-9heteroaryl, and Ci-dictcro
  • R 12b is selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, -CH 2 -C3-iocycloalkyl, C 2. gheterocycloalkyl, -CH 2 -C 2 -9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 -Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, -CH 2 -C3-iocycloalkyl, C 2 -9heterocycloalkyl, -CH 2 - C 2 -9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH
  • X is C(R 3 ) or N
  • R 3 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, Ce-ioaryl, Ci- 9 heteroaiyl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0) 2 R
  • each R 12 is independently selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, -CH 2 -C3-
  • gheterocycloalkyl, -CH 2 -C 2 -9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 -Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci-ehaloalkyl, Ci- 6 alkoxy, Ci- 6 haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(0)0R 22 , -C(0)N(R 22 )(R 23 ), - C(0)C(0)N(R 22 )(R 23 ), -0C(0)N(R 22 )(R 23 ), -N(R 24 )C(0)N(R 22 )(R 23 ), -N(R 24 )C(0)0
  • each R 22 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- siheterocycloalkyl, C 6 -ioaryl, and Ci-dictcroaryl: each R 23 is independently selected from H and Ci- 6 alkyl; each R 24 is independently selected from H and Ci- 6 alkyl; each R 25 is independently selected from Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, Ce- ioaryl, and Ci-gheteroaryl; and indicates a single or double bond such that all valences are satisfied.
  • X is C(R 3 ). In embodiments, X is N. In embodiments, J is C(R 16 ) and V is C(R 17 ). In embodiments, W is C(O).
  • the compound, or a pharmaceutically acceptable salt or solvate thereof has the structure: , , , Formula (IA12). [0008] In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure:
  • the compound, or a pharmaceutically acceptable salt or solvate thereof has the structure:
  • L 7 is a bond. [0011] In embodiments, L 7 is -NH-.
  • R 7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 ; and wherein two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i 2 cycloalkyl, Ci- li heterocycloalkyl, C 6 -i 2 aryl, or Ci-nheteroaryl, wherein the C3-i 2 cycloalkyl, Ci-nheterocycloalkyl, C 6 -i 2 aryl, or Ci- nheteroaryl are optionally substituted with one, two, or three R 20a .
  • R 16 is independently selected from hydrogen and halogen. In embodiments, R 16 is independently selected from hydrogen and fluoro.
  • R 8 is selected from Ci- 6 alkyl, C3-iocycloalkyl, and C2-s > heterocycloalkyl, wherein Ci- 6 alkyl, C3-iocycloalkyl, and C2-s > heterocycloalkyl are optionally substituted with one, two, or three R 20c independently selected from halogen, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl.
  • R 8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R 20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl.
  • R 8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
  • R 3 is hydrogen or CN.
  • L 1 is a bond.
  • L 1 is selected from a Ci-Cealkyl, C2-C6alkenyl, C2- Cealkynyl, -C(O)-, -NHC(O)-, -C(0)NH-, CH 2 0, CH 2 NH, and CH 2 .
  • R 19 is a monocyclic ring. In embodiments, R 19 is a bicyclic ring system. In embodiments, R 19 is a polycyclic ring system.
  • Q 1 , Q 3 , and Q 5 are independently N or C(R ld );
  • Q 4 and Q 6 are independently O, S, C(R la )(R lb ), or N(R lc );
  • X 4 , X 5 , X 6 , X 9 , X 10 , X 11 , X 12 , and X 16 are independently selected from C(R la ) or N;
  • X 7 and X 8 are independently selected from C(R la ), C(R la )(R lb ), N, or N(R lc );
  • X 13 is selected from a bond, C(O), C(R la )(R lb ), C(0)C(R la )(R lb ), C(R la )(R lb )C(R la )(R lb ), C(R la )(R lb )N(R lc ), and N(R lc );
  • X 14 and X 15 are independently selected from a bond, C(O), C(R la )(R lb ), and N(R lc ); each R la , R lb , R ld , R lf , R lg , and R lh are each independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, Ci- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-dictcroarvl.
  • C 6 -ioaryl, and Cj-dictcroaryl are optionally substituted with one, two, or three R 201 ; or R la and R lb bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-iocycloalkyl ring are optionally substituted with one, two, or three R 201 ; or two R la bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C 6 -ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C 6 -ioaryl ring, 5-12 membered heteroaryl ring, or C3-iocycloalkyl ring
  • C 6 -ioaryl, and Cj-dictcroaryl are optionally substituted with one, two, or three R 201 .
  • each L 2 is independently a bond.
  • each R 5 is independently selected from:
  • R 4 is independently -C(0)R 15 .
  • R 4 is independently -C(0)R 15 and the R 15 is independently selected from C 2-6 alkenyl, C 2-6 alkynyl, C 2 -9heterocycloalkyl, and CiActcroaryl. wherein C 2. 6 alkenyl, C 2-6 alkynyl, C 2 -9heterocycloalkyl, and CiAeteroaryl are optionally substituted with one, two, or three R 20f .
  • R 4 is independently -C(0)R 15 and the R 15 is independently C 2-6 alkenyl, wherein C 2-6 alkenyl is optionally substituted with one, two, or three R 20f .
  • R 4 is independently -C(0)R 15 and the R 15 is independently C 2 -9heterocycloalkyl, wherein C 2 -9heterocycloalkyl is optionally substituted with one, two, or three R 20f .
  • R 4 is independently -C(0)R 15 and the R 15 is independently CiAeteroaryl, wherein Ci- gheteroaryl is optionally substituted with one, two, or three R 20f .
  • R 4 is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein.
  • A is a monovalent form of a compound described herein;
  • L AB is a covalent linker bonded to A and B; and
  • B is a monovalent form of a degradation enhancer.
  • 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, TRIP 12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHL (von-Hippel-
  • ubiquitin ligase XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBX04, FBX031, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885.
  • the compound of claim 74 wherein 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, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.
  • a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, U
  • L AB is -L AB1 -L AB2 -L AB3 -L AB4 -L AB5 -; L AB I . IT 02 .
  • L ab ⁇ L AB and L ABS are independently a bond, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, - N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, Ci- 6 alkylene, (-0-Ci- 6 alkyl) z -, (-Ci- 6 alkyl-0) z -, C 2-6 alkenylene, C 2-6 alkynylene, Ci- 6 haloalky
  • narylene, or Ci-nheteroarylene are optionally substituted with one, two, or three R 20j ; wherein each Ci- 6 alkyl of (-0-Ci- 6 alkyl) z - and (-Ci- 6 alkyl-0) z - is optionally substituted with one, two, or three R 20j ; z is independently an integer from 0 to 10; each R 12 is independently selected from hydrogen, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, G- 6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 - Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alky
  • Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 alkoxy, Ci- 6 haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), - C(0)0R 22 , -C(0)N(R 22 )(R 23 ), -C(0)C(0)N(R 22 )(R 23 ), -0C(0)N(R 22 )(R 23 ), -N(R 24 )C(0)N(R 22 )
  • L AB is -(0-C 2 alkyl) z - and z is an integer from 1 to 10. In embodiments, L AB is -(C 2 alkyl-0-) z - and z is an integer from 1 to 10. In embodiments, L AB is -(CH 2 ) Z IL AB2 (CH 2 0) Z2 -, wherein L Ali2 is a bond, a 5 or 6 membered heterocycloalkylene or heteroarylene, phenylene, -(C2-
  • L AB is -(CH 2 ) zi (CH 2 0) z2 -, wherein zl and z2 are each independently an integer from 0 to 10.
  • L AB is a PEG linker.
  • B is a monovalent form of a compound selected from
  • a pharmaceutical composition comprising a compound described herein 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 described herein, or a pharmaceutically acceptable salt or solvate thereof.
  • a method of modulating activity of a Ras protein comprising contacting a Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.
  • the method includes administering an additional agent or therapy.
  • a method of inhibiting cell growth comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells.
  • the method includes administering an additional agent to said cell.
  • the additional agent comprises (1) an inhibitor of MEK; (2) an inhibitor of epidermal growth factor receptor (EGFR) and/or of mutants thereof; (3) an immunotherapeutic agent; (4) a taxane; (5) an anti-metabolite; (6) an inhibitor of FGFR1 and/or FGFR2 and/or FGFR3 and/or of mutants thereof; (7) a mitotic kinase inhibitor; (8) an anti-angiogenic drag; (9) a topoisomerase inhibitor; (10) a platinum-containing compound; (12) an inhibitor of c-MET and/or of mutants thereof; (13) an inhibitor of BCR-ABL and/or of mutants thereof; (14) an inhibitor of ErbB2 (Her2) and/or of mutants thereof; (15) an inhibitor of AXL and/or of mutants thereof; (16) an inhibitor of NTRK1 and/or of mutants thereof; (17) an inhibitor of RET and/or of mutants thereof; (18) an inhibitor of A-Raf and or
  • the additional agent comprises an inhibitor of SHP2 selected from RMC-4630, TN0155, JAB-3068, IACS-13909/BBP-398, SHP099, ERAS-601, and RMC-4550.
  • the additional agent comprises an inhibitor of SOS selected from RMC-5845, BI-3406, BI-1701963, MRTX0902, and BAY 293.
  • the additional agent comprises an inhibitor of EGFR selected from afatinib, erlotinib, gefitinib, lapatinib, cetuximab panitumumab, osimertinib, olmutinib, and EGF-816.
  • the additional agent comprises an inhibitor of MEK selected from trametinib, cobimetinib, binimetinib, selumetinib, refametinib, and AZD6244.
  • the additional agent comprises an inhibitor of ERK selected from ulixertinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, and ravoxertinib.
  • the additional agent comprises an inhibitor of CDK4/6 selected from palbociclib, ribociclib, and abemaciclib.
  • the additional agent comprises an inhibitor of BRAF selected from sorafenib, vemurafenib, dabrafenib, encorafenib, regorafenib, and GDC-879.
  • W is C(O), S(O), or S(0) 2 ;
  • V is C(R 17 ) and J is C(R 16 ), or V is C(R 17 ) and J is N, or J is C(R 17 ) and V is C(R 16 ), or J is C(R 17 ) and V is N;
  • R 10 is -L 7 -R 7 ;
  • L 7 is a bond, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -
  • R 7 is a 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl, wherein the 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl are optionally substituted with one or more R 1 , one or more R 4 , or one or more R 6 ; wherein two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R 20a ; each R 1 is independently selected from hydrogen, Ci- 6 alkyl, C2-6alkenyl, C
  • R 6 is -L 2 -R 5 ; each L 2 is independently selected from a bond, Ci-Cealkyl, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, - S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, -OCON(R 14 )-, - N(R 14 )C(0)0-, and -N(R 14 )C(0)N(R 14 )-; each R 5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
  • R 8 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(H)(R 12 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0) 2 R
  • R 17 is -LkR 19 ;
  • L 1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R 14 )-, -C(0)-, -N(R 14 )C(0)-, - C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, - OCON(R 14 )-, -N(R 14 )C(0)0-, N(R le ), C(0)N(R lc ), S(0) 2 N(R lc ), S(0)N(R lc ), C(R lf )(R lg )0, C(R lf )(R lg )N(R lc ), and C(R
  • R le , R lf , and R lg are independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), - C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , - S(0)R 15 , -0C(0)R 15 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )
  • R lc is selected from hydrogen, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-dictcroaiyl. wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 201
  • R 19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the G- ncycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R 11 ; each R 11 is independently selected from halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C2-6alkynyl, G- 6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , - 0C(0)N(R 12 )(R 13
  • R 16 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, G- gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0)
  • R 12a is selected from Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl, wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH2-Ci-9heteroaryl, and Ci-
  • R 12b is selected from hydrogen, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CEC-Ci-gheteroaryl, and Ci- gheteroaryl, wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CEC-Ci-ghetero
  • X is C(R 3 ) or N; R 3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -ioaryl, Ci-yhctcroan l.
  • each R 12 is independently selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 -C 1 - gheteroaryl, and Ci-gheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C
  • Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 20f ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 201 are each independently selected from halogen, -CN, Ci- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2 - gheterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl,
  • X is C(R 3 ). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is N. [0040] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
  • V is C(R 16 ) and J is C(R 17 ). In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is N and J is C(R 17 ). In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, J is N and V is C(R 17 ). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, J is C(R 16 ) and V is C(R 17 ). In lurther embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is C(O). In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(O). In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(0) 2 .
  • the compound has the structure:
  • the compound has the structure: ), , 12).
  • L 7 is a bond. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L 7 is -NH-.
  • R 7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R 1 , one or more R 4 , or one or more R 6 ; and wherein two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci- li heterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R 20a .
  • R 7 is
  • R 7 is integer from 0 to 12.
  • R 7 In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 7
  • R 16 is independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, and C3- 6 cycloalkyl, wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl are optionally substituted with one, two, or three R 20g .
  • R 16 is independently selected from hydrogen and halogen.
  • R 16 is independently selected from hydrogen and fluoro.
  • R 8 is selected from halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaiyl, -OR 12 , -SR 12 , -N(H)(R 12 ), -C(0)OR 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -OC(0)R 15 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ),
  • R 8 is selected from Ci- 6 alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl, wherein Ci- 6 alkyl, C3-iocycloalkyl, and C2- gheterocycloalkyl are optionally substituted with one, two, or three R 20c independently selected from halogen, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl.
  • R 8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R 20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl.
  • R 8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
  • R 3 is hydrogen or CN. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 3 is hydrogen.
  • L 1 is a bond. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L 1 is selected from a Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C(O)-, -NHC(O)-, -C(0)NH-, CH 2 0, CH 2 NH, and CH 2 .
  • R 19 is a monocyclic ring. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 19 is a bicyclic ring system. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 19 is a polycyclic ring system. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 19 is:
  • Q 1 , Q 3 , and Q 5 are independently N or C(R ld );
  • Q 4 and Q 6 are independently O, S, C(R la )(R lb ), or N(R lc );
  • X 4 , X 5 , X 6 , X 9 , X 10 , X 11 , and X 12 are independently selected from C(R la ) or N;
  • X 7 and X 8 are independently selected from C(R la ), C(R la )(R lb ), N, or N(R lc ); each R la , R lb , R ld , and R lh are each independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-dictcroaiyl.
  • Ci-dictcroaiyl wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- dictcrocycloalkyl.
  • C 6 -ioaryl, and Cj-dictcroaryl are optionally substituted with one, two, or three R 201 .
  • R 2 is [0057] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, each R 5 is independently selected from:
  • V is C(R 16 ) or N;
  • R 10 is -L 7 -R 7 ;
  • L 7 is a bond, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -
  • R 7 is a 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl are optionally substituted with one or more R 1 , one or more R 4 , or one or more R 6 ; two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i 2 cycloalkyl, Ci-nheterocycloalkyl, C 6 -i 2 aryl, or Ci-nheteroaryl, wherein the C3- i 2 cycloalkyl.
  • Ci-nheterocycloalkyl, C 6 -i 2 aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R 20a ; each R 1 is independently selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci- 6 haloalkyl, C3- i 2 cycloalkyl.
  • R 6 is -L 2 -R 5 ; each L 2 is independently selected from a bond, G-Galkyl, -0-, -N(R 14 )-, -C(0)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, - S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, -OCON(R 14 )-, - N(R 14 )C(0)0-, and -N(R 14 )C(0)N(R 14 )-; each R 5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
  • R 8 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2. gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(H)(R 12 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0) 2 R
  • R 17 is -G-R 19 ;
  • L 1 is selected from a bond, G-Galkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -0-, -N(R 14 )-, -C(0)-, -N(R 14 )C(0)-, - C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, - OCON(R 14 )-, -N(R 14 )C(0)0-, N(R le ), C(0)N(R lc ), S(0) 2 N(R lc ), S(0)N(R lc ), C(R lf )(R lg )0, C(R lf )(R lg )N(R lc ), and
  • R le , R lf , and R lg are independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-dictcroarvl.
  • gheterocycloalkyl, C 6 -ioaryl, and Ci-dictcroarvl are optionally substituted with one, two, or three R 201 ; or R lf and R lg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R 201 ;
  • R lc is selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 201
  • R 19 is selected from a C3-i 2 cycloalkyl, C 2 -nheterocycloalkyl, C 6 -i 2 aryl, and C 2 -i 2 heteroaryl, wherein the C3- i 2 cycloalkyl.
  • C 2 -nheterocycloalkyl, C 6 -i 2 aryl, and C 2 -i 2 heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R 11 ; each R 11 is independently selected from halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3- 6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , - 0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)
  • R 16 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2. gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0)
  • R 12a is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, -CH 2 -C3-iocycloalkyl, C 2. gheterocycloalkyl, -CH 2 -C 2 -9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 -Ci-9heteroaryl, and Ci- yhctcroan l.
  • R 12b is selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -CH 2 -C 3 -iocycloalkyl, C 2 - gheterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 -Ci- 9 heteroaryl, and Ci- gheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -CH 2 -C 3 -iocycloalkyl, C 2 - gheterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl,
  • X is C(R 3 ) or N
  • R 3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 ,
  • each R 12 is independently selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 -C 1 - gheteroaryl, and Ci-gheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -io
  • Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 20f ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 201 are each independently selected from halogen, -CN, Ci- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2 - gheterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl,
  • X is C(R 3 ). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is N. [0060] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is C(R 16 ). In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is N.
  • W is C(O). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(O). In lurther embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(0) 2 .
  • the compound has the structure: , Formula Formula (IIA9), Formula (IIA10), Formula (IIA11), or Formula (IIA12).
  • L 7 is a bond. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L 7 is -NH-.
  • R 7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R 1 , one or more R 4 , or one or more R 6 ; and wherein two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci- l i heterocycloalkyl, C6-i2aryl, or Ci-iiheteroaryl, wherein the C3-i2cycloalkyl, Ci-iiheterocycloalkyl, C6-i2aryl, or Ci- nheteroaryl are optionally substituted with one, two, or three R 20a .
  • p is an integer from 0 to 12;
  • X 2 is selected from N, C, C(R 6 ), C(R 4 ), CH, N(R'). N(R 4 ), N(R 6 ), O, S, S(O), C(H)(R 6 ), C(R 4 ) 2 , CH 2 , C(R 4 )(R 6 ),
  • X 3 is selected from N, C, C(R 6 ), and C(R 4 ).
  • R 7 In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 7
  • R 7 integer from 0 to 12.
  • R 7 In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 7
  • R 16 is independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl, wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl are optionally substituted with one, two, or three R 20g .
  • R 16 is independently selected from hydrogen and halogen.
  • R 16 is independently selected from hydrogen and fluoro.
  • R 8 is selected from halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaiyl, -OR 12 , -SR 12 , -N(H)(R 12 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -C(0)C
  • R 8 is selected from Ci- 6 alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl, wherein Ci- 6 alkyl, C3-iocycloalkyl, and C2- gheterocycloalkyl are optionally substituted with one, two, or three R 20c independently selected from halogen, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl.
  • R 8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R 20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl.
  • R 8 is selected from methyl, cyclopropyl, cyclobutyl, oxetanylmethyl, and oxetanyl.
  • R 8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
  • R 3 is hydrogen or CN. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 3 is hydrogen.
  • L 1 is a bond. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L 1 is selected from a Ci-Cealkyl, C2-C6alkenyl, C2-Cealkynyl, -C(O)-, -NHC(O)-, -C(0)NH-, CH 2 0, CH 2 NH, and CH 2 .
  • R 19 is a monocyclic ring. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 19 is a bicyclic ring system. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 19 is a polycyclic ring system. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 19 is:
  • Q 1 , Q 3 , and Q 5 are independently N or C(R ld );
  • Q 4 and Q 6 are independently O, S, C(R la )(R lb ), or N(R lc );
  • X 4 , X 5 , X 6 , X 9 , X 10 , X 11 , and X 12 are independently selected from C(R la ) or N;
  • X 7 and X 8 are independently selected from C(R la ), C(R la )(R lb ), N, or N(R lc ); each R la , R lb , R ld , and R lh are each independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-dictcroaiyl.
  • Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- siheterocycloalkyl, C 6 -ioaryl, and Cj-dictcroaryl are optionally substituted with one, two, or three R 201 .
  • R 19 is: [0076] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 2
  • each R 5 is independently selected from:
  • A is a monovalent form of a compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV;
  • L AB is a covalent linker bonded to A and B; and B is a monovalent form of a degradation enhancer.
  • 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, SMURF 1, SMURF2, STUB1, TOPORS, TRIP 12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHL (von-Hippel- Lindau ubiquitin ligase), WWP1, WWP2, Parkin, MK
  • 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, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.
  • a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2DR, UBE2E
  • L AB is -L AB I -L AB1 -L AB, -L AB I -L AB5 -: independently a bond, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, - )N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, Ci- 6 alkylene, (-0-Ci.
  • R 20e each are each independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6c loalkyl, C 2 -9heterocycloalkyl, -CH 2 -C 2 -9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, - CH 2 - roaiyl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(0)0R 22 , -C(0)N(R 22 )(R 23 ), - C(0) 0)N(R 22 )(R 23 ), -N(R 24 )C(0)N(R 22 )(R 23 ), -N(R 24 )C(0)0R 25 , -N(R 24 )C(0)R 25 , -N(R 24 )S(0) 2 R 25 , -
  • ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 -Ci-9heteroaryl, and GAeteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, CXalkyl, Ci- 6 haloalkyl, Ci- 6 alkoxy, Ci- 6 haloalkoxy, -OR 21 , - SR 21 , -N(R 22 )(R 23 ), -C(0)0R 22 , -C(0)N(R 22 )(R 23 ), -C(0)C(0)N(R 22 )(R 23 ), -0C(0)N(R 22 )(R 23 ), - N(R 24 )C(0)N(R 22 )(R 23 ), -N(R 24 )C(0)0R 25 , -N(R 24 )C(0)R 25 , -N(R 24 )S(0) 2 R 25 ,
  • each R 22 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2.
  • each R 23 is independently selected from H and Ci- 6 alkyl
  • each R 24 is independently selected from H and Ci- 6 alkyl
  • each R 25 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and G- gheteroaryl.
  • L AB is -(0-C 2 alkyl) z - and z is an integer from 1 to 10.
  • L AB is -(C 2 alkyl-0-) z - and z is an integer from 1 to 10.
  • L AB is -(CH 2 ) Z IL AB2 (CH 2 0) z2 -, wherein L Ali2 is a bond, a 5 or 6 membered heterocycloalkylene or heteroarylene, phenylene, -(C 2 -C4)alkynylene, -S0 2 - or -NH-; and zl and z2 are independently an integer from 0 to 10.
  • L AB is -(CH 2 ) Z I(CH 2 0) /2 -. wherein zl and z2 are each independently an integer from 0 to 10.
  • L AB is a PEG linker (e.g., divalent linker of 1 to 10 ethylene glycol subunits).
  • B is a monovalent form of a compound selected from
  • a pharmaceutical composition comprising a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula G, IF, I”, II”, 1-1, 1-G, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • a compound described herein e.g., compound of Formula I, IA1, IA2, IA3, IA
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, 1 A3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, II A 11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-F, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof.
  • a compound described herein e.g., compound of Formula I, I
  • a method of modulating activity of a Ras comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, 1 A3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-r, 1-1”, I-G”, 1-3, 1-4, II-l, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof
  • a compound described herein e.g., compound of Formula I, IA1,
  • the subject method comprises administering an additional agent or therapy.
  • a method of inhibiting cell growth comprising administering an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-G, 1-1”, I-F”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras (e.g., K- Ras) protein,
  • a Ras e.g
  • a Ras (e.g., K-Ras) protein bound by a compound described herein e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-G, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein activity of said Ras (e.g., K-Ras) protein is
  • 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.
  • Ci-C x includes C1-C2, C1-C3 . . . Ci-C x .
  • Ci-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 18, 1 to 12, 1 to 10, 1 to 8, or 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 “Ci-Cealkyl” or similar designations.
  • “Ci-Cealkyl” 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, neopentyl, 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 -CoCH, -CoCCH 3 , -CoCCH 2 CH 3 and -CoCCH 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 p-electron system containing 4n+2 p 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 a monocyclic aromatic ring wherein each of the atoms forming the ring is a carbon atom (e.g., phenyl) or a polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is carbocyclic and aromatic, 2) a bond to the remainder of the compound is directly bonded to a carbocyclic aromatic ring of the aryl ring system, and 3) the carbocyclic aromatic ring of the aryl ring system of 2) is not directly bonded (e.g., fused) to a heteroaryl ring in the polycyclic ring system.
  • a carbon atom e.g., phenyl
  • a polycyclic ring system e.g., bicyclic or tricyclic
  • 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.
  • an aryl group can be a monoradical or a diradical (i.e., an arylene group).
  • the aryl radical is a monocyclic, bicyclic, or tricyclic ring system.
  • an aryl is a monocyclic ring.
  • an aryl is a fused ring polycyclic system.
  • an aryl is a bridged ring polycyclic system.
  • the aryl is a “fused ring aryl” wherein the aryl ring is fused with a cycloalkyl or a heterocycloalkyl ring.
  • Carboxy refers to -CO2H.
  • 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, and the like.
  • cycloalkyl refers to a monocyclic carbocyclic saturated or partially unsaturated non-aromatic ring or a polycyclic carbocyclic (i.e., does not include heteroatom(s)) ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is carbocyclic saturated or partially unsaturated and non-aromatic, 2) a bond to the remainder of the compound is directly bonded to a carbocyclic saturated or partially unsaturated non-aromatic ring of the ring system, and 3) the carbocyclic saturated or partially unsaturated non-aromatic ring of the ring system of 2) is not directly bonded (e.g., fused or spirocyclic) to a heterocycloalkyl ring in the polycyclic ring system.
  • heteroatom(s) ring system
  • Cycloalkyls may be saturated or partially unsaturated.
  • a cycloalkyl ring is a spirocyclic cycloalkyl ring.
  • a cycloalkyl is a monocyclic ring.
  • a cycloalkyl is a fused ring polycyclic system.
  • a cycloalkyl is a bridged ring polycyclic system.
  • a cycloalkyl is a spirocyclic polycyclic ring system.
  • cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • a cycloalkyl group can be a monoradical or a diradical (i.e., a cycloalkylene group).
  • heteroaryl or, alternatively, “heteroaromatic” refers to an monocyclic aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur; or a polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is aromatic and includes one or more heteroatoms selected from nitrogen, oxygen and sulfur and 2) a bond to the remainder of the compound is directly bonded to an aromatic ring including one or more heteroatoms selected from nitrogen, oxygen and sulfur or an aromatic ring directly bonded (e.g., fused) to an aromatic ring including one or more heteroatoms selected from nitrogen, oxygen and sulfur, of the aryl ring system.
  • the heteroaryl radical may be a monocyclic, bicyclic, or tricyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated (i.e., aromatic) and includes a heteroatom.
  • a heteroaryl is a monocyclic ring.
  • a heteroaryl is a fused ring polycyclic system.
  • a heteroaryl is a bridged ring polycyclic system.
  • Y-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).
  • a “heterocycloalkyl” group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom of a saturated or partially unsaturated non-aromatic ring is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.
  • a heterocycloalkyl refers to a monocyclic saturated or partially unsaturated nonaromatic ring including one or more heteroatoms or a polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is saturated or partially unsaturated, non-aromatic, and includes one or more heteroatoms and 2) a bond to the remainder of the compound is directly bonded to a ring of the ring system that is a saturated or partially unsaturated and non-aromatic ring that includes one or more heteroatoms or a non-aromatic ring directly bonded (e.g., fused) to a saturated or partially unsaturated and non-aromatic ring that includes one or more heteroatoms of the ring system.
  • a polycyclic ring system e.g., bicyclic or tricyclic
  • Heterocycloalkyls may be saturated or partially unsaturated.
  • 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.
  • a heterocycloalkyl is a monocyclic ring.
  • a heterocycloalkyl is a fused ring polycyclic system.
  • a heterocycloalkyl is a bridged ring polycyclic system.
  • a heterocycloalkyl is a spirocyclic polycyclic ring system. Unless otherwise noted, heterocycloalkyls have from 2 to 13 carbons in the ring or ring system. 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).
  • 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.
  • haloalkyl 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 C1, -CF , -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.
  • heteroalky lene linker refers to a divalent 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.
  • the heteroatom(s) may be placed at one or both terminal positions of the heteroalkylene linker (i.e., position(s) directly bonded to portion(s) of the molecule other than the heteroalkylene linker).
  • Examples include, but are not limited to, -CH 2 -0-, -CH 2 -CH 2 -0-, -CH 2 -NH-, -CH 2 -CH 2 -NH-, -CH 2 -N(CH 3 )-, -CH 2 -CH 2 -N(CH 3 )-, -CH 2 -S-, -CH 2 - CH 2 -S-, -CH 2 -CH 2 -S(0)-, -CH 2 -CH 2 -S(0) 2 -, -CH 2 -S(0)-, -CH 2 -S(0)-, -CH 2 -S(0) 2 -, -CH 2 -CH 2 -CH 2 -S(0)-, -CH 2 -CH 2 -CH 2 -S(0)-, -CH 2 -CH 2 -CH 2 -S(0)-, -CH 2 -CH 2 -CH 2 -S(0)-, -CH 2 -CH 2 -CH 2 -S
  • Examples include, but are not limited to, -0-CH 2 -, -0-CH 2 -CH 2 -, -NH-CH 2 -, -NH-CH 2 - CH 2 -, -N(CH 3 )-CH 2 -, -N(CH 3 )-CH 2 -CH 2 -, -S-CH 2 -, -S-CH 2 -CH 2 -, -S(0)-CH 2 -CH 2 -, -S(0) 2 -CH 2 -CH 2 -, -S(0) 2 -CH 2 -, -S(0)-CH 2 -, -S(0) 2 -CH 2 -, -S(0)-CH 2 -CH 2 -, -S(0)-CH 2 -CH 2 -, -S(0)-CH 2 -CH 2 -CH 2 -, -S(0) 2 -CH 2 -CH 2 -, -S(0) 2 -CH 2 -CH 2 -, -S(0) 2 -
  • heteroatoms may be consecutive, such as, by way of example, -CH 2 -NH-0- and -0-Si(CH 3 ) 2 -.
  • examples include, but are not limited to, -P(0)(CH 3 )-CH 2 -, -P(0)(CH 3 )-CH 2 -CH 2 -, -P(0)(CH 3 )-CH 2 -CH 2 -,-CH 2 -P(0)(CH 3 )-, -CH 2 -CH 2 -P(0)(CH 3 )-, and -CH 2 -CH 2 -CH 2 -P(0)(CH 3 )-.
  • heteroatoms may be consecutive, such as, by way of example, -CH 2 -NH-0- and -0-Si(CH 3 ) 2 -.
  • A“heteroalkylene linker” may have from 2 to 4 main chain atoms unless specified otherwise.
  • 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, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.
  • “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, trifluoroacetates, 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, Y, ⁇ -dibcnzylcthylcncdiaminc.
  • 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 deoxy ribonucleotides 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 eukaryotic cell.
  • 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.
  • 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. 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.
  • therapeutic benefit is meant any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms under treatment.
  • 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.
  • 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.
  • 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 ran 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 (also used interchangeably herein as K-Ras, K-ras, 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 also used interchangeably herein as K-Ras, K-ras, 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 lurther 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).
  • [00144] indicates the location of attachment (e.g., location of a bond to another atom) of the depicted chemical formula or atom to a substituent, a further component of a molecule, or an atom.
  • a substituent e.g., location of a bond to another atom
  • a further component of a molecule e.g., a further component of a molecule
  • an atom e.g., a further component of a molecule, or an atom.
  • a selected residue in a protein corresponds to Cysl2 of a human Ras (e.g., human K-Ras) protein when the selected residue occupies the same essential spatial or other structural position as Cysl2 in the human Ras (e.g., human K-Ras) protein.
  • a selected protein is aligned for maximum homology with the human Ras (e.g., human K-Ras) protein
  • the position in the aligned selected protein aligning with Cysl2 is said to correspond to Cysl2.
  • a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the human K-Ras protein and the overall structures compared.
  • an amino acid that occupies the same essential position as Cysl2 in the structural model is said to correspond to the Cysl2 residue.
  • a selected residue in a protein corresponds to Cysl3 of a human Ras (e.g., human K-Rasa) protein when the selected residue occupies the same essential spatial or other structural position as Cysl3 in a human Ras (e.g., human K-Ras) protein, similar to the example of Cysl2 above.
  • a human Ras e.g., human K-Rasa
  • a C3-iocycloalkyl is a 3 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 4 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 5 membered cycloalkyl. In embodiments, a C3- l ocycloalkyl is a 6 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 7 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 8 membered cycloalkyl.
  • a C3-iocycloalkyl is a 9 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 10 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 3-10 membered cycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 3 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 4 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 5 membered heterocycloalkyl.
  • a C2-9heterocycloalkyl is a 6 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 7 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 8 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 9 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 10 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a ll membered heterocycloalkyl.
  • a C2-9heterocycloalkyl is a 12 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 3-12 membered heterocycloalkyl. In embodiments, a C2- li heterocycloalkyl is a 3 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 4 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 5 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 6 membered heterocycloalkyl.
  • a C2-iiheterocycloalkyl is a 7 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 8 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 9 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 10 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 11 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 12 membered heterocycloalkyl.
  • a C2-iiheterocycloalkyl is a 3-12 membered heterocycloalkyl.
  • a Ci-nheterocycloalkyl is a 3 membered heterocycloalkyl.
  • a Ci-nheterocycloalkyl is a 4 membered heterocycloalkyl.
  • a Ci-nheterocycloalkyl is a 5 membered heterocycloalkyl.
  • a Ci-nheterocycloalkyl is a 6 membered heterocycloalkyl.
  • a Ci-nheterocycloalkyl is a 7 membered heterocycloalkyl.
  • a Ci-nheterocycloalkyl is a 8 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 9 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 10 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 11 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 12 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 3-12 membered heterocycloalkyl.
  • a C6-i2aryl is a 6 membered aryl. In embodiments, a C6-i2aryl is a 7 membered aryl. In embodiments, a C6-i2aryl is a 8 membered aryl. In embodiments, a C6-i2aryl is a 9 membered aryl. In embodiments, a C6-i2aryl is a 10 membered aryl. In embodiments, a C6-i2aryl is a 11 membered aryl. In embodiments, a C6-i2aryl is a 12 membered aryl.
  • a C6-i2aryl is a 6-12 membered aryl.
  • a Ci-nheteroaryl is a 5 membered heterocycloalkyl.
  • a Ci-nheteroaryl is a 6 membered heterocycloalkyl.
  • a Ci- nheteroaryl is a 7 membered heterocycloalkyl.
  • a Ci-nheteroaryl is a 8 membered heterocycloalkyl.
  • a Ci-nheteroaryl is a 9 membered heterocycloalkyl.
  • a Ci-nheteroaryl is a 10 membered heterocycloalkyl. In embodiments, a Ci-nheteroaryl is a 11 membered heterocycloalkyl. In embodiments, a Ci-nheteroaryl is a 12 membered heterocycloalkyl. In embodiments, a Ci-nheteroaryl is a 5-12 membered heterocycloalkyl. In embodiments, a C3-6cycloalkyl is a 3 membered cycloalkyl. In embodiments, a C3- 6 cycloalkyl is a 4 membered cycloalkyl.
  • a C3-6cycloalkyl is a 5 membered cycloalkyl. In embodiments, a C3-6cycloalkyl is a 6 membered cycloalkyl. In embodiments, a C 6 -ioaryl is a 6 membered aryl. In embodiments, a C 6 -ioaryl is a 7 membered aryl. In embodiments, a C 6 -ioaryl is a 8 membered aryl. In embodiments, a C 6 -ioaryl is a 9 membered aryl. In embodiments, a C 6 -ioaryl is a 10 membered aryl.
  • a Ci- gheteroaryl is a 5 membered heterocycloalkyl. In embodiments, a Ci-gheteroaryl is a 6 membered heterocycloalkyl. In embodiments, a Ci-gheteroaryl is a 7 membered heterocycloalkyl. In embodiments, a Ci-gheteroaryl is a 8 membered heterocycloalkyl. In embodiments, a Ci-gheteroaryl is a 9 membered heterocycloalkyl. In embodiments, a Ci-gheteroaryl is a 10 membered heterocycloalkyl.
  • a Ci-gheteroaryl is a 11 membered heterocycloalkyl.
  • a Cj-dictcroaryl is a 12 membered heterocycloalkyl.
  • a Ci- yhctcroan l is a 5-12 membered heterocycloalkyl.
  • W is C(O), S(O), or S(0) 2 ;
  • V is C(R 17 ) and J is C(R 16 ), or V is C(R 17 ) and J is N, or J is C(R 17 ) and V is C(R 16 ), or J is C(R 17 ) and V is N;
  • R 10 is -L 7 -R 7 ;
  • L 7 is a bond, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -
  • R 7 is a 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl, wherein the 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl are optionally substituted with one or more R 1 , one or more R 4 , or one or more R 6 ; wherein two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i 2 cycloalkyl, Ci-nheterocycloalkyl, C 6 -i 2 aryl, or Ci-nheteroaryl, wherein the C3-i 2 cycloalkyl, Ci-nheterocycloalkyl, C 6 -i 2 aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R 20a ; each R 1 is independently selected from hydrogen, Ci- 6 alkyl, C 2-6
  • R 6 is -L 2 -R 5 ; each L 2 is independently selected from a bond, Ci-Cealkyl, -0-, -N(R 14 )-, -C(0)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, - S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, -OCON(R 14 )-, - N(R 14 )C(0)0-, and -N(R 14 )C(0)N(R 14 )-; each R 5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
  • R 8 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C 2 - dictcrocycloalkyl. C 6 -ioaryl, Ci-dictcroaiyl.
  • R 17 is -LkR 19 ;
  • L 1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R 14 )-, -C(0)-, -N(R 14 )C(0)-, - C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, - OCON(R 14 )-, -N(R 14 )C(0)0-, N(R le ), C(0)N(R lc ), S(0) 2 N(R lc ), S(0)N(R lc ), C(R lf )(R lg )0, C(R lf )(R lg )N(R lc ), and C(R
  • R le , R lf , and R lg are independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), - C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , - S(0)R 15 , -0C(0)R 15 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )
  • R lc is selected from hydrogen, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,- ioaryl, and Ci-gheteroaryl, wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 201
  • R 19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3- ncycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R 11 ; each R 11 is independently selected from halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , - 0C(0)N(R 12 )(R
  • R 16 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C 2 - gheterocycloalkyl, C 6 -ioaryl, Ci- ⁇ ) hctcroan l.
  • R 12a is selected from Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, G- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6 -ioaryl, -CEC-G-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl, wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, G- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6 -ioaryl, -CEC-G-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroary
  • R 12b is selected from hydrogen, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, G- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CEh-Ci-gheteroaryl, and Ci- gheteroaryl, wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C 2 - gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CEh-Ci-ghe
  • X is C(R 3 ) or N
  • R 3 is selected from hydrogen, halogen, -CN, Ci ⁇ alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C 2 - gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S
  • Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 20f ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 201 are each independently selected from halogen, -CN, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH2-Ci-9he
  • W is C(O), S(O), or S(0) 2 ;
  • V is C(R 17 ) and J is C(R 16 ), or V is C(R 17 ) and J is N, or J is C(R 17 ) and V is C(R 16 ), or J is C(R 17 ) and V is N;
  • R 10 is -L 7 -R 7 ;
  • L 7 is a bond, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -
  • R 7 is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 ; wherein two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nhetero
  • R 6 is -L 2 -R 5 ; each L 2 is independently selected from a bond, G-Galkyl, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, - S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, -OCON(R 14 )-, - N(R 14 )C(0)0-, and -N(R 14 )C(0)N(R 14 )-; each R 5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
  • R 8 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(H)(R 12 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0) 2 R
  • R 17 is -G-R 19 ;
  • L 1 is selected from a bond, G-Galkyl, C2-C6alkenyl, G-Galkynyl, -0-, -N(R 14 )-, -C(0)-, -N(R 14 )C(0)-, - C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, - OCON(R 14 )-, -N(R 14 )C(0)0-, N(R le ), C(0)N(R lc ), S(0) 2 N(R lc ), S(0)N(R lc ), C(R lf )(R lg )0, C(R lf )(R lg )N(R lc ), and C(R l
  • R le , R lf , and R lg are independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-dictcroarvl.
  • gheterocycloalkyl, C 6 -ioaryl, and Ci-dictcroarvl are optionally substituted with one, two, or three R 201 ; or R lf and R lg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R 201 ;
  • R lc is selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 201
  • R 19 is selected from a C3-i 2 cycloalkyl, C 2 -nheterocycloalkyl, C 6 -i 2 aryl, and C 2 -i 2 heteroaryl, wherein the C3- i 2 cycloalkyl.
  • C 2 -nheterocycloalkyl, C 6 -i 2 aryl, and C 2 -i 2 heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R 11 ; each R 11 is independently selected from halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3- 6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , - 0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)
  • R 16 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2. gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0)
  • R 12a is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, -C(R 12c ) 2 -C3-iocycloalkyl, C 2.
  • R 12b is selected from hydrogen, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocyeloalkyl, C 2 - gheterocycloalkyl, -C(R 12c ) 2 -C 2-9 heterocyeloalkyl, C6-ioaryl, -C(R 12c ) 2 -C 6 -ioaryl, -C(R 12c ) 2 -Ci- 9 heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocyeloalkyl, C 2-9 heterocycloalkyl, -C(R 12c ) 2
  • R 12c is independently selected from hydrogen and R 20k ;
  • X is C(R 3 ) or N
  • R 3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 ,
  • each R 12 is independently selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 -C 1 - gheteroaryl, and Ci-gheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -io
  • Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 20f ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 201 , and R 20k are each independently selected from halogen, oxo, - CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2 - gheterocycloalkyl, C 6 -ioaryl, -CH 2
  • X is C(R 3 ). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is N.
  • V is C(R 16 ) and J is C(R 17 ). In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is N and J is C(R 17 ). In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, J is N and V is C(R 17 ). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, J is C(R 16 ) and V is C(R 17 ). In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is C(O). In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(O). In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(0) 2 .
  • the compound has the structure: Formula (IA6), 12).
  • the compound has the structure: ), , 2).
  • L 7 is a bond. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L 7 is -NH-.
  • L 7 is a bond. In embodiments, L 7 is -0-. In embodiments, L 7 is -N(R 14 )-. In embodiments, L 7 is -C(O)-. In embodiments, L 7 is -N(R 14 )C(0)-. In embodiments, L 7 is -C(0)N(R 14 )-. In embodiments, L 7 is -S-. In embodiments, L 7 is -S(0) 2 -. In embodiments, L 7 is -S(O)-. In embodiments, L 7 is - S(0) 2 N(R 14 )-. In embodiments, L 7 is -S(0)N(R 14 )-.
  • L 7 is -N(R 14 )S(0)-. In embodiments, L 7 is - N(R 14 )S(0) 2 -. In embodiments, L 7 is Ci-Cealkyl. In embodiments, L 7 is C2-C6alkenyl. In embodiments, L 7 is C2- Cealkynyl. In embodiments, L 7 is 2 to 4 membered heteroalkylene linker. In embodiments, L 7 is Ci-Cealkyl optionally substituted with one, two, or three R 20a . In embodiments, L 7 is C2-C6alkenyl optionally substituted with one, two, or three R 20a .
  • L 7 is C2-Cealkynyl optionally substituted with one, two, or three R 20a . In embodiments, L 7 is 2 to 4 membered heteroalkylene linker optionally substituted with one, two, or three R 20a . In embodiments, L 7 is -N(H)-. In embodiments, L 7 is -N(H)C(0)-. In embodiments, L 7 is -C(0)N(H)-. In embodiments, L 7 is -S(0) 2 N(H)-. In embodiments, L 7 is -S(0)N(H)-. In embodiments, L 7 is -N(H)S(0)-. In embodiments, L 7 is -N(H)S(0) 2 -.
  • R 7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the a 4- 12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 ; wherein two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent
  • R 7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R 1 , one or more R 4 , or one or more R 6 ; and wherein two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci- li heterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R 20a .
  • R 7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 ; and wherein two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, G,.
  • naryl, or Ci-nheteroaryl wherein the C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or G-iiheteroaryl are optionally substituted with one, two, or three R 20a .
  • R 7 is a 3-12 membered cycloalkyl. In embodiments, R 7 is a 5-12 membered cycloalkyl.
  • R 7 is 3-12 membered heterocycloalkyl. In embodiments, R 7 is 6-12 membered aryl. In embodiments, R 7 is 7-12 membered aryl. In embodiments, R 7 is 5-12 membered heteroaryl.
  • R 7 is a 3-12 membered cycloalkyl comprising one or more ring nitrogen atoms. In embodiments, R 7 is a 5-12 membered cycloalkyl comprising one or more ring nitrogen atoms. In embodiments, R 7 is 3-12 membered heterocycloalkyl comprising one or more ring nitrogen atoms. In embodiments, R 7 is 6-12 membered aryl comprising one or more ring nitrogen atoms. In embodiments, R 7 is 7-12 membered aryl comprising one or more ring nitrogen atoms. In embodiments, R 7 is 5-12 membered heteroaryl comprising one or more ring nitrogen atoms.
  • R 7 is a 3-12 membered cycloalkyl comprising one or more ring oxygen atoms. In embodiments, R 7 is a 5-12 membered cycloalkyl comprising one or more ring oxygen atoms. In embodiments, R 7 is 3-12 membered heterocycloalkyl comprising one or more ring oxygen atoms. In embodiments, R 7 is 6-12 membered aryl comprising one or more ring oxygen atoms. In embodiments, R 7 is 7-12 membered aryl comprising one or more ring oxygen atoms. In embodiments, R 7 is 5-12 membered heteroaryl comprising one or more ring oxygen atoms.
  • R 7 is a 3-12 membered cycloalkyl optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is a 5-12 membered cycloalkyl optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is 3-12 membered heterocycloalkyl optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is 6-12 membered aryl optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is 7-12 membered aryl optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is 5-12 membered heteroaryl optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is a 3-12 membered cycloalkyl comprising one or more ring nitrogen atoms optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is a 5-12 membered cycloalkyl comprising one or more ring nitrogen atoms optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is 3-12 membered heterocycloalkyl comprising one or more ring nitrogen atoms optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is 6-12 membered aryl comprising one or more ring nitrogen atoms optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is 7-12 membered aryl comprising one or more ring nitrogen atoms optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is 5-12 membered heteroaryl comprising one or more ring nitrogen atoms optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is a 3-12 membered cycloalkyl comprising one or more ring oxygen atoms optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is a 5-12 membered cycloalkyl comprising one or more ring oxygen atoms optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is 3-12 membered heterocycloalkyl comprising one or more ring oxygen atoms optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is 6-12 membered aryl comprising one or more ring oxygen atoms optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is 7-12 membered aryl comprising one or more ring oxygen atoms optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is 5-12 membered heteroaryl comprising one or more ring oxygen atoms optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 .
  • R 7 is a C3cycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cicycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cecycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a C7cycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 . In embodiments, R 7 is a Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 . In embodiments, R 7 is a Ciocycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 . In embodiments, R 7 is a monocyclic Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 . In embodiments, R 7 is a monocyclic Cicycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Cecycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic C7cycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Ciocycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cecycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic C7cycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cecycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Ciocycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cecycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic C7cycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Ciocycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cecycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic C7cycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Ciocycloalkyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cicycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cecycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a C7cycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a Ciocycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Cicycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Cecycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic C7cycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a monocyclic Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a monocyclic Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a monocyclic Ciocycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cecycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic C7cycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Ciocycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cecycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic C7cycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Ciocycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cecycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic C7cycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Ciocycloalkyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cecycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a C7cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 . In embodiments, R 7 is a Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 . In embodiments, R 7 is a Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 . In embodiments, R 7 is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cecycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a C7cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Cycvcloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 3 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 4 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 3 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 4 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 3 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 4 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 3 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 4 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 3 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 4 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 3 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 4 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 3 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 4 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 3 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 4 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cearyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a C-aiyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Csaryl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cearyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cioaryl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Cearyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic C-aiy 1 optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Csaryl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Cearyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Cioaryl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Csaryl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cearyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic C-aiyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Csaryl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Co aryl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cioaryl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Csaryl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cearyl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic C-arvl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Csaryl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Coaryl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cioaryl optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a C-arvl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Csaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Csaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cioaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cearyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic C-arvl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic arvl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cioaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cearyl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic C-arvl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic arvl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cioaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cearyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a C-arvl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Csaryl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Co aryl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cioaryl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Cearyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic C-aiy 1 optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Csaryl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Gaiyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic Cioaryl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Csaryl optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a fused bicyclic Csaryl optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a fused bicyclic C-arv 1 optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a fused bicyclic Csaryl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Gaiyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cioaryl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Csaryl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cearyl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Caryl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Csaryl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Caryl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cioaryl optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Caryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Csaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Csaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cioaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cearyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Caryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Caryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cioaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cearyl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Caryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Caryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cioaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a C-arvl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Csaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cyarvl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a Cioaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Giaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic C-arvl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Coaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cioaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cearyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic C-arvl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cearyl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cioaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a C-arvl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Csaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Csaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a Cioaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cearyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic C-arvl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cearyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic Cioaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cearyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic C-aiyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cyaiyl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic Cioaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 10 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 11 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 12 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 11 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 12 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 11 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 12 membered aryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 10 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 11 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 12 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 11 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 12 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 11 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 12 membered aryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 10 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 11 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 12 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 11 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 12 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 11 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 12 membered aryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 10 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 11 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 12 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 11 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 12 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 11 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 12 membered aryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 5 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 5 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 11 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 12 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 11 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 12 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 11 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 12 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 5 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 5 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 5 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 5 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 6 and optionally substituted with one or more R 4 .
  • R 7 is a 5 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . [00243] In embodiments, R 7 is a monocyclic 5 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 . In embodiments, R 7 is a monocyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a monocyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a fused bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a bridged bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 7 is a spirocyclic bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R 1 and optionally substituted with one or more R 4 .
  • R 4 is independently halogen. In embodiments, R 4 is independently R 4 is independently oxo. In embodiments, R 4 is independently -CN. In embodiments, R 4 is independently Ci- 6 alkyl. In embodiments,
  • R 4 is independently C2-6alkenyl. In embodiments, R 4 is independently C2-6alkynyl. In embodiments, R 4 is independently Ci- 6 haloalkyl. In embodiments, R 4 is independently C3-i2cycloalkyl. In embodiments, R 4 is independently -CH2-C3-i2cycloalkyl. In embodiments, R 4 is independently Ci-nheterocycloalkyl. In embodiments, R 4 is independently -CtC-Ci-nheterocycloalkyl. In embodiments, R 4 is independently C6-i2aryl. In embodiments,
  • R 4 is independently -CH 2 -C6-i2aryl. In embodiments, R 4 is independently -CtC-Ci-nheteroaryl. In embodiments, R 4 is independently Ci-nheteroaryl. In embodiments, R 4 is independently -OR 12 . In embodiments, R 4 is independently -SR 12 . In embodiments, R 4 is independently -N(R 12 )(R 13 ). In embodiments, R 4 is independently -C(0)0R 12 . In embodiments, R 4 is independently -0C(0)N(R 12 )(R 13 ). In embodiments, R 4 is independently - N(R 14 )C(0)N(R 12 )(R 13 ).
  • R 4 is independently -N(R 14 )C(0)0R 15 . In embodiments, R 4 is independently -N(R 14 )S(0) 2 R 15 . In embodiments, R 4 is independently -C(0)R 15 . In embodiments, R 4 is independently -S(0)R 15 . In embodiments, R 4 is independently -0C(0)R 15 . In embodiments, R 4 is independently - C(0)N(R 12 )(R 13 ). In embodiments, R 4 is independently -C(0)C(0)N(R 12 )(R 13 ). In embodiments, R 4 is independently -N(R 14 )C(0)R 15 . In embodiments, R 4 is independently -S(0) 2 R 15 .
  • R 4 is independently C2-6alkenyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently C2-6alkynyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Ci- 6 haloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently C3-i2cycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently -CH2-C3- ncycloalkyl optionally substituted with one, two, or three R 20a .
  • R 4 is independently Ci- li heterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 4 is independently -CH2-C1- li heterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 4 is independently C6-i2aryl optionally substituted with one, two, or three R 20a .
  • R 4 is independently -CH 2 -C6-i2aryl optionally substituted with one, two, or three R 20a .
  • R 4 is independently -CtC-Ci-nheteroaryl optionally substituted with one, two, or three R 20a .
  • R 4 is independently Ci-nheteroaryl optionally substituted with one, two, or three R 20a .
  • L 2 is a bond. In embodiments, L 2 is Ci-Cealkyl. In embodiments, L 2 is -0-. In embodiments, L 2 is -N(R 14 )-. In embodiments, L 2 is -C(O)-. In embodiments, L 2 is -N(R 14 )C(0)-. In embodiments, L 2 is -C(0)N(R 14 )-. In embodiments, L 2 is -S-. In embodiments, L 2 is -S(0) 2 -. In embodiments, L 2 is -S(O)-. In embodiments, L 2 is -S(0) 2 N(R 14 )-.
  • L 2 is -S(0)N(R 14 )-. In embodiments, L 2 is -N(R 14 )S(0)-. In embodiments, L 2 is -N(R 14 )S(0) 2 -. In embodiments, L 2 is -OCON(R 14 )-. In embodiments, L 2 is -N(R 14 )C(0)0-. In embodiments, L 2 is -N(R 14 )C(0)N(R 14 )-. In embodiments, L 2 is -N(H)-. In embodiments, L 2 is -N(H)C(0)-. In embodiments, L 2 is -C(0)N(H)-. In embodiments, L 2 is -S(0) 2 N(H)-.
  • L 2 is -S(0)N(H)-. In embodiments, L 2 is -N(H)S(0)-. In embodiments, L 2 is -N(H)S(0) 2 -. In embodiments, L 2 is -OCON(H)-. In embodiments, L 2 is -N(H)C(0)0-. In embodiments, L 2 is -N(H)C(0)N(R 14 )-.
  • R 4 is independently Cialkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently C2alkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cialkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cialkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cialkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cealkyl optionally substituted with one, two, or three R 20a .
  • R 4 is independently C2alkenyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cialkcnyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cialkcnyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Csalkcnyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cealkenyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently C2alkynyl optionally substituted with one, two, or three R 20a .
  • R 4 is independently Cialkynyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cialkynyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Csalkynvi optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cealkynyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cihaloalkyl. In embodiments, R 4 is independently Cihaloalkyl. In embodiments, R 4 is independently Cihaloalkyl. In embodiments, R 4 is independently Cihaloalkyl. In embodiments, R 4 is independently Cihaloalkyl. In embodiments, R 4 is independently Cihaloalkyl. In embodiments, R 4 is independently Cehaloalkyl. In embodiments, R 4 is independently Cehaloalkyl.
  • R 4 is independently Ci cycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cicycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cscycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cecycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently C7cycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cscycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cscycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cscycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Ciocyclo
  • R 4 is independently Cihetcrocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cihetcrocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cihetcrocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cihetcrocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 4 is independently Ciheterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Gsaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently C-arvl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Csaryl optionally substituted with one, two, or three R 20a .
  • R 4 is independently Csaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cioaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cnaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cnaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cihctcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cihctcroarvl optionally substituted with one, two, or three R 20a .
  • R 4 is independently Cihctcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cihctcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Ceheteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cihctcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Csheteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cihctcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cioheteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently Cioheteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is
  • R 4 is independently 3 membered cycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 4 membered cycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 5 membered cycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 6 membered cycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 7 membered cycloalkyl optionally substituted with one, two, or three R 20a .
  • R 4 is independently 8 membered cycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 9 membered cycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 10 membered cycloalkyl optionally substituted with one, two, or three R 20a .
  • R 4 is independently 3 membered heterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 4 membered heterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 5 membered heterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 6 membered heterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 7 membered heterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 4 is independently 8 membered heterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 9 membered heterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 10 membered heterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 6 membered aryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 7 membered aryl optionally substituted with one, two, or three R 20a .
  • R 4 is independently 8 membered aryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 9 membered aryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 10 membered aryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 11 membered aryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 12 membered aryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 5 membered heteroaryl optionally substituted with one, two, or three R 20a .
  • R 4 is independently 6 membered heteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 7 membered heteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 8 membered heteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 9 membered heteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 10 membered heteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 11 membered heteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 4 is independently 12 membered heteroaryl optionally substituted with one, two, or three R 20a .
  • R 4 is independently -OH. In embodiments, R 4 is independently -SH. In embodiments, R 4 is independently -NH 2 . In embodiments, R 4 is independently -C(0)OH. In embodiments, R 4 is independently - OC(0)NH 2 . In embodiments, R 4 is independently -N(H)C(0)NH 2 . In embodiments, R 4 is independently - N(H)C(0)OH. In embodiments, R 4 is independently -N(H)S(0) 2 CH 3 . In embodiments, R 4 is independently - C(0)H. In embodiments, R 4 is independently -S(0)CH 3 . In embodiments, R 4 is independently -0C(0)CH 3 .
  • R 4 is independently -OCH 3 . In embodiments, R 4 is independently -SCH 3 . In embodiments, R 4 is independently - N(CH 3 )(H). In embodiments, R 4 is independently -C(0)0CH 3 . In embodiments, R 4 is independently - 0C(0)N(CH 3 )(H). In embodiments, R 4 is independently -N(H)C(0)N(CH 3 )(H). In embodiments, R 4 is independently -N(H)C(0)0CH 3 . In embodiments, R 4 is independently -N(H)S(0) 2 CH 3 . In embodiments, R 4 is independently -C(0)CH 3 . In embodiments, R 4 is independently -S(0)CH 3 .
  • R 4 is independently -CH 2 N(H)C(0)CH 3 . In embodiments, R 4 is independently -CH 2 S(0) 2 CH 3 . In embodiments, R 4 is independently and -CH 2 S(0) 2 N(CH 3 )(H). In embodiments, R 4 is independently -0C(0)N(CH 3 ) 2 . In embodiments, R 4 is independently -N(H)C(0)N(CH 3 ) 2 . In embodiments, R 4 is independently -C(0)(CH 3 ). In embodiments, R 4 is independently -C(0)N(CH 3 ) 2 . In embodiments, R 4 is independently -C(0)C(0)N(CH 3 ) 2 . In embodiments, R 4 is independently -C(0)C(0)N(CH 3 ) 2 .
  • R 4 is capable of forming a covalent bond with the 12 th amino acid of a G12D KRas mutant. In embodiments, R 4 is capable of forming a covalent bond with the 12 th amino acid of a G12C KRas mutant. In embodiments, R 4 is capable of forming a covalent bond with the 12 th amino acid of a G12S KRas mutant. In embodiments, R 4 is capable of forming a covalent bond with the 13 th amino acid of a G13D KRas mutant. In embodiments, R 4 is capable of forming a covalent bond with the 13 th amino acid of a G13C KRas mutant. In embodiments, R 4 is capable of forming a covalent bond with the 13 th amino acid of a G13S KRas mutant.
  • R 4 is selected from the group consisting of
  • each R b is independently hydrogen, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-7carboalkyl, C2-7carboxyalkyl, phenyl, or phenyl optionally substituted with one or more halogen, Ci- 6alkoxy, trifluoromethyl, amino, Ci-3alkylamino, C2-6dialkylamino, nitro
  • R 4 is independently selected from the group consisting of hydrogen, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl, or two R b are optionally join to form heterocycle having 3-12 ring atoms or C3-C6 cycloalkyl. In embodiments, R 4 is independently selected from the group consisting of
  • R 4 is independently -C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , or -C(0)R 15 . In embodiments, R 4 is independently -C(0)N(R 12 )(R 13 ). In embodiments, R 4 is independently -N(R 14 )C(0)R 15 . In embodiments, R 4 is independently -C(0)R 15 .
  • R 15 is C2-6alkenyl optionally substituted with one, two, or three R 20f , - C(0)R 15 wherein R 15 is C2-6alkynyl optionally substituted with one, two, or three R 20f , -C(0)R 15 wherein R 15 is C3- 6cycloalkyl optionally substituted with one, two, or three R 20f , -C(0)R 15 wherein R 15 is C2-9heterocycloalkyl optionally substituted with one, two, or three R 20f , -C(0)R 15 wherein R 15 is C 6 -ioaryl optionally substituted with one, two, or three R 20f , and -C(0)R 15 wherein R 15 is Ci-dictcroaryl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -C(0)NH(R 12 ) and R 12 is independently Ci-dictcroaryl. wherein Ci- ihctcroaiyl is optionally substituted with one, two, or three R 20d .
  • R 4 is independently - C(0)NH(R 12 ) and R 12 is independently Ci-shctcroan l. wherein Ci-shctcroaiy l is optionally substituted with one, two, or three R 20d .
  • R 4 is independently -C(0)NH(R 12 ) and R 12 is independently Ci-ihctcroaryl.
  • R 12 is independently Cialkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently C2alkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cialkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cialkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cialkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cialkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cialkyl optionally substituted with one, two, or three R 20d .
  • R 12 is independently C2alkenyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cialkcnyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cialkcnyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cialkcnyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cealkenyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently C2alkynyl optionally substituted with one, two, or three R 20d .
  • R 12 is independently Cialkynyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cialkynyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Csalkynyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cealkynyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cihaloalkyl. In embodiments, R 12 is independently Cihaloalkyl.
  • R 12 is independently Cihaloalkyl. In embodiments, R 12 is independently Cihaloalkyl. In embodiments, R 12 is independently Cshaloalkyl. In embodiments, R 12 is independently Cehaloalkyl.
  • R 12 is independently Cscycloalkyl optionally substituted with one, two, or three R 20d .
  • R 12 is independently Cicycloalkyl optionally substituted with one, two, or three R 20d .
  • R 12 is independently Cscycloalkyl optionally substituted with one, two, or three R 20d .
  • R 12 is independently Cecycloalkyl optionally substituted with one, two, or three R 20d .
  • R 12 is independently C7cycloalkyl optionally substituted with one, two, or three R 20d .
  • R 12 is independently Cscycloalkyl optionally substituted with one, two, or three R 20d .
  • R 12 is independently Cscycloalkyl optionally substituted with one, two, or three R 20d .
  • R 12 is independently Ciocycloalkyl optionally substituted with one, two, or three R 20d .
  • R 12 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cdictcrocycloalkyl optionally substituted with one, two, or three R 20d .
  • R 12 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cdictcrocycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently C-hetcrocycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20d .
  • R 12 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cearyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently C-aryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Csaryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Csaryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cioaryl optionally substituted with one, two, or three R 20d .
  • R 12 is independently Cnaryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cnaryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cihctcroaiyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cihctcroaiyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cihctcroaiy l optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently C die tcro aryl optionally substituted with one, two, or three R 20d .
  • R 12 is independently Ceheteroaryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently C 7 he tcro aryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Csheteroaryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cihctcroaiy l optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cioheteroaryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently Cnheteroaryl optionally substituted with one, two, or three R 20d .
  • R 12 is independently 3 membered cycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 4 membered cycloalkyl optionally substituted with one, two, or three
  • R 20d is independently 5 membered cycloalkyl optionally substituted with one, two, or three
  • R 12 is independently 6 membered cycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 7 membered cycloalkyl optionally substituted with one, two, or three
  • R 20d is independently 8 membered cycloalkyl optionally substituted with one, two, or three
  • R 20d is independently 9 membered cycloalkyl optionally substituted with one, two, or three
  • R 20d is independently 10 membered cycloalkyl optionally substituted with one, two, or three
  • R 12 is independently 3 membered heterocycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 4 membered heterocycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 5 membered heterocycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 6 membered heterocycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 7 membered heterocycloalkyl optionally substituted with one, two, or three R 20d .
  • R 12 is independently 8 membered heterocycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 9 membered heterocycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 10 membered heterocycloalkyl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 6 membered aryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 7 membered aryl optionally substituted with one, two, or three R 20d .
  • R 12 is independently 8 membered aryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 9 membered aryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 10 membered aryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 11 membered aryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 12 membered aryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 5 membered heteroaryl optionally substituted with one, two, or three R 20d .
  • R 12 is independently 6 membered heteroaryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 7 membered heteroaryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 8 membered heteroaryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 9 membered heteroaryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 10 membered heteroaryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 11 membered heteroaryl optionally substituted with one, two, or three R 20d . In embodiments, R 12 is independently 12 membered heteroaryl optionally substituted with one, two, or three R 20d .
  • R 15 is independently Cialkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently C2alkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cialkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cialkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Csalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cealkyl optionally substituted with one, two, or three R 20f .
  • R 15 is independently C2alkenyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Ci alkenyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently C4alkenyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Csalkcnyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cealkenyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently C2alkynyl optionally substituted with one, two, or three R 20f .
  • R 15 is independently Cialkynyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently C4alkynyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Csalkynyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cealkynyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cihaloalkyl. In embodiments, R 15 is independently Cihaloalkyl.
  • R 15 is independently Cihaloalkyl. In embodiments, R 15 is independently Cihaloalkyl. In embodiments, R 15 is independently Cshaloalkyl. In embodiments, R 15 is independently Cehaloalkyl.
  • R 15 is independently Cscycloalkyl optionally substituted with one, two, or three R 20f .
  • R 15 is independently Cicycloalkyl optionally substituted with one, two, or three R 20f .
  • R 15 is independently Cscycloalkyl optionally substituted with one, two, or three R 20f .
  • R 15 is independently Cecycloalkyl optionally substituted with one, two, or three R 20f .
  • R 15 is independently C7cycloalkyl optionally substituted with one, two, or three R 20f .
  • R 15 is independently Cscycloalkyl optionally substituted with one, two, or three R 20f .
  • R 15 is independently Cscycloalkyl optionally substituted with one, two, or three R 20f .
  • R 15 is independently Ciocycloalkyl optionally substituted with one, two, or three R 20f .
  • R 15 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R 20f .
  • R 15 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cdictcrocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently C-hetcrocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20f .
  • R 15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cearyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently C-aiyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Csaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Csaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cioaryl optionally substituted with one, two, or three R 20f .
  • R 15 is independently Cnaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cearyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cihctcroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cihctcroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cihctcroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cshctcroarvl optionally substituted with one, two, or three R 20f .
  • R 15 is independently Ceheteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently C-hetcroarvl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Csheteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cdictcroarvl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cioheteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Cnheteroaryl optionally substituted with one, two, or three R 20f .
  • R 15 is independently 3 membered cycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 4 membered cycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 5 membered cycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 6 membered cycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 7 membered cycloalkyl optionally substituted with one, two, or three R 20f .
  • R 20f is independently 8 membered cycloalkyl optionally substituted with one, two, or three
  • R 20f is independently 9 membered cycloalkyl optionally substituted with one, two, or three
  • R 20f is independently 10 membered cycloalkyl optionally substituted with one, two, or three
  • R 15 is independently 3 membered heterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 4 membered heterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 5 membered heterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 6 membered heterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 7 membered heterocycloalkyl optionally substituted with one, two, or three R 20f .
  • R 15 is independently 8 membered heterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 9 membered heterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 10 membered heterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 6 membered aryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 7 membered aryl optionally substituted with one, two, or three R 20f .
  • R 15 is independently 8 membered aryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 9 membered aryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 10 membered aryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 11 membered aryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 12 membered aryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 5 membered heteroaryl optionally substituted with one, two, or three R 20f .
  • R 15 is independently 6 membered heteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 7 membered heteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 8 membered heteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 9 membered heteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 10 membered heteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 11 membered heteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently 12 membered heteroaryl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -C(0)R 15 and R 15 is independently selected from C2-6alkenyl, C2- 6 alkynyl, C2-s>heterocycloalkyl, and C’ l -yhctcroarvl. wherein C2-6alkenyl, C2-6alkynyl, C2-s>heterocycloalkyl, and Ci- yhctcroarvl are optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently C2alkenyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -C(0)R 15 and R 15 is independently Cialkcnyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Cialkcnyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Csalkcnyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Cealkenyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -C(0)R 15 and R 15 is independently C2alkynyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Cialkynyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Cialkynyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently - C(0)R 15 and R 15 is independently Csalkynyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -C(0)R 15 and R 15 is independently Cealkynyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -C(0)R 15 and R 15 is independently Cohctcrocycloalkyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -C(0)R 15 and R 15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently - C(0)R 15 and R 15 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -C(0)R 15 and R 15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently C-hctcrocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Csheterocycloalkyl optionally substituted
  • R 4 is independently -C(0)R 15 and R 15 is independently Ciheteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Ciheteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Ciheteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Ciheteroaryl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -C(0)R 15 and R 15 is independently Cshctcroarvl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Ceheteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Ciheteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Csheteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -C(0)R 15 and R 15 is independently Ceheteroaryl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently selected from C2-6alkenyl, C2- 6 alkynyl, C2-9heterocycloalkyl, and C’ l -dictcroarvl. wherein C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, and Ci- eheteroaryl are optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently C2alkenyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently Cialkcnyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently Cialkcnyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -NHC(0)R 15 and R 15 is independently Csalkcnyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -NHC(0)R 15 and R 15 is independently Cealkenyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently C2alkynyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -NHC(0)R 15 and R 15 is independently Csalkynyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -NHC(0)R 15 and R 15 is independently Cialkynyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -NHC(0)R 15 and R 15 is independently Csalkynyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently Cealkynyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently C 2 heterocycloalkyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently C3heterocycloalkyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently - NHC(0)R 15 and R 15 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently Cshctcrocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -NHC(0)R 15 and R 15 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently - NHC(0)R 15 and R 15 is independently C7heterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -NHC(0)R 15 and R 15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -NHC(0)R 15 and R 15 is independently Cdictcrocycloalkyl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently Ciheteroaryl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently C 2 heteroaryl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently Cihctcroarvl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently Ciheteroaryl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently Cshctcroarvl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -NHC(0)R 15 and R 15 is independently Ceheteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -NHC(0)R 15 and R 15 is independently C7heteroaryl optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -NHC(0)R 15 and R 15 is independently Csheteroaryl optionally substituted with one, two, or three R 20f .
  • R 4 is independently -NHC(0)R 15 and R 15 is independently Csheteroaryl optionally substituted with one, two, or three R 20f .
  • R 4 is capable of forming a covalent bond with a Ras amino acid sidechain. In embodiments, R 4 is capable of forming a covalent bond with a KRas amino acid. In embodiments, R 4 is capable of forming a covalent bond with the 12 th amino acid of a human KRas protein. In embodiments, R 4 is capable of forming a covalent bond with the 12 th amino acid of a mutant KRas protein selected from KRas G12D, KRas G12C, and KRas G12S. In embodiments, R 4 is capable of forming a covalent bond with the 13 th amino acid of a human KRas protein. In embodiments, R 4 is capable of forming a covalent bond with the 13 th amino acid of a mutant KRas protein selected from KRas G13D, KRas G13C, and KRas G13S.
  • R 4 is selected from
  • R 4 is selected from
  • R 15 is independently C 2-6 alkenyl optionally substituted with one, two, or three
  • R 15 is independently C 2-6 alkenyl optionally substituted with one, two, or three halogen. In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with one, two, or three F. In embodiments,
  • R 15 is independently C 2-6 alkenyl optionally substituted with -OR 21 . In embodiments, R 15 is independently C 2 - 6alkenyl optionally substituted with -N(R 22 )(R 23 ). In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with C 2-9 heterocycloalkyl. In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with Ci- 5 heteroaryl optionally substituted with one, two, or three Ci-6alkyl. In embodiments, R 15 is independently C 2 - 6alkenyl optionally substituted with Ci-shctcroarvl optionally substituted with methyl.
  • R 15 is independently C 2-6 alkenyl optionally substituted with -CN. In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with Ci-shctcroarvl optionally substituted with -N(R 24 )C(0)R 25 . In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with Ci- hctcroarvl and/or CN. In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with one, two, or three halogen.
  • R 15 is independently C 2-6 alkenyl optionally substituted with one, two, or three F. In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with -OR 21 . In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with -N(R 22 )(R 23 ). In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with C 2-9 heterocycloalkyl. In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with Ci-shctcroarvl optionally substituted with one, two, or three Ci-6alkyl.
  • R 15 is independently C 2-6 alkenyl optionally substituted with Ci-shctcroarvl optionally substituted with methyl. In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with - CN. In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with Ci-shctcroarvl optionally substituted with -N(R 24 )C(0)R 25 . In embodiments, R 15 is independently C 2-6 alkenyl optionally substituted with - C(0)N(R 22 )(R 23 ). In embodiments, R 15 is independently C 2-6 alkenyl substituted with Cl and optionally substituted with one or two R 20f .
  • R 15 is independently C 2-6 alkynyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with one, two, or three halogen. In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with one, two, or three F. In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with -OR 21 . In embodiments, R 15 is independently C 2 - 6alkynyl optionally substituted with -N(R 22 )(R 23 ). In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with C 2-9 heterocycloalkyl.
  • R 15 is independently C 2-6 alkynyl optionally substituted with Ci-sheteroaryl optionally substituted with one, two, or three Ci-6alkyl. In embodiments, R 15 is independently C 2 - 6alkynyl optionally substituted with Ci-shctcroarvl optionally substituted with methyl. In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with -CN. In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with Ci-sheteroaryl optionally substituted with -N(R 24 )C(0)R 25 .
  • R 15 is independently C 2-6 alkynyl optionally substituted with Ci-sheteroaryl and/or CN. In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with one, two, or three halogen. In embodiments, R 15 is independently C 2 - 6 alkynyl optionally substituted with one, two, or three F. In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with -OR 21 . In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with - N(R 22 )(R 23 ).
  • R 15 is independently C 2-6 alkynyl optionally substituted with C 2 -s > heterocycloalkyl. In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with C’ l -shctcroarvl optionally substituted with one, two, or three Ci- 6 alkyl. In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with Ci- sheteroaryl optionally substituted with methyl. In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with -CN.
  • R 15 is independently C 2-6 alkynyl optionally substituted with C’ l -shctcroarvl optionally substituted with -N(R 24 )C(0)R 25 . In embodiments, R 15 is independently C 2-6 alkynyl optionally substituted with -C(0)N(R 22 )(R 23 ). In embodiments, R 15 is independently C 2-6 alkynyl substituted with Cl and optionally substituted with one or two R 20f . In embodiments, R 15 is independently C 3 -scycloalkyl, optionally substituted with one, two, or three R 20f .
  • R 15 is independently C 3 -scycloalkyl, optionally substituted with Ci- 6 alkyl optionally substituted with one, two, or three halogen. In embodiments, R 15 is independently C 3 - scycloalkyl, optionally substituted with Ci- 6 alkyl optionally substituted with one, two, or three F. In embodiments, R 15 is independently Ci-shctcrocycloalkyl. optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Ci-shctcrocycloalkyl. optionally substituted with Ci- 6 alkyl optionally substituted with one, two, or three halogen.
  • R 15 is independently Ci-shctcrocycloalkyl. optionally substituted with Ci- 6 alkyl optionally substituted with one, two, or three F. In embodiments, R 15 is independently Ci- 6 alkyl, optionally substituted with one, two, or three R 20f . In embodiments, R 15 is independently Ci- 6 alkyl, substituted with Cl and optionally substituted with one, two, or three R 20f . In embodiments, R 4 is independently -CN.
  • L 2 is independently a bond, -C(0)NH-, -NHC(O)-, or -C(O)-; and R 5 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -i 2 cycloalkyl, -CFF-Cs-ncycloalkyl, Ci- li heterocycloalkyl, -CFF-Ci-nheterocycloalkyl, Gs-naryl, -CH 2 -C 6 -i 2 aryl, -CFF-Ci-nheteroaryl, Ci-nheteroaryl, - OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ;
  • L 2 is independently -C(O)-; and R 5 is independently a Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -i 2 cycloalkyl, -CH 2 -C 3 -i 2 cycloalkyl, Ci-nheterocycloalkyl, -CFF-Ci-nheterocycloalkyl, C 6 -i 2 aryl, -CH 2 -C 6 -i 2 aryl, - CH 2 -Ci-nheteroaryl, or Ci-nheteroaryl, wherein the Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -i 2 cycloalkyl, -CH 2 -C 3 - ncycloalkyl, Ci-nheterocycloalkyl, -CFF-Ci-nheterocycloalkyl, C 6 -
  • L 2 is independently -C(O)-; and R 5 is independently a C 3 -i 2 cycloalkyl, Ci- li heterocycloalkyl, C 6 -i 2 aryl, or Ci-nheteroaryl, wherein the C 3 -i 2 cycloalkyl, Ci-nheterocycloalkyl, C 6 -i 2 aryl, and Ci- nheteroaryl are optionally substituted with one, two, or three R 20a .
  • L 2 is independently a bond, -C(0)NH-, -NHC(O)-, or -C(O)-; L 2 is independently bonded to a carbon atom of R 5 ; and R 5 is independently selected from -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3- ncycloalkyl, C6-i2aryl, and Ci-nheteroaryl, wherein C h alky 1, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, Gs-naryl, and Ci-iiheteroaryl, are optionally substituted with one, two, or three R 20a .
  • L 2 is independently -C(O)-; L 2 is independently bonded to a carbon atom of R 5 ; and R 5 is independently selected from Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, C6-i2aryl, and Ci-nheteroaryl, wherein the C h alky 1, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, Gs-naryl, and Ci-nheteroaryl, are optionally substituted with one, two, or three R 20a .
  • L 2 is independently -C(O)-; L 2 is independently bonded to a carbon atom of R 5 ; and R 5 is independently selected from Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and 5-6 membered heteroaryl, wherein the Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R 20a .
  • L 2 is independently -C(O)-;
  • R 5 is independently ;
  • R 5a is independently CH, C(R 20a ), CH(R 20a ), QH, C(R 20a )2, N, NH, or N(R 20a );
  • R 5 comprises 0-3 independent R 20a ; and
  • 0-4 R 5a are independently N, NH, or N(R 20a ).
  • L 2 is independently -C(O)-; and R 5 is independently C3-iocycloalkyl, wherein C3- l ocycloalkyl is independently optionally substituted with one, two, or three R 20a .
  • L 2 is independently -C(O)-; and R 5 is independently cyclopropyl, wherein cyclopropyl is independently optionally substituted with one, two, or three F.
  • L 2 is independently -C(O)-; and R 5 is independently cyclopropyl, wherein cyclopropyl is independently optionally substituted with one, two, or three CN.
  • L 2 is independently -C(O)-; and R 5 is independently cyclopropyl, wherein cyclopropyl is independently optionally substituted with one, two, or three halogen.
  • R 5 is independently hydrogen. In embodiments, R 5 is independently halogen. In embodiments, R 5 is independently R 5 is independently oxo. In embodiments, R 5 is independently -CN. In embodiments, R 5 is independently Ci- 6 alkyl. In embodiments, R 5 is independently C2-6alkenyl. In embodiments, R 5 is independently C2-6alkynyl. In embodiments, R 5 is independently Ci- 6 haloalkyl. In embodiments, R 5 is independently C3-i2cycloalkyl. In embodiments, R 5 is independently -CH 2 -C3-i2cycloalkyl. In embodiments, R 5 is independently Ci-nheterocycloalkyl.
  • R 5 is independently -QH-Ci-nheterocycloalkyl. In embodiments, R 5 is independently C6-i2aryl. In embodiments, R 5 is independently -CH 2 -C6-i2aryl. In embodiments, R 5 is independently -Cfh-Ci-nheteroaryl. In embodiments, R 5 is independently Ci-nheteroaryl. In embodiments,
  • R 5 is independently -OR 12 . In embodiments, R 5 is independently -SR 12 . In embodiments, R 5 is independently - N(R 12 )(R 13 ). In embodiments, R 5 is independently -C(0)0R 12 . In embodiments, R 5 is independently - 0C(0)N(R 12 )(R 13 ). In embodiments, R 5 is independently -N(R 15 )C(0)N(R 12 )(R 13 ). In embodiments, R 5 is independently -N(R 15 )C(0)0R 15 . In embodiments, R 5 is independently -N(R 15 )S(0) 2 R 15 . In embodiments, R 5 is independently -C(0)R 15 .
  • R 5 is independently -CH 2 C(0)N(R 12 )(R 13 ). In embodiments, R 5 is independently -CH 2 N(R 15 )C(0)R 15 . In embodiments, R 5 is independently -CH 2 S(0) 2 R 15 . In embodiments, R 5 is independently and -CH 2 S(0) 2 N(R 12 )(R 13 ). In embodiments, R 5 is independently Ci- 6 alkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently C2-6alkenyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently C2-6alkynyl optionally substituted with one, two, or three R 20a .
  • R 5 is independently Ci- 6 haloalkyl optionally substituted with one, two, or three R 20a .
  • R 5 is independently C3-i2cycloalkyl optionally substituted with one, two, or three R 20a .
  • R 5 is independently -CH 2 -C3-i2cycloalkyl optionally substituted with one, two, or three R 20a .
  • R 5 is independently Ci-nheterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 5 is independently -Cfh-Ci-nheterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 5 is independently C6-i2aryl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently -CH 2 -C6-i2aryl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently -Cfh-Ci-nheteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cmheteroaryl optionally substituted with one, two, or three R 20a .
  • R 5 is independently selected from hydrogen, halogen, oxo, -CN, Ci-ealkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), and -C(0)R 12 , wherein Ci- 6 alkyl, C2-6alkenyl, and C2-6alkynyl, are optionally substituted with one, two, or three R 20a .
  • R 5 is independently hydrogen.
  • R 5 is independently halogen.
  • R 5 is independently oxo. In some embodiments of the subject compound, R 5 is independently -CN. In additional embodiments of the subject compound, R 5 is independently Ci- 6 alkyl. In embodiments of the subject compound, R 5 is independently C 2 - 6 alkenyl. In some embodiments of the subject compound, R 5 is independently C2-6alkynyl. In further embodiments of the subject compound, R 5 is independently -OR 12 . In select embodiments of the subject compound, R 5 is independently -N(R 12 )(R 13 ). In additional embodiments of the subject compound, R 5 is independently -C(0)0R 12 .
  • R 5 is independently -0C(0)N(R 12 )(R 13 ). In some embodiments of the subject compound, R 5 is independently -C(0)R 12 . In select embodiments of the subject compound, R 5 is independently -NH 2 . In further embodiments of the subject compound, R 5 is independently -C(0)0H. In additional embodiments of the subject compound, R 5 is independently -0C(0)NH 2 . In embodiments of the subject compound, R 5 is independently -C(0)CH 3 .
  • R 5 is independently Cialkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently C2alkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cialkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cialkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Csalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cealkyl optionally substituted with one, two, or three R 20a .
  • R 5 is independently C2alkenyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cialkcnyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cialkcnyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Csalkcnyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cealkenyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently C2alkynyl optionally substituted with one, two, or three R 20a .
  • R 5 is independently Cialkynyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cialkynyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Chalky m l optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cealkynyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cihaloalkyl. In embodiments, R 5 is independently C2haloalkyl. In embodiments, R 5 is independently Cihaloalkyl. In embodiments, R 5 is independently Cihaloalkyl. In embodiments, R 5 is independently Cshaloalkyl. In embodiments, R 5 is independently Cehaloalkyl. In embodiments, R 5 is independently Cehaloalkyl.
  • R 5 is independently Cicycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cicycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cscycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cecycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently C7cycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cscycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cscycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cscycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Ciocycloal
  • R 5 is independently C2heterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cshetcrocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 5 is independently C-hetcrocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 5 is independently Cearyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently C-arvl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Csaryl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Csaryl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cioaryl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cnaryl optionally substituted with one, two, or three R 20a .
  • R 5 is independently Cearyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently C2heteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cihctcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cihctcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cshctcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Ceheteroaryl optionally substituted with one, two, or three R 20a .
  • R 5 is independently C-hctcroaiy l optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Csheteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cdictcroaiyl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cioheteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently Cnheteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 5 is independently -OH. In embodiments, R 5 is independently -SH.
  • R 5 is independently -NH 2 . In embodiments, R 5 is independently -C(0)0H. In embodiments, R 5 is independently - 0C(0)NH 2 . In embodiments, R 5 is independently -N(H)C(0)NH 2 . In embodiments, R 5 is independently - N(H)C(0)0H. In embodiments, R 5 is independently -N(H)S(0) 2 CH . In embodiments, R 5 is independently - C(0)H. In embodiments, R 5 is independently -S(0)CH . In embodiments, R 5 is independently -0C(0)CH 3 . In embodiments, R 5 is independently -C(0)NH 2 . In embodiments, R 5 is independently -C(0)C(0)NH 2 .
  • R 5 is independently -OCH 3 . In embodiments, R 5 is independently -SCH 3 . In embodiments, R 5 is independently -N(CH 3 )(H). In embodiments, R 5 is independently -C(0)0CH 3 . In embodiments, R 5 is independently -0C(0)N(CH 3 )(H). In embodiments, R 5 is independently -N(H)C(0)N(CH 3 )(H). In embodiments, R 5 is independently -N(H)C(0)0CH 3 . In embodiments, R 5 is independently -N(H)S(0) 2 CH 3 . In embodiments, R 5 is independently -C(0)CH 3 . In embodiments, R 5 is independently -S(0)CH 3 .
  • R 5 is independently -CH 2 N(H)C(0)CH 3 . In embodiments, R 5 is independently -CH 2 S(0) 2 CH 3 . In embodiments, R 5 is independently and -CH 2 S(0) 2 N(CH 3 )(H).
  • R 5 is independently -CH 3 . In embodiments, R 5 is independently -CF 3 . In embodiments, R 5 is independently -CHF 2 . In embodiments, R 5 is independently -CFH 2 . In embodiments, R 5 is independently ethyl. In embodiments, R 5 is independently propyl. In embodiments, R 5 is independently isopropyl. In embodiments, R 5 is independently butyl. In embodiments, R 5 is independently tert-butyl.
  • R 6 is independently halogen. In embodiments, R 6 is independently R 6 is independently oxo. In embodiments, R 6 is independently -CN. In embodiments, R 6 is independently Ci- 6 alkyl. In embodiments, R 6 is independently C 2-6 alkenyl. In embodiments, R 6 is independently C 2-6 alkynyl. In embodiments, R 6 is independently Ci- 6 haloalkyl. In embodiments, R 6 is independently C 3 -i 2 cycloalkyl. In embodiments, R 6 is independently -CH 2 -C 3 -i 2 cycloalkyl. In embodiments, R 6 is independently Ci-nheterocycloalkyl. In embodiments, R 6 is independently -Cfh-Ci-nheterocycloalkyl. In embodiments, R 6 is independently C6-i2aryl. In embodiments,
  • R 6 is independently -CH 2 -C6-i2aryl. In embodiments, R 6 is independently -Cfh-Ci-nheteroaryl. In embodiments, R 6 is independently Ci-nheteroaryl. In embodiments, R 6 is independently -OR 12 . In embodiments, R 6 is independently -SR 12 . In embodiments, R 6 is independently -N(R 12 )(R 13 ). In embodiments, R 6 is independently -C(0)0R 12 . In embodiments, R 6 is independently -0C(0)N(R 12 )(R 13 ). In embodiments, R 6 is independently - N(R 16 )C(0)N(R 12 )(R 13 ).
  • R 6 is independently -N(R 16 )C(0)0R 15 . In embodiments, R 6 is independently -N(R 16 )S(0) 2 R 15 . In embodiments, R 6 is independently -C(0)R 15 . In embodiments, R 6 is independently -S(0)R 15 . In embodiments, R 6 is independently -0C(0)R 15 . In embodiments, R 6 is independently - C(0)N(R 12 )(R 13 ). In embodiments, R 6 is independently -C(0)C(0)N(R 12 )(R 13 ). In embodiments, R 6 is independently -N(R 16 )C(0)R 15 . In embodiments, R 6 is independently -S/CfhR 15 .
  • R 6 is independently C2-6alkenyl optionally substituted with one, two, or three R 20a . In embodiments, R 6 is independently C2-6alkynyl optionally substituted with one, two, or three R 20a . In embodiments, R 6 is independently Ci- 6 haloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 6 is independently C3- ncycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 6 is independently -CH2-C3- ncycloalkyl optionally substituted with one, two, or three R 20a .
  • R 6 is independently Ci- li heterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 6 is independently -CH2-C1- li heterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 6 is independently C6-i2aryl optionally substituted with one, two, or three R 20a .
  • R 6 is independently -CH 2 -C6-i2aryl optionally substituted with one, two, or three R 20a .
  • R 6 is independently -Cfh-Ci-nheteroaryl optionally substituted with one, two, or three R 20a .
  • R 6 is independently Ci-nheteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently hydrogen. In select embodiments of the compound, R 1 is independently Ci- 6 alkyl optionally substituted with one, two, or three R 20a . In embodiments of the compound, R 1 is independently methyl optionally substituted with one or two R 20a . In further embodiments of the compound, R 1 is independently methyl. In some embodiments of the compound, R 1 is independently ethyl optionally substituted with one, two, or three R 20a . In embodiments of the compound, R 1 is independently ethyl. In some embodiments of the compound, R 1 is independently propyl optionally substituted with one, two, or three R 20a . In embodiments of the compound, R 1 is independently propyl.
  • R 1 is independently -CH2-C2- dictcrocycloalkyl optionally substituted with one, two, or three R 20a . In some embodiments, R 1 is independently - CH2-(monocyclic C2-8heterocycloalkyl) optionally substituted with one, two, or three R 20a . In some embodiments,
  • R 1 is independently -CH2-(monocyclic C3-5heterocycloalkyl) optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH2-(spirocyclic C2-nheterocycloalkyl) optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH2-(spirocyclic C3-iiheterocycloalkyl) optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH2-(fused C2- li heterocycloalkyl) optionally substituted with one, two, or three R 20a .
  • R 1 is independently - CH2-(spirocyclic Ce-sheterocycloalkyl) optionally substituted with one, two, or three R 20a .
  • R 1 is independently Ci- 6 alkyl.
  • R 1 is independently C2-6alkenyl.
  • R 1 is independently C2- 6alkynyl.
  • R 1 is independently C 3 -iocycloalkyl.
  • R 1 is independently -CH 2 -C 3 - l ocycloalkyl.
  • R 1 is independently C 2-9 heterocycloalkyl.
  • R 1 is independently - CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is independently C6-ioaryl. In embodiments, R 1 is independently - CH 2 -C6-ioaryl. In embodiments, R 1 is independently -CEb-Ci-gheteroaryl. In embodiments, R 1 is independently Ci- gheteroaryl. In embodiments, R 1 is independently Ci-6alkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently C 2-6 alkenyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently C 2-6 alkynyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently C 3 -iocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently -CH 2 -C 3 -iocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently -CH 2 -C 2-9 heterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently C6-ioaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently - CH 2 -C6-ioaryl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently -CH 2 -C 1 - gheteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Ci-gheteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently Ci-6alkyl. In embodiments, R 1 is independently C 2-6 alkenyl. In embodiments, R 1 is independently C 2-6 alkynyl. In embodiments, R 1 is independently Ci-6haloalkyl. In embodiments, R 1 is independently C 3 -i 2 cycloalkyl. In embodiments, R 1 is independently -CH 2 -C 3 -i 2 cycloalkyl. In embodiments, R 1 is independently Ci-nheterocycloalkyl. In embodiments, R 1 is independently -CH 2 -C 1 - li heterocycloalkyl. In embodiments, R 1 is independently C 6 -i 2 aryl.
  • R 1 is independently -CH 2 -C 6 - naryl. In embodiments, R 1 is independently -CEC-Ci-nheteroaryl. In embodiments, R 1 is independently Ci- nheteroaryl.
  • R 1 is independently Ci-6alkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently C 2-6 alkenyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently C 2-6 alkynyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently Ci-6haloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently C 3 -i 2 cycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C 3 - ncycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently Ci- li heterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C 1 - li heterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently C 6 -i 2 aryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C 6 -i 2 aryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -Qk-Ci-nheteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Ci-nheteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently Cialkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently C 2 alkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently C ialky l optionally substituted with one, two, or three R 20a .
  • R 1 is independently Cialkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently Cialkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently Cealkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently C 2 alkenyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cialkcnyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cialkcnyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Csalkcnyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cealkenyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently C2alkynyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently Cialkynyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cialkynyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Csalkynyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cealkynyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cihaloalkyl. In embodiments, R 1 is independently Cihaloalkyl. In embodiments, R 1 is independently Cihaloalkyl. In embodiments, R 1 is independently Cihaloalkyl. In embodiments, R 1 is independently Cihaloalkyl. In embodiments, R 1 is independently Cehaloalkyl. In embodiments, R 1 is independently Cehaloalkyl.
  • R 1 is independently Ci cycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cicycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cscycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cecycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently C7cycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cscycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cscycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cscycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Ciocyclo
  • R 1 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cdictcrocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently Cvheterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Csheterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently Cearyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently C-arvl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Csaryl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Csaryl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cioaryl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cnaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently Cearyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cihctcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cihctcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cihctcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cihctcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Ceheteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently C-hetcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Csheteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cihctcroarvl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cioheteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently Cnheteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C 3 cycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C4cycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CFF-Cscycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C 6 cycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C7cycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CFF-Cscycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently -CFF-Cgcycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently -CH 2 -Ciocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C 2 heterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C 3 heterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C4heterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CFF-Csheterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C 6 heterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently -CH 2 -C7heterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently -CFF-Csheterocycloalkyl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently -CFF-Csiheterocycloalkyl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C 6 aryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C7aryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CFF-Csaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C9aryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -Cioaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -Cnaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -Ci 2 aryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C 2 heteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C3heteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C4heteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CFF-Csheteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C 6 heteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -C7heteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CFF-Csheteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -Cs>heteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 2 -Cioheteroaryl optionally substituted with one, two, or three R 20a . In embodiments, R 1 is independently -CH 2 -Cnheteroaryl optionally substituted with one, two, or three R 20a .
  • R 1 is independently -CH 3 . In embodiments, R 1 is independently -CF 3 . In embodiments, R 1 is independently -CHF 2 . In embodiments, R 1 is independently -CFH 2 . In embodiments, R 1 is independently ethyl. In embodiments, R 1 is independently propyl. In embodiments, R 1 is independently isopropyl. In embodiments, R 1 is independently butyl. In embodiments, R 1 is independently tert-butyl. [00313] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 7 p is an integer from 0 to 12;
  • R 7 is p is an integer from 0 to 12;
  • R 7 is
  • R 16 is independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three R 20g .
  • R 16 is independently selected from hydrogen and halogen.
  • R 16 is independently selected from hydrogen and fluoro. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 16 is hydrogen. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 16 is fluoro.
  • R 8 is selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, and C 2-9 heterocycloalkyl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three R 20c .
  • R 8 is selected from hydrogen, Ci- 6 alkyl, C 3 -iocycloalkyl, and C 2-9 heterocycloalkyl, wherein Ci- 6 alkyl, C 3 -iocycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three R 20c independently selected from halogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3 -iocycloalkyl, and C 2-9 heterocycloalkyl.
  • R 8 is selected from hydrogen, methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R 20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl.
  • R 8 is selected from hydrogen, methyl, cyclopropyl, cyclobutyl, and oxetanyl.
  • R 8 is selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(H)(R 12 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -N(
  • R 8 is selected from Ci- 6 alkyl, C3-iocycloalkyl, and C2-s>heterocycloalkyl, wherein Ci- 6 alkyl, C3-iocycloalkyl, and C2-s>heterocycloalkyl are optionally substituted with one, two, or three R 20c independently selected from halogen, Ci- 6 alkyl, C2- 6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl.
  • R 8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R 20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl.
  • R 8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
  • R 3 is hydrogen or CN. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 3 is hydrogen. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 3 is CN.
  • L 1 is a bond. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L 1 is selected from a Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -C(O)-, -NHC(O)-, -C(0)NH-,
  • L 1 is a bond. In embodiments, L 1 is Ci-Cealkyl. In embodiments, L 1 is C2-C6alkenyl. In embodiments, L 1 is C2-C6alkynyl. In embodiments, L 1 is -0-. In embodiments, L 1 is -N(R 14 )-. In embodiments, L 1 is -C(O)-. In embodiments, L 1 is -N(R 14 )C(0)-. In embodiments, L 1 is -C(0)N(R 14 )-. In embodiments, L 1 is -S-. In embodiments, L 1 is -S(0) 2 -. In embodiments, L 1 is -S(O)-.
  • L 1 is -S(0) 2 N(R 14 )-. In embodiments, L 1 is -S(0)N(R 14 )-. In embodiments, L 1 is -N(R 14 )S(0)-. In embodiments, L 1 is -N(R 14 )S(0) 2 -. In embodiments, L 1 is -OCON(R 14 )-. In embodiments, L 1 is - N(R 14 )C(0)0-. In embodiments, L 1 is N(R le ). In embodiments, L 1 is C(0)N(R lc ). In embodiments, L 1 is S(0) 2 N(R 1c ). In embodiments, L 1 is S(0)N(R lc ).
  • L 1 is C(R lf )(R lg )0. In embodiments, L 1 is C(R lf )(R lg )N(R lc ). In embodiments, L 1 is C(R lf )(R lg ). In embodiments, L 1 is -N(H)-. In embodiments, L 1 is -N(H)C(0)-. In embodiments, L 1 is -C(0)N(H)-. In embodiments, L 1 is -S(0) 2 N(H)-. In embodiments, L 1 is -S(0)N(H)-. In embodiments, L 1 is -N(H)S(0)-. In embodiments, L 1 is -N(H)S(0) 2 -.
  • L 1 is -OCON(H)-. In embodiments, L 1 is -N(H)C(0)0-. In embodiments, L 1 is -N(H)-.
  • L 1 is -C(0)N(H)-. In embodiments, L 1 is -S(0) 2 N(H)-. In embodiments, L 1 is - S(0)N(H)-. In embodiments, L 1 is -CH2O-. In embodiments, L 1 is -CH 2 N(H)-. In embodiments, L 1 is -
  • R 19 is a monocyclic ring. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 19 is a bicyclic ring system. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R 19 is a polycyclic ring system. In embodiments of the
  • R 19 is: X 6
  • Q 1 , Q 3 , and Q 5 are independently N or C(R ld );
  • Q 4 and Q 6 are independently O, S, C(R la )(R lb ), or N(R lc );
  • X 4 , X 5 , X 6 , X 9 , X 10 , X 11 , and X 12 are independently selected from C(R la ) or N;
  • X 7 and X 8 are independently selected from C(R la ), C(R la )(R lb ), N, or N(R lc ); each R la , R lb , R ld , and R lh are each independently selected from hydrogen, halogen, -CN, CYr, alkyl. CY (Jialoalkyl. CYr, alkenyl. CYr,alkynyl.
  • CYr alkenyl. CYr,alkynyl.
  • C3-iocycloalkyl, C 2 -9heterocycloalkyl, Ce-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 201 ; or R la and R lb bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-iocycloalkyl ring are optionally substituted with one, two, or three R 201 ; or two R la bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a Ce-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloal
  • CYr alkenyl. CYr,alkynyl. C3-iocycloalkyl, C 2. 9heterocycloalkyl, Ce-ioaryl, Ci-9heteroaryl, wherein CYr, alkyl. CYr, alkenyl. CYr,alkynyl. C3- l ocycloalkyl, C 2-9 heterocycloalkyl, Ce-ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 201 .
  • R 2 is selected from
  • each R 5 is independently selected from:
  • W is C(0), S(0), or S(0) 2 ;
  • V is C(R 16 ) or N;
  • R 10 is -L 7 -R 7 ;
  • V is a bond, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -
  • R 7 is a 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl are optionally substituted with one or more R 1 , one or more R 4 , or one or more R 6 ; two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i 2 cycloalkyl, Ci-nheterocycloalkyl, C 6 -i 2 aryl, or Ci-nheteroaryl, wherein the C3- i 2 cycloalkyl.
  • Ci-nheterocycloalkyl, C 6 -i 2 aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R 20a ; each R 1 is independently selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci- 6 haloalkyl, C3- i 2 cycloalkyl.
  • R 6 is -L 2 -R 5 ; each L 2 is independently selected from a bond, G-Galkyl, -0-, -N(R 14 )-, -C(0)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, - S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, -OCON(R 14 )-, - N(R 14 )C(0)0-, and -N(R 14 )C(0)N(R 14 )-; each R 5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
  • R 8 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2. gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(H)(R 12 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0) 2 R
  • R 17 is -G-R 19 ;
  • L 1 is selected from a bond, G-Galkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -0-, -N(R 14 )-, -C(0)-, -N(R 14 )C(0)-, - C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, - OCON(R 14 )-, -N(R 14 )C(0)0-, N(R le ), C(0)N(R lc ), S(0) 2 N(R lc ), S(0)N(R lc ), C(R lf )(R lg )0, C(R lf )(R lg )N(R lc ), and
  • R lc is selected from hydrogen, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-dictcroarvl. wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 201
  • R 19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3- ncycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R 11 ; each R 11 is independently selected from halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , - 0C(0)N(R 12 )(R
  • R 16 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0)
  • R 12a is selected from Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl, wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- yhctcrocycloalkvl.
  • Ci- gheteroaryl are optionally substituted with one, two, or three R 20d ;
  • R 12b is selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, -CH 2 -C3-iocycloalkyl, C 2. gheterocycloalkyl, -CH 2 -C 2 -9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 -Ci-9heteroaryl, and Ci- gheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, -CH 2 -C3-iocycloalkyl, C 2.
  • gheterocycloalkyl, -CH 2 -C 2 -9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 -Ci-9heteroaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R 20d ;
  • X is C(R 3 ) or N
  • R 3 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2. gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0)
  • each R 12 is independently selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, -CH 2 -C3- 6cycloalkyl, C 2 -9heterocycloalkyl, -CH 2 -C 2 -9heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 -C I - gheteroaryl, and Ci-gheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, -CH 2 -C 3 - 6cycloalkyl, C 2 -9heterocycloalkyl, -CH 2 -C 2 -9heterocycloalkyl
  • Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 20f ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , and R 201 are each independently selected from halogen, -CN, Ci- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, -CH 2 -C3-6cycloalkyl, C 2 -9heterocycloalkyl, -CH 2 -C 2.
  • each R 22 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2.
  • W is C(O), S(O), or S(0) 2 ;
  • V is C(R 16 ) or N;
  • R 10 is -L 7 -R 7 ;
  • L 7 is a bond, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -
  • Ci-Cealkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R 20a ;
  • R 7 is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 ; two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i 2 cycloalkyl, Ci-nheterocycl
  • Ci-nheterocycloalkyl, C 6 -i 2 aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R 20a ; each R 1 is independently selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci- 6 haloalkyl, C3- i 2 cycloalkyl.
  • R 6 is -L 2 -R 5 ; each L 2 is independently selected from a bond, Ci-Cealkyl, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, - S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, -OCON(R 14 )-, - N(R 14 )C(0)0-, and -N(R 14 )C(0)N(R 14 )-; each R 5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
  • R 8 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2. dictcrocycloalkyl. C 6 -ioaryl, Ci-yhctcroan l.
  • R 17 is -lA-R 19 ;
  • L 1 is selected from a bond, Ci-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -0-, -N(R 14 )-, -C(0)-, -N(R 14 )C(0)-, - C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, - OCON(R 14 )-, -N(R 14 )C(0)0-, N(R le ), C(0)N(R lc ), S(0) 2 N(R lc ), S(0)N(R lc ), C(R lf )(R lg )0, C(R lf )(R lg )N(R lc ),
  • R le , R lf , and R lg are independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), - C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , - S(0)R 15 , -0C(0)R 15 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12
  • gheterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 201 ; or R lf and R lg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R 201 ;
  • R lc is selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, CV,- ioaryl, and Ci-gheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 201
  • R 19 is selected from a C3-i 2 cycloalkyl, C 2 -nheterocycloalkyl, C 6 -i 2 aryl, and C 2 -i 2 heteroaryl, wherein the C3- i 2 cycloalkyl, C 2 -nheterocycloalkyl, C 6 -i 2 aryl, and C 2 -i 2 heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R 11 ; each R 11 is independently selected from halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3- 6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -
  • R 12a is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, -C(R 12c ) 2 -C3-iocycloalkyl, C 2.
  • Ci-9heterocycloalkyl gheterocycloalkyl, -C(R 12c ) 2 -C 2 -9heterocyeloalkyl, C 6 -ioaryl, -C(R 12c ) 2 -C 6 -ioaryl, -C(R 12c ) 2 -Ci-9heteroaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, -C(R 12c ) 2 -C3-iocycloalkyl, C 2 -9heterocycloalkyl, -C(R 12c ) 2 -C 2 -9heterocycloalkyl, C 6 -ioaryl, -C(R 12c ) 2 -C 6 -ioaryl, -C(R 12c ) 2 -Ci-9heter
  • R 12b is selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, -C(R 12c ) 2 -C3-iocycloalkyl, C 2.
  • Ci-9heterocycloalkyl gheterocycloalkyl, -C(R 12c ) 2 -C 2 -9heterocyeloalkyl, C 6 -ioaryl, -C(R 12c ) 2 -C 6 -ioaryl, -C(R 12c ) 2 -Ci-9heteroaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, -C(R 12c ) 2 -C3-iocycloalkyl, C 2 -9heterocycloalkyl, -C(R 12c ) 2 -C 2 -9heterocycloalkyl, C 6 -ioaryl, -C(R 12c ) 2 -C 6 -ioaryl, -C(R 12c ) 2 -Ci-9heter
  • R 12c is independently selected from hydrogen and R 20k ;
  • X is C(R 3 ) or N
  • R 3 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2. gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0)
  • Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R 20f ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 201 , and R 20k are each independently selected from halogen, oxo, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2 - gheterocycloalkyl, C 6 -ioaryl, -CFF-
  • R 7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the a 4- 12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 ; wherein two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent
  • W is C(O), S(O), or S(0) 2 ;
  • V is C(R 17 ) and J is C(R 16 ), or V is C(R 17 ) and J is N, or J is C(R 17 ) and V is C(R 16 ), or J is C(R 17 ) and V is N;
  • R 10 is -L 7 -R 7 ;
  • L 7 is a bond, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -
  • Ci-Cealkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and 2 to 4 membered heteroalkylene linker are unsubstituted or optionally substituted;
  • R 7 is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are unsubstituted or optionally substituted;
  • R 8 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2. dictcrocycloalkyl. C 6 -ioaryl, Ci-dictcroarvl.
  • R 17 is -G-R 19 ;
  • L 1 is selected from a bond, G-Galkyl, C 2 -C 6 alkenyl, C 2 -Galkynyl, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, - C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, - OCON(R 14 )-, -N(R 14 )C(0)0-, N(R le ), C(0)N(R lc ), S(0) 2 N(R lc ), S(0)N(R lc ), C(R lf )(R lg )0, C(R lf )(R lg )N(R lc
  • R le , R lf , and R lg are independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), - C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , - S(0)R 15 , -0C(0)R 15 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12
  • gheterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted; or R lf and R lg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4- 7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are unsubstituted or optionally substituted;
  • R lc is selected from hydrogen, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, G,. loaryl, and Ci- ⁇ j hctcroaiyl. wherein Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted;
  • R 19 is selected from a C 3 -i 2 cycloalkyl, C 2 -nheterocycloalkyl, C 6 -i 2 aryl, and C 2 -i 2 heteroaryl, wherein the G- ncycloalkyl, C 2 -iiheterocycloalkyl, C 6 -i 2 aryl, and C 2 -i 2 heteroaryl are unsubstituted or optionally substituted;
  • R 16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, G- gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S
  • R 12a is selected from Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -G-iocycloalkyl, G- gheterocycloalkyl, -C(R 12c ) 2 -G- 9 heterocyeloalkyl, C 6 -ioaryl, -C(R 12c ) 2 -G-ioaryl, -C(R 12c ) 2 -G- 9 heteroaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2-9 heterocycloalkyl, -C(R 12c ) 2 -C 2-9 heterocycloalkyl, C 6 -
  • R 12b is selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2 - gheterocycloalkyl, -C(R 12c ) 2 -C 2-9 heterocyeloalkyl, C 6 -ioaryl, -C(R 12c ) 2 -C 6 -ioaryl, -C(R 12c ) 2 -Ci- 9 heteroaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2-9 heterocycloalkyl, -C(R 12c ) 2 -C 2-9 hetero
  • R 12c is selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C6-ioaryl, -CH 2 -C6-ioaryl, -CH 2 -C 1.
  • Ci-sheteroaiyl Ci-sheteroaiyl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(0)0R 22 , -C(0)N(R 22 )(R 23 ), - C(0)C(0)N(R 22 )(R 23 ), -0C(0)N(R 22 )(R 23 ), -N(R 24 )C(0)N(R 22 )(R 23 ), -N(R 24 )C(0)0R 25 , -N(R 24 )C(0)R 25 , - N(R 24 )S(0) 2 R 25 , -C(0)R 25 , -S(0) 2 R 25 , -S(0) 2 N(R 22 )(R 23 ), -0CH 2 C(0)0R 22 , and -0C(0)R 25 , wherein Ci- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycl
  • X is C(R 3 ) or N
  • R 3 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -ioaryl, Ci-dictcroarvl.
  • each R 12 is independently selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 -C 1 - gheteroaryl, and Ci-gheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -ioaryl,
  • R 7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the a 4- 12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted or unsubstituted.
  • W is C(O), S(O), or S(0) 2 ;
  • V is C(R 16 ) or N;
  • R 10 is -L 7 -R 7 ;
  • L 7 is a bond, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -
  • Ci-Cealkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and 2 to 4 membered heteroalkylene linker are unsubstituted or optionally substituted;
  • R 7 is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are unsubstituted or optionally substituted;
  • R 8 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2. dictcrocycloalkyl. C 6 -ioaryl, Ci-dictcroarvl.
  • R 17 is -G-R 19 ;
  • L 1 is selected from a bond, G-Galkyl, C 2 -C 6 alkenyl, C 2 -Galkynyl, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, - C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, - OCON(R 14 )-, -N(R 14 )C(0)0-, N(R le ), C(0)N(R lc ), S(0) 2 N(R lc ), S(0)N(R lc ), C(R lf )(R lg )0, C(R lf )(R lg )N(R lc
  • R le , R lf , and R lg are independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), - C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , - S(0)R 15 , -0C(0)R 15 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12
  • gheterocycloalkyl, C 6 -ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted; or R lf and R lg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4- 7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are unsubstituted or optionally substituted;
  • R lc is selected from hydrogen, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, G,. loaryl, and Ci- ⁇ j hctcroaiyl. wherein Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted;
  • R 19 is selected from a C 3 -i 2 cycloalkyl, C 2 -nheterocycloalkyl, C 6 -i 2 aryl, and C 2 -i 2 heteroaryl, wherein the G- ncycloalkyl, C 2 -iiheterocycloalkyl, C 6 -i 2 aryl, and C 2 -i 2 heteroaryl are unsubstituted or optionally substituted;
  • R 16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, G- gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S
  • R 12a is selected from Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -G-iocycloalkyl, G- gheterocycloalkyl, -C(R 12c ) 2 -G- 9 heterocyeloalkyl, C 6 -ioaryl, -C(R 12c ) 2 -G-ioaryl, -C(R 12c ) 2 -G- 9 heteroaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2-9 heterocycloalkyl, -C(R 12c ) 2 -C 2-9 heterocycloalkyl, C 6 -
  • R 12b is selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2 - gheterocycloalkyl, -C(R 12c ) 2 -C 2-9 heterocyeloalkyl, C 6 -ioaryl, -C(R 12c ) 2 -C 6 -ioaryl, -C(R 12c ) 2 -Ci- 9 heteroaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2-9 heterocycloalkyl, -C(R 12c ) 2 -C 2-9 hetero
  • R 12c is selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C6-ioaryl, -CH 2 -C6-ioaryl, -CH 2 -C 1.
  • Ci-sheteroaiyl Ci-sheteroaiyl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(0)0R 22 , -C(0)N(R 22 )(R 23 ), - C(0)C(0)N(R 22 )(R 23 ), -0C(0)N(R 22 )(R 23 ), -N(R 24 )C(0)N(R 22 )(R 23 ), -N(R 24 )C(0)0R 25 , -N(R 24 )C(0)R 25 , - N(R 24 )S(0) 2 R 25 , -C(0)R 25 , -S(0) 2 R 25 , -S(0) 2 N(R 22 )(R 23 ), -0CH 2 C(0)0R 22 , and -0C(0)R 25 , wherein Ci- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycl
  • X is C(R 3 ) or N
  • R 3 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -ioaryl, Ci-gheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 ,
  • each R 12 is independently selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -ioaryl, -CH 2 -C 6 -ioaryl, -CH 2 -C 1 - gheteroaryl, and Ci-gheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -ioaryl,
  • R 7 is a 4- 12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the a 4- 12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted or unsubstituted.
  • V is C(R 17 ) and J is C(R 16 ), or V is C(R 17 ) and J is N, or J is C(R 17 ) and V is C(R 16 ), or J is C(R 17 ) and V is N;
  • R 10 is -L 7 -R 7 ;
  • L 7 is a bond, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -
  • Ci-Cealkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R 20a ;
  • R 7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 ; wherein two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent atoms are optionally joined to form a 3-12 membered cycloalkyl, 3-12 membered
  • R 6 is -L 2 -R 5 ; each L 2 is independently selected from a bond, G-Galkyl, -0-, -N(R 14 )-, -C(0)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, - S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, -OCON(R 14 )-, - N(R 14 )C(0)0-, and -N(R 14 )C(0)N(R 14 )-; each R 5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
  • R 8 is selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, C 2 -9heterocycloalkyl, G- i 2 aryl, Ci-nheteroaiyl, -OR 12 , -SR 12 , -N(H)(R 12 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , -C(0)N(R 12 )(R 13 ), - C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S
  • R 17 is -L ! -R 19 ;
  • L 1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, - C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, - OCON(R 14 )-, -N(R 14 )C(0)0-, N(R le ), C(0)N(R lc ), S(0) 2 N(R lc ), S(0)N(R lc ), C(R lf )(R lg )0, C(R lf )(R lg )N(R lc ), and C
  • R le , R lf , and R lg are independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-i2aryl, Ci-nheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), - C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , - S(0)R 15 , -0C(0)R 15 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12
  • R lc is selected from hydrogen, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, naryl, Ci-nheteroaryl, wherein C h alky 1, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, CV,. naryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R 201 ;
  • R 19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3- ncycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R 11 ; each R 11 is independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, C2-9heterocycloalkyl, Gs-naryl, Ci-nheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , - 0C(0)N(R 12
  • R 16 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-i2aryl, Ci-nheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -
  • R 12a is selected from Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2 - gheterocycloalkyl, -C(R 12c ) 2 -C 2-9 heterocyeloalkyl, C6-ioaryl, -C(R 12c ) 2 -C 6 -ioaryl, -C(R 12c ) 2 -Ci- 9 heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2-9 heterocycloalkyl, -C(R 12c ) 2 -C 2-9 heterocycloal
  • R 12b is selected from hydrogen, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2 - gheterocycloalkyl, -C(R 12c ) 2 -C 2-9 heterocyeloalkyl, C6-ioaryl, -C(R 12c ) 2 -C 6 -ioaryl, -C(R 12c ) 2 -Ci- 9 heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2-9 heterocycloalkyl, -C(R 12c ) 2 -C 2-9 heterocycl
  • R 12c is independently selected from hydrogen and R 20k ;
  • X is C(R 3 ) or N
  • R 3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, C 2 - gheterocycloalkyl, C 6 -i 2 aryl, Ci-nheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15
  • each R 12 is independently selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -CH 2 -C 3 - locycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 2 aryl, -CH 2 -C 6 -i 2 aryl, -CH 2 -C 1 - nheteroaryl, and Ci-nheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -CH 2 -C 3 - locycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C
  • each R 22 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, C 2. dictcrocycloalkyl.
  • C 6 -i 2 aryl, and Ci-nheteroaryl each R 23 is independently selected from H and Ci- 6 alkyl; each R 24 is independently selected from H and Ci- 6 alkyl; each R 25 is independently selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, C 2. siheterocycloalkyl, C 6 -i 2 aryl, and Ci-nheteroaryl; and indicates a single or double bond such that all valences are satisfied.
  • W is C(O), S(O), or S(0) 2 ;
  • V is C(R 16 ) or N;
  • R 10 is -L 7 -R 7 ;
  • L 7 is a bond, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(O)-, -S(0) 2 N(R 14 )-, -
  • Ci-Cealkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R 20a ;
  • R 7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R 1 , optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 ; two substituents selected from R 1 , R 4 , and R 6 that are bonded to the same or adjacent atoms are optionally joined to form a 3-12 membered cycloalkyl, 3-12 membered heterocycl
  • R 6 is -L 2 -R 5 ; each L 2 is independently selected from a bond, Ci-Cealkyl, -0-, -N(R 14 )-, -C(O)-, -N(R 14 )C(0)-, -C(0)N(R 14 )-, - S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, -OCON(R 14 )-, - N(R 14 )C(0)0-, and -N(R 14 )C(0)N(R 14 )-; each R 5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
  • R 8 is selected from halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, i 2 aryl, Ci-nheteroaiyl, -OR 12 , -SR 12 , -N(H)(R 12 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , -C(0)N(R 12 )(R 13 ), - C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15 , -S(0) 2 R
  • R 17 is -lA-R 19 ;
  • L 1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R 14 )-, -C(0)-, -N(R 14 )C(0)-, - C(0)N(R 14 )-, -S-, -S(0) 2 -, -S(0)-, -S(0) 2 N(R 14 )-, -S(0)N(R 14 )-, -N(R 14 )S(0)-, -N(R 14 )S(0) 2 -, - OCON(R 14 )-, -N(R 14 )C(0)0-, N(R le ), C(0)N(R lc ), S(0) 2 N(R lc ), S(0)N(R lc ), C(R lf )(R lg )0, C(R lf )(R lg )N(R lc ), and C(R
  • R le , R lf , and R lg are independently selected from hydrogen, halogen, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, Gs-naryl, Ci-nheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), - C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , - S(0)R 15 , -0C(0)R 15 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12
  • R 19 is selected from a C 3 -i 2 cycloalkyl, C 2 -nheterocycloalkyl, C 6 -i 2 aryl, and C 2 -i 2 heteroaryl, wherein the C 3 - ncycloalkyl, C 2 -iiheterocycloalkyl, C 6 -i 2 aryl, and C 2 -i 2 heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R 11 ; each R 11 is independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - locycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 2 aryl, Ci-nheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12
  • R 16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, C 2 - gheterocycloalkyl, C 6 -i 2 aryl, Ci-nheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R 15
  • R 12a is selected from Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2 - gheterocycloalkyl, -C(R 12c ) 2 -C 2-9 heterocyeloalkyl, C 6 -ioaryl, -C(R 12c ) 2 -C 6 -ioaryl, -C(R 12c ) 2 -Ci- 9 heteroaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2-9 heterocycloalkyl, -C(R 12c ) 2 -C 2-9 heterocycloal
  • R 12b is selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2 - gheterocycloalkyl, -C(R 12c ) 2 -C 2-9 heterocyeloalkyl, C 6 -ioaryl, -C(R 12c ) 2 -C 6 -ioaryl, -C(R 12c ) 2 -Ci- 9 heteroaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -C(R 12c ) 2 -C 3 -iocycloalkyl, C 2-9 heterocycloalkyl, -C(R 12c ) 2 -C 2-9 hetero
  • R 12c is independently selected from hydrogen and R 20k ;
  • X is C(R 3 ) or N
  • R 3 is selected from hydrogen, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, C 2 - gheterocycloalkyl, C 6 -i 2 aryl, Ci-nheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), - N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0)R 15 , -0C(0)R 15 , - C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)R
  • gheterocycloalkyl, C 6 -i 2 aryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R 20f ; each R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 201 , and R 20k is independently selected from halogen, oxo, -CN, G- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-iocycloalkyl, -CH 2 -C3-iocycloalkyl, C 2 -9heterocycloalkyl, -CH 2 -C 2.
  • one R 4 is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein;
  • one R 4 is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein;
  • W is C(O); V is C(R 17 ) and J is C(R 16 );
  • R 10 is -L 7 -R 7 ;
  • L 7 is a bond, -0-, or -N(R 14 )-;
  • R 7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more R 4 , and optionally substituted with one or more R 6 ; each R 4 is independently selected from halogen, oxo, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C 2 -9heterocycloalkyl, C 6 -i2aiyl, Ci-nheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R
  • naryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R 20a ;
  • one R 4 is optionally independently an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein;
  • R 6 is -L 2 -R 5 ; each L 2 is independently selected from a bond and -C(O)-; each R 5 is independently hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein; each R 5 is independently selected from hydrogen, halogen, oxo, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, C2-9heterocycloalkyl, Gs-naryl, Ci-nheteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , - 0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14
  • R 8 is selected from -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, and -C(0)R 12 , wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R 20c ;
  • R 17 is -LCR 19 ;
  • L 1 is a bond;
  • R 19 is selected from a C 6 -i 2 aryl and C 2 -i 2 heteroaryl, wherein the C 6 -i 2 aryl and C 2 -i 2 heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R 11 ; each R 11 is independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6 cycloalkyl, Cz-sheterocycloalkyl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(0)0R 12 , -C(0)R 12 , -C(0)N(R 12 )(R 13 ), and -N(R 14 )C(0)R 12 , wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6
  • R 16 is selected from hydrogen and halogen
  • R 2 is -0-R 12a ;
  • R 12a is -C(R 12c ) 2 -C 2-9 heterocycloalkyl, wherein -C(R 12c ) 2 -C 2-9 heterocyeloalkyl is optionally substituted with one, two, or three R 20d ;
  • R 12c is independently selected from hydrogen and Ci- 3 alkyl
  • X is C(R 3 ) orN
  • R 3 is selected from hydrogen and -CN; each R 12 is independently selected from hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -CH 2 -C 3 - locycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 2 aryl, -CH 2 -C 6 -i 2 aryl, -CH 2 -C 1 - nheteroaryl, and Ci-nheteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -CH 2 -C 3 - locycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 2 aryl, -CH 2 -C 6 -
  • each R 20a , R 20c , R 20d , R 20e , R 20f , and R 201 is independently selected from halogen, oxo, -CN, Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3 -iocycloalkyl, -CH 2 -C 3 -iocycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2 - gheterocycloalkyl, C 6 -i 2 aryl, -CH 2 -C 6

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Abstract

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

Description

FUSED HETEROARYL COMPOUNDS USEFUL AS ANTICANCER AGENTS
CROSS-REFERENCE
[0001] This application claims priority to U.S. Provisional Application Nos. 63/210,474 filed on June 14, 2021, 63/291,320 filed on December 17, 2021, and 63/313,132 filed on February 23, 2022, each of which is incorporated by reference in its entirety.
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. In particular, mutations in the Kirsten Ras oncogene (K-Ras) gene are one of the most frequent Ras mutations detected in human cancers including lung adenocarcinomas (LUADs) and pancreatic ductal adenocarcinoma (PD AC).
[0003] 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 draggable target. However, such therapeutic approach is still limiting, as the G12C mutation in Ras has a low prevalence rate (e.g., about 3% in PD AC) as compared to other known Ras mutations.
SUMMARY
[0004] In view of the foregoing, there remains a considerable need for a new design of therapeutics and diagnostics that can specifically target Ras mutants and/or associated proteins of Ras to reduce Ras pathway signaling. 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.
[0005] In an aspect is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O), S(O), or S(0)2;
V is C(R17) and J is C(R16), or V is C(R17) and J is N, or J is C(R17) and V is C(R16), or J is C(R17) and V is N;
R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, - N(R14)S(0)-, -N(R14)S(0)2-, Ci-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein Ci-Cealkyl, C2-C6alkenyl, and C2-C6alkynyl, are optionally substituted with one, two, or three R20a; R7 is a 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl, wherein the 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6; wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-iiheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R1 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3-i2cycloalkyl, - CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CH2-Ci-nheterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and Ci-nheteroaryl, wherein Chalky 1, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3-i2cycloalkyl, - CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CH2-Ci-nheterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R4 is independently selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), (e.g. wherein R4 is optionally an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R20a;
R6 is -L2-R5; each L2 is independently selected from a bond, Ci-Cealkyl, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, - S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, -N(R14)C(0)0-, and - N(R14)C(0)N(R14)-; each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), - N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), - CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C^alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20c;
R17 is -lA-R19;
L1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -
C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, - N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg); Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R201 R19 is selected from a C3-i2cycloalkyl (e.g., monocyclic, bicyclic, or polycyclic), C2-iiheterocycloalkyl (e.g., monocyclic, bicyclic, or polycyclic), C6-i2aryl (e.g., monocyclic, bicyclic, or polycyclic), and C2-i2heteroaryl (e.g., monocyclic, bicyclic, or polycyclic), wherein the C3-i2cycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2- nheteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20g;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)- , S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R12)(R13), - (Ci-C6alkyl)-R12b, -(C2-6alkenyl)-R12b, -(C2-6alkynyl)-R12b, -0-R12a, -N(R14)-R12b, -S-R12b, -(C3. iocycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(G5-ioaryl)-R12b, or -(Ci-9heteroaryl)-R12b, wherein said Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d;
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-G5-ioaryl, -CH2-Ci-9heteroaryl, and Ci-dictcroan l are optionally substituted with one, two, or three R20d;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, Ce-ioaryl, Ci-9heteroaiyl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), - N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), - CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three
£20b. each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-
6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R201 are each independently selected from halogen, oxo, -CN, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2. gheterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, Ci-gheteroaryl, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci-ehaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- siheterocycloalkyl, C6-ioaryl, and Ci-dictcroaryl: each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, Ce- ioaryl, and Ci-gheteroaryl; and indicates a single or double bond such that all valences are satisfied.
[0006] In embodiments, X is C(R3). In embodiments, X is N. In embodiments, J is C(R16) and V is C(R17). In embodiments, W is C(O).
[0007] In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure: , , , Formula (IA12). [0008] In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure:
[0009] In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure:
[0010] In embodiments, L7 is a bond. [0011] In embodiments, L7 is -NH-.
[0012] In embodiments, R7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6; and wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci- liheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci- nheteroaryl are optionally substituted with one, two, or three R20a.
[0013] In embodiments, C(R4)2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2; and X3 is selected from N, C, C(R6), and C(R4).
[0015] In embodiments, R16 is independently selected from hydrogen and halogen. In embodiments, R16 is independently selected from hydrogen and fluoro.
[0016] In embodiments, R8 is selected from Ci-6alkyl, C3-iocycloalkyl, and C2-s>heterocycloalkyl, wherein Ci-6alkyl, C3-iocycloalkyl, and C2-s>heterocycloalkyl are optionally substituted with one, two, or three R20c independently selected from halogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl. In embodiments, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
[0017] In embodiments, R3 is hydrogen or CN.
[0018] In embodiments, L1 is a bond. In embodiments, L1 is selected from a Ci-Cealkyl, C2-C6alkenyl, C2- Cealkynyl, -C(O)-, -NHC(O)-, -C(0)NH-, CH20, CH2NH, and CH2.
[0019] In embodiments, R19 is a monocyclic ring. In embodiments, R19 is a bicyclic ring system. In embodiments, R19 is a polycyclic ring system.
Q1, Q3, and Q5 are independently N or C(Rld);
Q4 and Q6 are independently O, S, C(Rla)(Rlb), or N(Rlc);
X4, X5, X6, X9, X10, X11, X12, and X16 are independently selected from C(Rla) or N;
X7 and X8 are independently selected from C(Rla), C(Rla)(Rlb), N, or N(Rlc);
X13 is selected from a bond, C(O), C(Rla)(Rlb), C(0)C(Rla)(Rlb), C(Rla)(Rlb)C(Rla)(Rlb), C(Rla)(Rlb)N(Rlc), and N(Rlc);
X14 and X15 are independently selected from a bond, C(O), C(Rla)(Rlb), and N(Rlc); each Rla, Rlb, Rld, Rlf, Rlg, and Rlh are each independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. -OR12, - SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, - S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, - CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, and Cj-dictcroaryl are optionally substituted with one, two, or three R201; or Rla and Rlb bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6-ioaryl ring, 5-12 membered heteroaryl ring, or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlh and one of Rla, Rlb, Rlc, and Rld bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, and C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201; and each Rlc is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, Ci-dictcroarvl. wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, and Cj-dictcroaryl are optionally substituted with one, two, or three R201.
[0023] In embodiments, each L2 is independently a bond.
[0024] In embodiments, each R5 is independently selected from:
unci m< when present, is 0. S , 2, or 3,
[0025] In embodiments, R4 is independently -C(0)R15. In embodiments, R4 is independently -C(0)R15 and the R15 is independently selected from C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, and CiActcroaryl. wherein C2. 6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, and CiAeteroaryl are optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and the R15 is independently C2-6alkenyl, wherein C2-6alkenyl is optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and the R15 is independently C2-9heterocycloalkyl, wherein C2-9heterocycloalkyl is optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and the R15 is independently CiAeteroaryl, wherein Ci- gheteroaryl is optionally substituted with one, two, or three R20f. In embodiments, R4 is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein.
[0026] In an aspect is provided a compound having the formula A-LAB-E> 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.
[0027] 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, TRIP 12, 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-RBX 1 -DDB 1 -CRBN (CRL4CRBN) ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBX04, FBX031, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885. [0028] The compound of claim 74 wherein 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, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.
[0029] In embodiments, LAB is -LAB1-LAB2-LAB3-LAB4-LAB5-; LAB I. IT02. Lab\ LAB and LABS are independently a bond, -O-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, - N(R14)S(0)-, -N(R14)S(0)2-, Ci-6alkylene, (-0-Ci-6alkyl)z-, (-Ci-6alkyl-0)z-, C2-6alkenylene, C2-6alkynylene, Ci- 6haloalkylene, C3-i2cycloalkylene, Ci-nheterocycloalkylene, C6-i2arylene, or Ci-nheteroarylene, wherein Ci- 6alkylene, C2-6alkenylene, C2-6alkynylene, Ci-6haloalkylene, C3-i2cycloalkylene, Ci-nheterocycloalkylene, G,. narylene, or Ci-nheteroarylene, are optionally substituted with one, two, or three R20j; wherein each Ci-6alkyl of (-0-Ci-6alkyl)z- and (-Ci-6alkyl-0)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, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, G- 6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2- Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -QB-Ci-gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20f; each R20d, R20e, R20f, and R20j are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, Ci-9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3. 6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2- Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; and each R25 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- gheteroaryl. In embodiments, LAB is -(0-C2alkyl)z- and z is an integer from 1 to 10. In embodiments, LAB is -(C2alkyl-0-)z- and z is an integer from 1 to 10. In embodiments, LAB is -(CH2)ZILAB2(CH20)Z2-, wherein LAli2 is a bond, a 5 or 6 membered heterocycloalkylene or heteroarylene, phenylene, -(C2-
C4)alkynylene, -SO2- or -NH-; and zl and z2 are independently an integer from 0 to 10. In embodiments, LAB is -(CH2)zi(CH20)z2-, wherein zl and z2 are each independently an integer from 0 to 10. In embodiments, LAB is a PEG linker. In embodiments, B is a monovalent form of a compound selected from
[0030] In an aspect is provided a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
[0031] In an aspect is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.
[0032] In an aspect is provided a method of modulating activity of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.
[0033] In embodiments, the method includes administering an additional agent or therapy.
[0034] In an aspect is provided a method of inhibiting cell growth, comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells.
[0035] In embodiments, the method includes administering an additional agent to said cell.
[0036] In some embodiments, the additional agent comprises (1) an inhibitor of MEK; (2) an inhibitor of epidermal growth factor receptor (EGFR) and/or of mutants thereof; (3) an immunotherapeutic agent; (4) a taxane; (5) an anti-metabolite; (6) an inhibitor of FGFR1 and/or FGFR2 and/or FGFR3 and/or of mutants thereof; (7) a mitotic kinase inhibitor; (8) an anti-angiogenic drag; (9) a topoisomerase inhibitor; (10) a platinum-containing compound; (12) an inhibitor of c-MET and/or of mutants thereof; (13) an inhibitor of BCR-ABL and/or of mutants thereof; (14) an inhibitor of ErbB2 (Her2) and/or of mutants thereof; (15) an inhibitor of AXL and/or of mutants thereof; (16) an inhibitor of NTRK1 and/or of mutants thereof; (17) an inhibitor of RET and/or of mutants thereof; (18) an inhibitor of A-Raf and or B-Raf and/or C-Raf and/or of mutants thereof; (19) an inhibitor of ERK and/or of mutants thereof; (20) anMDM2 inhibitor; (21) an inhibitor of mTOR; (23) an inhibitor of IGF 1/2 and/or of IGF1-R; (24) an inhibitor of CDK9; (25) an inhibitor of famesyl transferase; (26) an inhibitor of SHIP pathway; (27) an inhibitor of SRC; (28) an inhibitor of JAK; (29) a PARP inhibitor, (31) a ROS1 inhibitor; (32) an inhibitor of SHP pathway, or (33) an inhibitor of Src, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl or AKT; (34) an inhibitor of KrasG12C mutant; (35) a SHC inhibitor (e.g., PP2, AID371185); (36) a GAB inhibitor; (38) a PI-3 kinase inhibitor; (39) a MARPK inhibitor; (40) a CDK4/6 inhibitor; (41) a MAPK inhibitor; (42) a SHP2 inhibitor; (43) a checkpoint immune blockade agent; (44) a SOS1 inhibitor; or (45) a SOS2 inhibitor. In some embodiments, the additional agent comprises an inhibitor of SHP2 selected from RMC-4630, TN0155, JAB-3068, IACS-13909/BBP-398, SHP099, ERAS-601, and RMC-4550. In some embodiments, the additional agent comprises an inhibitor of SOS selected from RMC-5845, BI-3406, BI-1701963, MRTX0902, and BAY 293. In some embodiments, the additional agent comprises an inhibitor of EGFR selected from afatinib, erlotinib, gefitinib, lapatinib, cetuximab panitumumab, osimertinib, olmutinib, and EGF-816. In some embodiments, the additional agent comprises an inhibitor of MEK selected from trametinib, cobimetinib, binimetinib, selumetinib, refametinib, and AZD6244. In some embodiments, the additional agent comprises an inhibitor of ERK selected from ulixertinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, and ravoxertinib. In some embodiments, the additional agent comprises an inhibitor of CDK4/6 selected from palbociclib, ribociclib, and abemaciclib. In some embodiments, the additional agent comprises an inhibitor of BRAF selected from sorafenib, vemurafenib, dabrafenib, encorafenib, regorafenib, and GDC-879.
[0037] In an aspect is provided a Ras protein bound by a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein activity of said Ras protein is reduced as compared to a Ras protein unbound to said compound.
[0038] In an aspect is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O), S(O), or S(0)2;
V is C(R17) and J is C(R16), or V is C(R17) and J is N, or J is C(R17) and V is C(R16), or J is C(R17) and V is N;
R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -
S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein Ci-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl, are optionally substituted with one, two, or three R20a;
R7 is a 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl, wherein the 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl are optionally substituted with one or more R1, one or more R4, or one or more R6; wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R1 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3- ncycloalkyl, -CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CH2-Ci-nheterocycloalkyl, C6-i2aryl, -CH2-C6- naryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3-i2cycloalkyl, -CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CH2-Ci-nheterocycloalkyl, C6-i2aryl, -CH2- C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R4 is independently selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20a;
R6 is -L2-R5; each L2 is independently selected from a bond, Ci-Cealkyl, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, - S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, - N(R14)C(0)0-, and -N(R14)C(0)N(R14)-; each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20c;
R17 is -LkR19;
L1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, - C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, - OCON(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg);
Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), - C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-dictcroaiyl. wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201
R19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the G- ncycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, G- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, G- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20g;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, - CH2S(0)2N(R12)(R13), -(Ci-C6alkyl)-R12b, -(C2-6alkenyl)-R12b, -(C2-6alkynyl)-R12b, -0-R12a, -N(R14)-R12b, - S-R12b, -(C3-iocycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-ioaryl)-R12b, or -(Ci-9heteroaryl)-R12b, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CEC-Ci-gheteroaryl, and Ci- gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CEC-Ci-gheteroaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
X is C(R3) or N; R3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-yhctcroan l. -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-<)hctcroan l are optionally substituted with one, two, or three R20b; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R201 are each independently selected from halogen, -CN, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, Ci-gheteroaryl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), - 0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; and indicates a single or double bond such that all valences are satisfied. [0039] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is C(R3). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is N. [0040] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
V is C(R16) and J is C(R17). In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is N and J is C(R17). In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, J is N and V is C(R17). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, J is C(R16) and V is C(R17). In lurther embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is C(O). In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(O). In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(0)2.
[0041] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure:
Formula (IA2), Formula (IA4), , Al 2).
[0042] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure: ), , 12).
[0043] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is a bond. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is -NH-.
[0044] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R1, one or more R4, or one or more R6; and wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci- liheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a.
[0045] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 C(R4)(R6)C=N-OR4, CH2C=NN(R4)(R6), C(R4)(R6)C(0)N(R4), C(R4)(R6)N(R4), C(R4)(R6)N(R6), C(R4)(R6)0, C(R4)(R6)OC(R4)(R6), C(R4)(R6)S, C(R4)(R6)SC(R4)(R6), C(R4)(R6)S(0), C(R4)(R6)S(0)C(R4)(R6), C(R4)(R6)S(0)2C(R4)(R6), C(R4)(R6)S(=0)(=NR4), C(R4)(R6)S(0)2N(R4), C(R4)(R6)N(R4)S(0)N(R4), C(R4)(R6)N(R4)S(0)2N(R4), C(R4)(R6)S(0)N(R4), C(R4)(R6)0C(0)N(R4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(R4)(R4)N(R4)C(0)N(R4), C(R4)(R4)S(0)2, C=NN(R4)(R4)C(R4)(R4), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R4)(R4), S(0)N(R4)C(R4)(R4), and 0C(0)N(R4)C(R4)(R4);
X2 is selected from N, C, C(R6), C(R4), CH, N(R4), N(R4), N(R6), O, S, S(O), C(H)(R6), C(R4)2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2; and X3 is selected from N, C, C(R6), and C(R4).
[0046] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is
[0047] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is integer from 0 to 12.
[0048] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7
[0049] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
[0050] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3- 6cycloalkyl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl are optionally substituted with one, two, or three R20g. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen and halogen. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen and fluoro.
[0051] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaiyl, -OR12, -SR12, -N(H)(R12), -C(0)OR12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), - N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -
CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-
6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20c. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from Ci-6alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl, wherein Ci-6alkyl, C3-iocycloalkyl, and C2- gheterocycloalkyl are optionally substituted with one, two, or three R20c independently selected from halogen, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
[0052] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen or CN. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen.
[0053] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L1 is a bond. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L1 is selected from a Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C(O)-, -NHC(O)-, -C(0)NH-, CH20, CH2NH, and CH2.
[0054] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
R19 is a monocyclic ring. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a bicyclic ring system. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a polycyclic ring system. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is:
Q1, Q3, and Q5 are independently N or C(Rld);
Q4 and Q6 are independently O, S, C(Rla)(Rlb), or N(Rlc);
X4, X5, X6, X9, X10, X11, and X12 are independently selected from C(Rla) or N;
X7 and X8 are independently selected from C(Rla), C(Rla)(Rlb), N, or N(Rlc); each Rla, Rlb, Rld, and Rlh are each independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroaiyl. -OR12, -SR12, -N(R12)(R13), - C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201; or Rla and Rlb bonded to the same carbon are joined to form a 3- 10 membered heterocycloalkyl ring or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3- locycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6-ioaryl ring, 5-12 membered heteroaryl ring, or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlh and one of Rla, Rlb, Rlc, and Rld bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, and C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; and each Rlc is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, Ci-dictcroaiyl. wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, and Cj-dictcroaryl are optionally substituted with one, two, or three R201.
[0055] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
[0056] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R2 is [0057] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, each R5 is independently selected from:
[0058] In an aspect is provided a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof: wherein W is C(O), S(O), or S(0)2;
V is C(R16) or N;
R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -
S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein Ci-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl, are optionally substituted with one, two, or three R20a;
R7 is a 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl are optionally substituted with one or more R1, one or more R4, or one or more R6; two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3- i2cycloalkyl. Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R1 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3- i2cycloalkyl. -CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CH2-Ci-nheterocycloalkyl, C6-i2aryl, -CH2-C6- i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3-i2cycloalkyl, -CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CH2-Ci-nheterocycloalkyl, C6-i2aryl, -CH2- C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R4 is independently selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroaiyl. -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20a;
R6 is -L2-R5; each L2 is independently selected from a bond, G-Galkyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, - S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, - N(R14)C(0)0-, and -N(R14)C(0)N(R14)-; each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20c;
R17 is -G-R19;
L1 is selected from a bond, G-Galkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, - C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, - OCON(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg);
Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. -OR12, -SR12, -N(R12)(R13), - C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-dictcroarvl are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201
R19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3- i2cycloalkyl. C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20g;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, - CH2S(0)2N(R12)(R13), -(Ci-C6alkyl)-R12b, -(C2.6alkenyl)-R12b, -(C2-6alkynyl)-R12b, -0-R12a, -N(R14)-R12b, - S-R12b, -(C3-iocycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-ioaryl)-R12b, or -(Ci-9heteroaryl)-R12b, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- yhctcroan l. wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20b; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R201 are each independently selected from halogen, -CN, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, Ci-gheteroaryl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), - 0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-yhctcroan l: each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-dictcroarvl: each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; and indicates a single or double bond such that all valences are satisfied.
[0059] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is C(R3). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is N. [0060] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is C(R16). In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is N.
[0061] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
W is C(O). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(O). In lurther embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(0)2.
[0062] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure: , Formula Formula (IIA9), Formula (IIA10), Formula (IIA11), or Formula (IIA12).
[0063] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is a bond. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is -NH-.
[0064] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R1, one or more R4, or one or more R6; and wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci- liheterocycloalkyl, C6-i2aryl, or Ci-iiheteroaryl, wherein the C3-i2cycloalkyl, Ci-iiheterocycloalkyl, C6-i2aryl, or Ci- nheteroaryl are optionally substituted with one, two, or three R20a.
[0065] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, p is an integer from 0 to 12;
X1 is selected from CH2, C(R4)(R6), C=N-OR4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), O, S, S(O), S(=0)(=NR4), S(0)2N(R4), N(R4)S(0)N(R4), N(R4)S(0)2N(R4), S(0)N(R4), 0C(0)N(R4), N(R4)C(0)N(R4), S(0)2,
CH2C(R4)(R6), CH2C(R4)(R6)CH2, C(R4)(R6)C(R4)(R6)C(R4)(R6), C(R4)(R6)C=N-OR4, CH2C=NN(R4)(R6), C(R4)(R6)C(0)N(R4), C(R4)(R6)N(R4), C(R4)(R6)N(R6), C(R4)(R6)0, C(R4)(R6)OC(R4)(R6), C(R4)(R6)S, C(R4)(R6)SC(R4)(R6), C(R4)(R6)S(0), C(R4)(R6)S(0)C(R4)(R6), C(R4)(R6)S(0)2C(R4)(R6), C(R4)(R6)S(=0)(=NR4), C(R4)(R6)S(0)2N(R4), C(R4)(R6)N(R4)S(0)N(R4), C(R4)(R6)N(R4)S(0)2N(R4), C(R4)(R6)S(0)N(R4), C(R4)(R6)0C(0)N(R4), C(R4)(R6)N(R4)C(0)N(R4), C(R4)(R6)S(0)2, C=NN(R4)(R6)C(R4)(R6),
C(0)N(R4)C(R4)(R6), S(0)2N(R4)C(R4)(R6), S(0)N(R4)C(R4)(R6), 0C(0)N(R4)C(R4)(R6), C(R4)(R4), C=N-OR4, C=NN(R4)(R4), CH2C(R4)(R4), CH2C(R4)(R4)CH2, C(R4)(R4)C(R4)(R6)C(R4)(R4), C(R4)(R4)C(R4)(R4)C(R4)(R4), C(R4)(R4)C=N-OR4, CH2C=NN(R4)(R4), C(R4)(R4)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0, C(R4)(R4)OC(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(R4), C(R4)(R4)S(0), C(R4)(R4)S(0)C(R4)(R4), C(R4)(R4)S(0)2C(R4)(R4), C(R4)(R4)S(=0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(R4)(R4)N(R4)C(0)N(R4), C(R4)(R4)S(0)2, C=NN(R4)(R4)C(R4)(R4), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R4)(R4), S(0)N(R4)C(R4)(R4), and 0C(0)N(R4)C(R4)(R4);
X2 is selected from N, C, C(R6), C(R4), CH, N(R'). N(R4), N(R6), O, S, S(O), C(H)(R6), C(R4)2, CH2, C(R4)(R6),
S(=0)(=NR4), S(0)2; and
X3 is selected from N, C, C(R6), and C(R4).
[0066] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7
[0067] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 integer from 0 to 12. [0068] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
[0069] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7
[0070] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl are optionally substituted with one, two, or three R20g. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen and halogen. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen and fluoro.
[0071] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaiyl, -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), - N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), - CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C^alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20c. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from Ci-6alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl, wherein Ci-6alkyl, C3-iocycloalkyl, and C2- gheterocycloalkyl are optionally substituted with one, two, or three R20c independently selected from halogen, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, oxetanylmethyl, and oxetanyl. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
[0072] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen or CN. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen.
[0073] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L1 is a bond. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L1 is selected from a Ci-Cealkyl, C2-C6alkenyl, C2-Cealkynyl, -C(O)-, -NHC(O)-, -C(0)NH-, CH20, CH2NH, and CH2.
[0074] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic ring. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a bicyclic ring system. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a polycyclic ring system. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is:
Q1, Q3, and Q5 are independently N or C(Rld);
Q4 and Q6 are independently O, S, C(Rla)(Rlb), or N(Rlc);
X4, X5, X6, X9, X10, X11, and X12 are independently selected from C(Rla) or N;
X7 and X8 are independently selected from C(Rla), C(Rla)(Rlb), N, or N(Rlc); each Rla, Rlb, Rld, and Rlh are each independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroaiyl. -OR12, -SR12, -N(R12)(R13), - C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201; or Rla and Rlb bonded to the same carbon are joined to form a 3- 10 membered heterocycloalkyl ring or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3- locycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6-ioaryl ring, 5-12 membered heteroaryl ring, or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlh and one of Rla, Rlb, Rlc, and Rld bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, and C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; and each Rlc is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, Ci-dictcroaiyl. wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- siheterocycloalkyl, C6-ioaryl, and Cj-dictcroaryl are optionally substituted with one, two, or three R201.
[0075] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is: [0076] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R2
[0077] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, each R5 is independently selected from:
[0078] In an aspect is provided a compound having the formula A-LAB-E> wherein
A is a monovalent form of a compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; LAB is a covalent linker bonded to A and B; and B is a monovalent form of a degradation enhancer.
[0079] In an aspect is provided a compound having the formula A-LAB-E> wherein
A is a monovalent form of a compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, F, IF, I”, II”, 1-1, 1-r, 1-1”, I-G”, 1-3, 1-4, II-l, XVI, XVII, XVIII, or XIX; I 3 is a covalent linker bonded to A and B; and B is a monovalent form of a degradation enhancer. [0080] 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, SMURF 1, SMURF2, STUB1, TOPORS, TRIP 12, 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-RBX 1 -DDB 1 -CRBN (CRL4CRBN) ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBX04, FBX031, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885. [0081] 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, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.
[0082] In embodiments LAB is -LAB I-LAB1-LAB,-LAB I-LAB5-: independently a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, - )N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-6alkylene, (-0-Ci.6alkyl)z-, (-Ci_ 6alkyl-0)z-, C2-6alkenylene, C2-6alkynylene, Ci-6haloalkylene, C3-i2cycloalkylene, Ci-iiheterocycloalkylene, G,. i2arylene, or Ci-iiheteroarylene, wherein Ci-6alkylene, C2-6alkenylene, C2-6alkynylene, Ci-6haloalkylene, G- i2cycloalkylene, Ci-iiheterocycloalkylene, C6-i2arylene, or Ci-nheteroarylene,are optionally substituted with one, two, or three R20j; wherein each Ci-6alkyl of (-0-Ci-6alkyl)z- and (-Ci-6alkyl-0)z- is optionally substituted with one, two, or three R20·': z is independently an integer from 0 to 10; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-G- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and CiHictcroarvl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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
R20e; each are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6c loalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, - CH2- roaiyl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0) 0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2.
6alkenyl, CXalkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, G,. ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and GAeteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, CXalkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, - SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, CXalkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; and each R25 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and G- gheteroaryl.
[0083] In embodiments, LAB is -(0-C2alkyl)z- and z is an integer from 1 to 10.
[0084] In embodiments, LAB is -(C2alkyl-0-)z- and z is an integer from 1 to 10.
[0085] In embodiments, LAB is -(CH2)ZILAB2(CH20)z2-, wherein LAli2 is a bond, a 5 or 6 membered heterocycloalkylene or heteroarylene, phenylene, -(C2-C4)alkynylene, -S02- or -NH-; and zl and z2 are independently an integer from 0 to 10.
[0086] In embodiments, LAB is -(CH2)ZI(CH20)/2-. wherein zl and z2 are each independently an integer from 0 to 10.
[0087] In embodiments, LAB is a PEG linker (e.g., divalent linker of 1 to 10 ethylene glycol subunits).
[0088] In embodiments, B is a monovalent form of a compound selected from
[0089] In an aspect is provided a pharmaceutical composition comprising a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula G, IF, I”, II”, 1-1, 1-G, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
[0090] In an aspect is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, 1 A3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, II A 11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-F, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof.
[0091] In an aspect is provided a method of modulating activity of a Ras (e.g., K-Ras) protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, 1 A3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-r, 1-1”, I-G”, 1-3, 1-4, II-l, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras (e.g., K-Ras) protein.
[0092] In some embodiments, the subject method comprises administering an additional agent or therapy.
[0093] In an aspect is provided a method of inhibiting cell growth, comprising administering an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-G, 1-1”, I-F”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras (e.g., K- Ras) protein, thereby inhibiting growth of said cells. In embodiments, the subject method comprises administering an additional agent to said cell.
[0094] In an aspect is provided a Ras (e.g., K-Ras) protein bound by a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-G, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein activity of said Ras (e.g., K-Ras) protein is reduced as compared to a Ras (e.g., K-Ras) protein unbound to said compound. INCORPORATION BY REFERENCE
[0095] 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
[0096] 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)).
[0097] 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.
[0098] 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.
[0099] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
[00100] 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.
[00101] 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. [00102] 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.
[00103] As used herein, Ci-Cx includes C1-C2, C1-C3 . . . Ci-Cx. Ci-Cx refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).
[00104] 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 18, 1 to 12, 1 to 10, 1 to 8, or 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 “Ci-Cealkyl” or similar designations. By way of example only, “Ci-Cealkyl” 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, neopentyl, 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).
[00105] An “alkoxy” refers to a “-O-alkyl” group, where alkyl is as defined herein.
[00106] 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)2and-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).
[00107] 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 -CºCH, -CºCCH3, -CºCCH2CH3 and -CºCCH2CH2CH3. 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).
[00108] “Amino” refers to a -NH2 group.
[00109] 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=l 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.
[00110] The term “aromatic” refers to a planar ring having a delocalized p-electron system containing 4n+2 p 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).
[00111] As used herein, the term “aryl” refers to a monocyclic aromatic ring wherein each of the atoms forming the ring is a carbon atom (e.g., phenyl) or a polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is carbocyclic and aromatic, 2) a bond to the remainder of the compound is directly bonded to a carbocyclic aromatic ring of the aryl ring system, and 3) the carbocyclic aromatic ring of the aryl ring system of 2) is not directly bonded (e.g., fused) to a heteroaryl ring in the polycyclic ring system. 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). As used herein, the aryl radical is a monocyclic, bicyclic, or tricyclic ring system. In embodiments, an aryl is a monocyclic ring. In embodiments, an aryl is a fused ring polycyclic system. In embodiments, an aryl is a bridged ring polycyclic system. In some embodiments the aryl is a “fused ring aryl” wherein the aryl ring is fused with a cycloalkyl or a heterocycloalkyl ring.
[00112] “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 acid include, but are not limited to, and the like.
[00113] The term “cycloalkyl” refers to a monocyclic carbocyclic saturated or partially unsaturated non-aromatic ring or a polycyclic carbocyclic (i.e., does not include heteroatom(s)) ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is carbocyclic saturated or partially unsaturated and non-aromatic, 2) a bond to the remainder of the compound is directly bonded to a carbocyclic saturated or partially unsaturated non-aromatic ring of the ring system, and 3) the carbocyclic saturated or partially unsaturated non-aromatic ring of the ring system of 2) is not directly bonded (e.g., fused or spirocyclic) to a heterocycloalkyl ring in the polycyclic ring system. Cycloalkyls may be saturated or partially unsaturated. In some embodiments, a cycloalkyl ring is a spirocyclic cycloalkyl ring. In embodiments, a cycloalkyl is a monocyclic ring. In embodiments, a cycloalkyl is a fused ring polycyclic system. In embodiments, a cycloalkyl is a bridged ring polycyclic system. In embodiments, a cycloalkyl is a spirocyclic polycyclic ring system. 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). [00114] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an monocyclic aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur; or a polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is aromatic and includes one or more heteroatoms selected from nitrogen, oxygen and sulfur and 2) a bond to the remainder of the compound is directly bonded to an aromatic ring including one or more heteroatoms selected from nitrogen, oxygen and sulfur or an aromatic ring directly bonded (e.g., fused) to an aromatic ring including one or more heteroatoms selected from nitrogen, oxygen and sulfur, of the aryl ring system. As used herein, the heteroaryl radical may be a monocyclic, bicyclic, or tricyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated (i.e., aromatic) and includes a heteroatom. In embodiments, a heteroaryl is a monocyclic ring. In embodiments, a heteroaryl is a fused ring polycyclic system. In embodiments, a heteroaryl is a bridged ring polycyclic system. In some embodiments is a “fused ring heteroaryl” wherein the heteroaryl ring is fused with a cycloalkyl, aryl, or heterocycloalkyl ring. An Y-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).
[00115] A “heterocycloalkyl” group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom of a saturated or partially unsaturated non-aromatic ring is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur. A heterocycloalkyl refers to a monocyclic saturated or partially unsaturated nonaromatic ring including one or more heteroatoms or a polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is saturated or partially unsaturated, non-aromatic, and includes one or more heteroatoms and 2) a bond to the remainder of the compound is directly bonded to a ring of the ring system that is a saturated or partially unsaturated and non-aromatic ring that includes one or more heteroatoms or a non-aromatic ring directly bonded (e.g., fused) to a saturated or partially unsaturated and non-aromatic ring that includes one or more heteroatoms of the ring system. Heterocycloalkyls may be saturated or partially unsaturated. 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 embodiments, a heterocycloalkyl is a monocyclic ring. In embodiments, a heterocycloalkyl is a fused ring polycyclic system. In embodiments, a heterocycloalkyl is a bridged ring polycyclic system. In embodiments, a heterocycloalkyl is a spirocyclic polycyclic ring system. Unless otherwise noted, heterocycloalkyls have from 2 to 13 carbons in the ring or ring system. 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).
[00116] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo.
[00117] The abbreviations “Fmoc”, “Ac”, “Bn”, “PMB”, “Tr”, “Ts”, “Boc”, and “Cbz” are used in accordance with their well understood common meanings in Chemistry and mean the monovalent chemical substituents fluorenylmethyloxycarbonyl, acetyl, benzyl, p-methoxybenzyl, trityl or triphenylmethyl, tosyl, tert- butyloxycarbonyl, and carbobenzyloxy, respectively.
[00118] The term “haloalkyl” 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, -CF , -CHF2, - CH2CF3, -CF2CF3, and the like.
[00119] 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.
[00120] The term “heteroalky lene linker” refers to a divalent 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. In some embodiments, the heteroatom(s) may be placed at any interior position of the heteroalkyl group. In some embodiments, the heteroatom(s) may be placed at one or both terminal positions of the heteroalkylene linker (i.e., position(s) directly bonded to portion(s) of the molecule other than the heteroalkylene linker). Examples include, but are not limited to, -CH2-0-CH2-, -CH2-CH2-0-CH2-, -CH2-NH-CH2-, -CH2-CH2-NH-CH2-, -CH2- N(CH3)-CH2-, -CH2-CH2-N(CH3)-CH2-, -CH2-S-CH2-CH2-, -CH2-CH2-S(0)-CH2-, -CH2-CH2-S(0)2-CH2-, -CH2- NH-O-CHz-, -CH2-0-Si(CH3)2-, -CH2-CH=N-0-CH2-, and -CH=CH-N(CH3)-CH2-. Examples include, but are not limited to, -CH2-0-, -CH2-CH2-0-, -CH2-NH-, -CH2-CH2-NH-, -CH2-N(CH3)-, -CH2-CH2-N(CH3)-, -CH2-S-, -CH2- CH2-S-, -CH2-CH2-S(0)-, -CH2-CH2-S(0)2-, -CH2-S(0)-, -CH2-S(0)2-, -CH2-CH2-CH2-S(0)-, -CH2-CH2-CH2- S(0)2-, -CH2-CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH2-CH2-CH2-S-, -CH2-CH2-CH2-S-, -CH2-CH2-CH2-NH-, -CH2-
CH2-CH2-NH-, -CH2-CH2-CH2-N(CH3)-, -CH2-CH2-CH2-N(CH3)-, -CH2-NH-0-, -0-Si(CH3)2-, -CH2-CH=N-O-, and -CH=CH-N(CH3)-. Examples include, but are not limited to, -0-CH2-, -0-CH2-CH2-, -NH-CH2-, -NH-CH2- CH2-, -N(CH3)-CH2-, -N(CH3)-CH2-CH2-, -S-CH2-, -S-CH2-CH2-, -S(0)-CH2-CH2-, -S(0)2-CH2-CH2-, -S(0)-CH2-, -S(0)2-CH2-, -S(0)-CH2-CH2-CH2-, -S(0)2-CH2-CH2-CH2-, -O-CH2-CH2-CH2-, -O-CH2-CH2-CH2-, -S-CH2-CH2- CH2-, -S-CH2-CH2-CH2-, -NH-CH2-CH2-CH2-, -NH-CH2-CH2-CH2-, -N(CH3)-CH2-CH2-CH2-, -N(CH3)-CH2-CH2- CH2-, -0-NH-CH2-, -Si(CH3)2-0-, -0-N=CH-CH2-, and -N(CH3)-CH=CH-. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-0- and -0-Si(CH3)2-. Examples include, but are not limited to, -P(0)(CH3)-CH2-, -P(0)(CH3)-CH2-CH2-, -P(0)(CH3)-CH2-CH2-CH2-,-CH2-P(0)(CH3)-, -CH2-CH2-P(0)(CH3)-, and -CH2-CH2-CH2-P(0)(CH3)-. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-0- and -0-Si(CH3)2-. A“heteroalkylene linker” may have from 2 to 4 main chain atoms unless specified otherwise.
[00121] 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, -CH2-0-CH3, -CH2-CH2-0-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(0)-CH3, -CH2-CH2-S(0)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 -CH2-0-Si(CH3)3. Excluding the number of heteroatoms, a “heteroalkyl” may have from 1 to 6 carbon atoms.
[00122] The term "oxo" refers to the =0 radical.
[00123] 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.
[00124] 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.
[00125] The suffix “-di-yl” will be understood to mean the substituent or linker is a divalent substituent or linker. [00126] As used herein, the substituent “R” appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.
[00127] "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.
[00128] The term “optionally substituted” or “substituted” means, unless otherwise specified, 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, Ci-C6alkylalkyne, halo, acyl, acyloxy, -CO2H, -C02-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, -0-, -C(=0)-, -S-, -S(=0)-, -S(=0)2-, -NH-, -NHC(O)-, -C(0)NH-, S(=0)2NH-, -NHS(=0)2, -0C(0)NH-, -NHC(0)0-, -(CI-C6 alkyl)-, or -(C2-C6alkenyl)-; and each Rs is independently selected from among H, (Ci-Cealkyl), (C3-Cscycloalkyl), aryl, heteroaryl, heterocycloalkyl, and Ci- Ceheteroalkyl. The protecting groups that may form the protective derivatives of the above substituents are found in sources such as Greene and Wuts, above.
[00129] "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.
[00130] "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, trifluoroacetates, 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 alginates, gluconates, and galacturonates (see, for example, Beige S.M. etal., "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.
[00131] "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, Y, \ -dibcnzylcthylcncdiaminc. chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, Y-mcthylglucaminc. glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine,
Y-cthylpipcridinc. polyamine resins and the like. See Berge et al., supra.
[00132] 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.
[00133] 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 deoxy ribonucleotides 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.
[00134] 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 eukaryotic cell.
[00135] 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.
[00136] 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.
[00137] 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).
[00138] 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.
[00139] The term in vivo ” refers to an event that takes place in a subject’s body.
[00140] 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. [00141] 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 ran 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.
[00142] 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 (also used interchangeably herein as K-Ras, K-ras, 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.
[00143] 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 lurther 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).
[00144] indicates the location of attachment (e.g., location of a bond to another atom) of the depicted chemical formula or atom to a substituent, a further component of a molecule, or an atom. may equivalently be located at the end of a bond or overlapping a bond.
[00145] The term "corresponds" or “corresponding” as used herein to refer to an amino acid or protein residue shall be understood to mean that the selected residue occupies the same essential structural position within the protein as the given residue. The essentially same structural position within the protein may be within the three dimensional conformation of the folded protein or may be the location of the residue in the primary sequence of the protein. For example, a selected residue in a protein corresponds to Cysl2 of a human Ras (e.g., human K-Ras) protein when the selected residue occupies the same essential spatial or other structural position as Cysl2 in the human Ras (e.g., human K-Ras) protein. In some embodiments, where a selected protein is aligned for maximum homology with the human Ras (e.g., human K-Ras) protein, the position in the aligned selected protein aligning with Cysl2 is said to correspond to Cysl2. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the human K-Ras protein and the overall structures compared. In this case, an amino acid that occupies the same essential position as Cysl2 in the structural model is said to correspond to the Cysl2 residue. For example, a selected residue in a protein corresponds to Cysl3 of a human Ras (e.g., human K-Rasa) protein when the selected residue occupies the same essential spatial or other structural position as Cysl3 in a human Ras (e.g., human K-Ras) protein, similar to the example of Cysl2 above.
[00146] In embodiments, a C3-iocycloalkyl is a 3 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 4 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 5 membered cycloalkyl. In embodiments, a C3- locycloalkyl is a 6 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 7 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 8 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 9 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 10 membered cycloalkyl. In embodiments, a C3-iocycloalkyl is a 3-10 membered cycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 3 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 4 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 5 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 6 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 7 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 8 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 9 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 10 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a ll membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 12 membered heterocycloalkyl. In embodiments, a C2-9heterocycloalkyl is a 3-12 membered heterocycloalkyl. In embodiments, a C2- liheterocycloalkyl is a 3 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 4 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 5 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 6 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 7 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 8 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 9 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 10 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 11 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 12 membered heterocycloalkyl. In embodiments, a C2-iiheterocycloalkyl is a 3-12 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 3 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 4 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 5 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 6 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 7 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 8 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 9 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 10 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 11 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 12 membered heterocycloalkyl. In embodiments, a Ci-nheterocycloalkyl is a 3-12 membered heterocycloalkyl. In embodiments, a C6-i2aryl is a 6 membered aryl. In embodiments, a C6-i2aryl is a 7 membered aryl. In embodiments, a C6-i2aryl is a 8 membered aryl. In embodiments, a C6-i2aryl is a 9 membered aryl. In embodiments, a C6-i2aryl is a 10 membered aryl. In embodiments, a C6-i2aryl is a 11 membered aryl. In embodiments, a C6-i2aryl is a 12 membered aryl. In embodiments, a C6-i2aryl is a 6-12 membered aryl. In embodiments, a Ci-nheteroaryl is a 5 membered heterocycloalkyl. In embodiments, a Ci-nheteroaryl is a 6 membered heterocycloalkyl. In embodiments, a Ci- nheteroaryl is a 7 membered heterocycloalkyl. In embodiments, a Ci-nheteroaryl is a 8 membered heterocycloalkyl. In embodiments, a Ci-nheteroaryl is a 9 membered heterocycloalkyl. In embodiments, a Ci-nheteroaryl is a 10 membered heterocycloalkyl. In embodiments, a Ci-nheteroaryl is a 11 membered heterocycloalkyl. In embodiments, a Ci-nheteroaryl is a 12 membered heterocycloalkyl. In embodiments, a Ci-nheteroaryl is a 5-12 membered heterocycloalkyl. In embodiments, a C3-6cycloalkyl is a 3 membered cycloalkyl. In embodiments, a C3- 6cycloalkyl is a 4 membered cycloalkyl. In embodiments, a C3-6cycloalkyl is a 5 membered cycloalkyl. In embodiments, a C3-6cycloalkyl is a 6 membered cycloalkyl. In embodiments, a C6-ioaryl is a 6 membered aryl. In embodiments, a C6-ioaryl is a 7 membered aryl. In embodiments, a C6-ioaryl is a 8 membered aryl. In embodiments, a C6-ioaryl is a 9 membered aryl. In embodiments, a C6-ioaryl is a 10 membered aryl. In embodiments, a Ci- gheteroaryl is a 5 membered heterocycloalkyl. In embodiments, a Ci-gheteroaryl is a 6 membered heterocycloalkyl. In embodiments, a Ci-gheteroaryl is a 7 membered heterocycloalkyl. In embodiments, a Ci-gheteroaryl is a 8 membered heterocycloalkyl. In embodiments, a Ci-gheteroaryl is a 9 membered heterocycloalkyl. In embodiments, a Ci-gheteroaryl is a 10 membered heterocycloalkyl. In embodiments, a Ci-gheteroaryl is a 11 membered heterocycloalkyl. In embodiments, a Cj-dictcroaryl is a 12 membered heterocycloalkyl. In embodiments, a Ci- yhctcroan l is a 5-12 membered heterocycloalkyl.
Compounds
[00147] The compounds of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, II A3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, G, IF, I”, II”, I-l, I-r, I-l”, I-r”, 1-3, 1-4, II-l, XVI, XVII, XVIII, orXIX, or a pharmaceutically acceptable salt or solvate thereof, are Ras (e.g., K-Ras, K-Ras WT, or K-Ras G12D) modulators (including Ras inhibitors) and have a wide range of applications in therapeutics, diagnostics, and other biomedical research.
[00148] In an aspect is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O), S(O), or S(0)2;
V is C(R17) and J is C(R16), or V is C(R17) and J is N, or J is C(R17) and V is C(R16), or J is C(R17) and V is N;
R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -
S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein Ci-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl, are optionally substituted with one, two, or three R20a;
R7 is a 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl, wherein the 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl are optionally substituted with one or more R1, one or more R4, or one or more R6; wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R1 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3- i2cycloalkyl. -CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CH2-Ci-nheterocycloalkyl, C6-i2aryl, -CH2-C6- i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3-i2cycloalkyl, -CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CH2-Ci-nheterocycloalkyl, C6-i2aryl, -CH2- C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R4 is independently selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroaryl. -OR12, -SR12, -N(R12)(R13), -C(0)OR12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-yhctcroan l are optionally substituted with one, two, or three R20a;
R6 is -L2-R5; each L2 is independently selected from a bond, Ci-Cealkyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, - S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, - N(R14)C(0)0-, and -N(R14)C(0)N(R14)-; each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, Ci-dictcroaiyl. -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20c;
R17 is -LkR19;
L1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, - C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, - OCON(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg);
Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), - C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,- ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201
R19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3- ncycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-yhctcroan l are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-<)hctcroan l. -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20g;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, - CH2S(0)2N(R12)(R13), -(Ci-C6alkyl)-R12b, -(C2-6alkenyl)-R12b, -(C2-6alkynyl)-R12b, -0-R12a, -N(R14)-R12b, - S-R12b, -(C3-iocycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-ioaryl)-R12b, or -(Ci-9heteroaryl)-R12b, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, G- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CEC-G-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, G- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CEC-G-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, G- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CEh-Ci-gheteroaryl, and Ci- gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CEh-Ci-gheteroaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20b; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R201 are each independently selected from halogen, -CN, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, Ci-gheteroaryl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), - 0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; and indicates a single or double bond such that all valences are satisfied.
[00149] In an aspect is provided a compound of Formula (G), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O), S(O), or S(0)2;
V is C(R17) and J is C(R16), or V is C(R17) and J is N, or J is C(R17) and V is C(R16), or J is C(R17) and V is N; R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -
S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, G-Galkyl, C2-C6alkenyl, C2-C6alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cealkyl, C2-C6alkenyl, C2-Cealkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R20a;
R7 is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6; wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R1 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3- ncycloalkyl, -CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CEC-Ci-nheterocycloalkyl, C6-i2aryl, -CH2-C6- naryl, -CEC-Ci-nheteroaryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3-i2cycloalkyl, -CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CEC-Ci-nheterocycloalkyl, C6-i2aryl, -CH2- C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R4 is independently selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20a;
R6 is -L2-R5; each L2 is independently selected from a bond, G-Galkyl, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, - S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, - N(R14)C(0)0-, and -N(R14)C(0)N(R14)-; each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20c;
R17 is -G-R19;
L1 is selected from a bond, G-Galkyl, C2-C6alkenyl, G-Galkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, - C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, - OCON(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg);
Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. -OR12, -SR12, -N(R12)(R13), - C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-dictcroarvl are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201
R19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3- i2cycloalkyl. C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20g;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, - CH2S(0)2N(R12)(R13), -(Ci-C6alkyl)-R12b, -(C2.6alkenyl)-R12b, -(C2-6alkynyl)-R12b, -0-R12a, -N(R14)-R12b, - S-R12b, -(C3-iocycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-ioaryl)-R12b, or -(Ci-9heteroaryl)-R12b, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2. gheterocycloalkyl, -C(R12c)2-C2-9heterocyeloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-siheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocyeloalkyl, C2- gheterocycloalkyl, -C(R12c)2-C2-9heterocyeloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocyeloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocyeloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d;
R12c is independently selected from hydrogen and R20k;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20b; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, R201, and R20k are each independently selected from halogen, oxo, - CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, Ci-gheteroaryl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), - 0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25; eachR21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- siheterocycloalkyl, C6-ioaryl, and Cj-dictcroaryl: each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- siheterocycloalkyl, C6-ioaryl, and Cj-dictcroaryl: each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C’l-dictcroarvl: and indicates a single or double bond such that all valences are satisfied.
[00150] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is C(R3). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is N.
[00151] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
V is C(R16) and J is C(R17). In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is N and J is C(R17). In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, J is N and V is C(R17). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, J is C(R16) and V is C(R17). In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is C(O). In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(O). In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(0)2.
[00152] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure: Formula (IA6), 12).
[00153] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure: ), , 2).
[00154] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is a bond. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is -NH-.
[00155] In embodiments, L7 is a bond. In embodiments, L7 is -0-. In embodiments, L7 is -N(R14)-. In embodiments, L7 is -C(O)-. In embodiments, L7 is -N(R14)C(0)-. In embodiments, L7 is -C(0)N(R14)-. In embodiments, L7 is -S-. In embodiments, L7 is -S(0)2-. In embodiments, L7 is -S(O)-. In embodiments, L7 is - S(0)2N(R14)-. In embodiments, L7 is -S(0)N(R14)-. In embodiments, L7 is -N(R14)S(0)-. In embodiments, L7 is - N(R14)S(0)2-. In embodiments, L7 is Ci-Cealkyl. In embodiments, L7 is C2-C6alkenyl. In embodiments, L7 is C2- Cealkynyl. In embodiments, L7 is 2 to 4 membered heteroalkylene linker. In embodiments, L7 is Ci-Cealkyl optionally substituted with one, two, or three R20a. In embodiments, L7 is C2-C6alkenyl optionally substituted with one, two, or three R20a. In embodiments, L7 is C2-Cealkynyl optionally substituted with one, two, or three R20a. In embodiments, L7 is 2 to 4 membered heteroalkylene linker optionally substituted with one, two, or three R20a. In embodiments, L7 is -N(H)-. In embodiments, L7 is -N(H)C(0)-. In embodiments, L7 is -C(0)N(H)-. In embodiments, L7 is -S(0)2N(H)-. In embodiments, L7 is -S(0)N(H)-. In embodiments, L7 is -N(H)S(0)-. In embodiments, L7 is -N(H)S(0)2-.
[00156] In some embodiments of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the a 4- 12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6; wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-iiheterocycloalkyl, C6-i2aryl, or Ci-iiheteroaryl, wherein the C3-i2cycloalkyl, Ci-iiheterocycloalkyl, C6-i2aryl, or Ci-iiheteroaryl are optionally substituted with one, two, or three R20a.
[00157] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R1, one or more R4, or one or more R6; and wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci- liheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a.
[00158] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6; and wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, G,. naryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or G-iiheteroaryl are optionally substituted with one, two, or three R20a.
[00159] In embodiments, R7 is a 3-12 membered cycloalkyl. In embodiments, R7 is a 5-12 membered cycloalkyl.
In embodiments, R7 is 3-12 membered heterocycloalkyl. In embodiments, R7 is 6-12 membered aryl. In embodiments, R7 is 7-12 membered aryl. In embodiments, R7 is 5-12 membered heteroaryl.
[00160] In embodiments, R7 is a 3-12 membered cycloalkyl comprising one or more ring nitrogen atoms. In embodiments, R7 is a 5-12 membered cycloalkyl comprising one or more ring nitrogen atoms. In embodiments, R7 is 3-12 membered heterocycloalkyl comprising one or more ring nitrogen atoms. In embodiments, R7 is 6-12 membered aryl comprising one or more ring nitrogen atoms. In embodiments, R7 is 7-12 membered aryl comprising one or more ring nitrogen atoms. In embodiments, R7 is 5-12 membered heteroaryl comprising one or more ring nitrogen atoms.
[00161] In embodiments, R7 is a 3-12 membered cycloalkyl comprising one or more ring oxygen atoms. In embodiments, R7 is a 5-12 membered cycloalkyl comprising one or more ring oxygen atoms. In embodiments, R7 is 3-12 membered heterocycloalkyl comprising one or more ring oxygen atoms. In embodiments, R7 is 6-12 membered aryl comprising one or more ring oxygen atoms. In embodiments, R7 is 7-12 membered aryl comprising one or more ring oxygen atoms. In embodiments, R7 is 5-12 membered heteroaryl comprising one or more ring oxygen atoms.
[00162] In embodiments, R7 is a 3-12 membered cycloalkyl optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is a 5-12 membered cycloalkyl optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 3-12 membered heterocycloalkyl optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 6-12 membered aryl optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 7-12 membered aryl optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 5-12 membered heteroaryl optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. [00163] In embodiments, R7 is a 3-12 membered cycloalkyl comprising one or more ring nitrogen atoms optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is a 5-12 membered cycloalkyl comprising one or more ring nitrogen atoms optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 3-12 membered heterocycloalkyl comprising one or more ring nitrogen atoms optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 6-12 membered aryl comprising one or more ring nitrogen atoms optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 7-12 membered aryl comprising one or more ring nitrogen atoms optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 5-12 membered heteroaryl comprising one or more ring nitrogen atoms optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6.
[00164] In embodiments, R7 is a 3-12 membered cycloalkyl comprising one or more ring oxygen atoms optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is a 5-12 membered cycloalkyl comprising one or more ring oxygen atoms optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 3-12 membered heterocycloalkyl comprising one or more ring oxygen atoms optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 6-12 membered aryl comprising one or more ring oxygen atoms optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 7-12 membered aryl comprising one or more ring oxygen atoms optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6. In embodiments, R7 is 5-12 membered heteroaryl comprising one or more ring oxygen atoms optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6.
[00165] In embodiments, R7 is a C3cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cicycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cecycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C7cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Ciocycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cicycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cecycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C7cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Ciocycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cecycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C7cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cecycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Ciocycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cecycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Ciocycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cecycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C7cycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Ciocycloalkyl optionally substituted with one R6 and optionally substituted with one or more R4.
[00166] In embodiments, R7 is a Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. [00167] In embodiments, R7 is a Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cicycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cecycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a C7cycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Ciocycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cicycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cecycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C7cycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Ciocycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4.
[00168] In embodiments, R7 is a fused bicyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cecycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C7cycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Ciocycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. [00169] In embodiments, R7 is a bridged bicyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cecycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7cycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Ciocycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cecycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C7cycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Ciocycloalkyl optionally substituted with one R1 and optionally substituted with one or more R4.
[00170] In embodiments, R7 is a Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cecycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C7cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Ciocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. [00171] In embodiments, R7 is a Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cecycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C7cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00172] In embodiments, R7 is a Cscycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cecycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a C7cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cscycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cecycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic C7cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cscycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Cycvcloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic Ciocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00173] In embodiments, R7 is a 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00174] In embodiments, R7 is a fused bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00175] In embodiments, R7 is a bridged bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00176] In embodiments, R7 is a spirocyclic bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00177] In embodiments, R7 is a 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00178] In embodiments, R7 is a fused bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00179] In embodiments, R7 is a bridged bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00180] In embodiments, R7 is a spirocyclic bicyclic 5 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 6 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 11 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 12 membered cycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00181] In embodiments, R7 is a 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00182] In embodiments, R7 is a fused bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00183] In embodiments, R7 is a bridged bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00184] In embodiments, R7 is a spirocyclic bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00185] In embodiments, R7 is a 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00186] In embodiments, R7 is a fused bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00187] In embodiments, R7 is a bridged bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00188] In embodiments, R7 is a spirocyclic bicyclic 5 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 6 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 11 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 12 membered cycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00189] In embodiments, R7 is a 3 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 4 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00190] In embodiments, R7 is a monocyclic 3 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 4 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00191] In embodiments, R7 is a fused bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. [00192] In embodiments, R7 is a bridged bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. [00193] In embodiments, R7 is a spirocyclic bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00194] In embodiments, R7 is a 3 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 4 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00195] In embodiments, R7 is a monocyclic 3 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 4 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. [00196] In embodiments, R7 is a fused bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. [00197] In embodiments, R7 is a bridged bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. [00198] In embodiments, R7 is a spirocyclic bicyclic 5 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 6 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 11 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 12 membered heterocycloalkyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00199] In embodiments, R7 is a 3 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 4 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00200] In embodiments, R7 is a monocyclic 3 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 4 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00201] In embodiments, R7 is a fused bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00202] In embodiments, R7 is a bridged bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. [00203] In embodiments, R7 is a spirocyclic bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00204] In embodiments, R7 is a 3 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 4 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00205] In embodiments, R7 is a monocyclic 3 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 4 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00206] In embodiments, R7 is a fused bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00207] In embodiments, R7 is a bridged bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. [00208] In embodiments, R7 is a spirocyclic bicyclic 5 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 6 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 11 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 12 membered heterocycloalkyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00209] In embodiments, R7 is a Cearyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a C-aiyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Csaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cearyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cioaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cearyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C-aiy 1 optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Csaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cearyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cioaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cearyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C-aiyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Co aryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cioaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cearyl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C-arvl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Coaryl optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cioaryl optionally substituted with one R6 and optionally substituted with one or more R4.
[00210] In embodiments, R7 is a C-arvl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Csaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Csaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cioaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cearyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C-arvl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic arvl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cioaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cearyl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C-arvl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic arvl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cioaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00211] In embodiments, R7 is a Cearyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a C-arvl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Csaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Co aryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cioaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cearyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic C-aiy 1 optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Csaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Gaiyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic Cioaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C-arv 1 optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Gaiyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cioaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cearyl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Caryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Caryl optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cioaryl optionally substituted with one R1 and optionally substituted with one or more R4.
[00212] In embodiments, R7 is a Caryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Csaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Csaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cioaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cearyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Caryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Caryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cioaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cearyl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Caryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Caryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cioaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00213] In embodiments, R7 is a C-arvl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Csaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cyarvl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a Cioaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Giaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C-arvl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Coaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cioaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cearyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C-arvl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cearyl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cioaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00214] In embodiments, R7 is a C-arvl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Csaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Csaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a Cioaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cearyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic C-arvl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cearyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic Cioaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cearyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic C-aiyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Csaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cyaiyl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic Cioaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00215] In embodiments, R7 is a 7 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00216] In embodiments, R7 is a fused bicyclic 7 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00217] In embodiments, R7 is a bridged bicyclic 7 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered aryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00218] In embodiments, R7 is a 7 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00219] In embodiments, R7 is a fused bicyclic 7 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00220] In embodiments, R7 is a bridged bicyclic 7 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered aryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00221] In embodiments, R7 is a 7 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00222] In embodiments, R7 is a fused bicyclic 7 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00223] In embodiments, R7 is a bridged bicyclic 7 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered aryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00224] In embodiments, R7 is a 7 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 11 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 12 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00225] In embodiments, R7 is a fused bicyclic 7 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00226] In embodiments, R7 is a bridged bicyclic 7 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered aryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00227] In embodiments, R7 is a 5 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00228] In embodiments, R7 is a monocyclic 5 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00229] In embodiments, R7 is a fused bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 11 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 12 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00230] In embodiments, R7 is a bridged bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 11 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 12 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00231] In embodiments, R7 is a spirocyclic bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 11 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 12 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00232] In embodiments, R7 is a 5 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00233] In embodiments, R7 is a monocyclic 5 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00234] In embodiments, R7 is a fused bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00235] In embodiments, R7 is a bridged bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00236] In embodiments, R7 is a spirocyclic bicyclic 6 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered heteroaryl including at least one nitrogen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00237] In embodiments, R7 is a 5 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00238] In embodiments, R7 is a monocyclic 5 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00239] In embodiments, R7 is a fused bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00240] In embodiments, R7 is a bridged bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00241] In embodiments, R7 is a spirocyclic bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R6 and optionally substituted with one or more R4.
[00242] In embodiments, R7 is a 5 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. [00243] In embodiments, R7 is a monocyclic 5 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a monocyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00244] In embodiments, R7 is a fused bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a fused bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00245] In embodiments, R7 is a bridged bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a bridged bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00246] In embodiments, R7 is a spirocyclic bicyclic 6 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 7 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 8 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 9 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4. In embodiments, R7 is a spirocyclic bicyclic 10 membered heteroaryl including at least one oxygen atom and optionally substituted with one R1 and optionally substituted with one or more R4.
[00247] In embodiments, R4 is independently halogen. In embodiments, R4 is independently R4 is independently oxo. In embodiments, R4 is independently -CN. In embodiments, R4 is independently Ci-6alkyl. In embodiments,
R4 is independently C2-6alkenyl. In embodiments, R4 is independently C2-6alkynyl. In embodiments, R4 is independently Ci-6haloalkyl. In embodiments, R4 is independently C3-i2cycloalkyl. In embodiments, R4 is independently -CH2-C3-i2cycloalkyl. In embodiments, R4 is independently Ci-nheterocycloalkyl. In embodiments, R4 is independently -CtC-Ci-nheterocycloalkyl. In embodiments, R4 is independently C6-i2aryl. In embodiments,
R4 is independently -CH2-C6-i2aryl. In embodiments, R4 is independently -CtC-Ci-nheteroaryl. In embodiments, R4 is independently Ci-nheteroaryl. In embodiments, R4 is independently -OR12. In embodiments, R4 is independently -SR12. In embodiments, R4 is independently -N(R12)(R13). In embodiments, R4 is independently -C(0)0R12. In embodiments, R4 is independently -0C(0)N(R12)(R13). In embodiments, R4 is independently - N(R14)C(0)N(R12)(R13). In embodiments, R4 is independently -N(R14)C(0)0R15. In embodiments, R4 is independently -N(R14)S(0)2R15. In embodiments, R4 is independently -C(0)R15. In embodiments, R4 is independently -S(0)R15. In embodiments, R4 is independently -0C(0)R15. In embodiments, R4 is independently - C(0)N(R12)(R13). In embodiments, R4 is independently -C(0)C(0)N(R12)(R13). In embodiments, R4 is independently -N(R14)C(0)R15. In embodiments, R4 is independently -S(0)2R15. In embodiments, R4 is independently -S(0)2N(R12)(R13)-. In embodiments, R4 is independently S(=0)(=NH)N(R12)(R13). In embodiments, R4 is independently -CH2C(0)N(R12)(R13). In embodiments, R4 is independently -CH2N(R14)C(0)R15. In embodiments, R4 is independently -CH2S(0)2R15. In embodiments, R4 is independently and -CH2S(0)2N(R12)(R13). [00248] In embodiments, R4 is independently Ci-6alkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C2-6alkenyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C2-6alkynyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Ci-6haloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C3-i2cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently -CH2-C3- ncycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Ci- liheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently -CH2-C1- liheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C6-i2aryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently -CH2-C6-i2aryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently -CtC-Ci-nheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Ci-nheteroaryl optionally substituted with one, two, or three R20a.
[00249] In embodiments, L2 is a bond. In embodiments, L2 is Ci-Cealkyl. In embodiments, L2 is -0-. In embodiments, L2 is -N(R14)-. In embodiments, L2 is -C(O)-. In embodiments, L2 is -N(R14)C(0)-. In embodiments, L2 is -C(0)N(R14)-. In embodiments, L2 is -S-. In embodiments, L2 is -S(0)2-. In embodiments, L2 is -S(O)-. In embodiments, L2 is -S(0)2N(R14)-. In embodiments, L2 is -S(0)N(R14)-. In embodiments, L2 is -N(R14)S(0)-. In embodiments, L2 is -N(R14)S(0)2-. In embodiments, L2 is -OCON(R14)-. In embodiments, L2 is -N(R14)C(0)0-. In embodiments, L2 is -N(R14)C(0)N(R14)-. In embodiments, L2 is -N(H)-. In embodiments, L2 is -N(H)C(0)-. In embodiments, L2 is -C(0)N(H)-. In embodiments, L2 is -S(0)2N(H)-. In embodiments, L2 is -S(0)N(H)-. In embodiments, L2 is -N(H)S(0)-. In embodiments, L2 is -N(H)S(0)2-. In embodiments, L2 is -OCON(H)-. In embodiments, L2 is -N(H)C(0)0-. In embodiments, L2 is -N(H)C(0)N(R14)-.
[00250] In embodiments, R4 is independently Cialkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C2alkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cialkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cialkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cialkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cealkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C2alkenyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cialkcnyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cialkcnyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Csalkcnyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cealkenyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C2alkynyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cialkynyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cialkynyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Csalkynvi optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cealkynyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cihaloalkyl. In embodiments, R4 is independently Cihaloalkyl. In embodiments, R4 is independently Cihaloalkyl. In embodiments, R4 is independently Cihaloalkyl. In embodiments, R4 is independently Cihaloalkyl. In embodiments, R4 is independently Cehaloalkyl.
[00251] In embodiments, R4 is independently Ci cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cicycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cscycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cecycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C7cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cscycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cscycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Ciocycloalkyl optionally substituted with one, two, or three R20a.
[00252] In embodiments, R4 is independently Cihetcrocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cihetcrocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cihetcrocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cihetcrocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Ciheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Gsaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently C-arvl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Csaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Csaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cioaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cnaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cnaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cihctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cihctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cihctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cihctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Ceheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cihctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Csheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cihctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cioheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently Cnheteroaryl optionally substituted with one, two, or three R20a.
[00253] In embodiments, R4 is independently 3 membered cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 4 membered cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 5 membered cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 6 membered cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 7 membered cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 8 membered cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 9 membered cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 10 membered cycloalkyl optionally substituted with one, two, or three R20a.
[00254] In embodiments, R4 is independently 3 membered heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 4 membered heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 5 membered heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 6 membered heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 7 membered heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 8 membered heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 9 membered heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 10 membered heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 6 membered aryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 7 membered aryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 8 membered aryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 9 membered aryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 10 membered aryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 11 membered aryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 12 membered aryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 5 membered heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 6 membered heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 7 membered heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 8 membered heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 9 membered heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 10 membered heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 11 membered heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R4 is independently 12 membered heteroaryl optionally substituted with one, two, or three R20a.
[00255] In embodiments, R4 is independently -OH. In embodiments, R4 is independently -SH. In embodiments, R4 is independently -NH2. In embodiments, R4 is independently -C(0)OH. In embodiments, R4 is independently - OC(0)NH2. In embodiments, R4 is independently -N(H)C(0)NH2. In embodiments, R4 is independently - N(H)C(0)OH. In embodiments, R4 is independently -N(H)S(0)2CH3. In embodiments, R4 is independently - C(0)H. In embodiments, R4 is independently -S(0)CH3. In embodiments, R4 is independently -0C(0)CH3. In embodiments, R4 is independently -C(0)NH2. In embodiments, R4 is independently -C(0)C(0)NH2. In embodiments, R4 is independently -N(H)C(0)H. In embodiments, R4 is independently -S(0)2CH . In embodiments, R4 is independently -S(0)2NH2-. In embodiments, R4 is independently S(=0)(=NH)NH2. In embodiments, R4 is independently -CH2C(0)NH2. In embodiments, R4 is independently -CH2N(H)C(0)CH . In embodiments, R4 is independently -CH2S(0)2CH3. In embodiments, R4 is independently and -CFFS/O^NFF. In embodiments, R4 is independently -OCH3. In embodiments, R4 is independently -SCH3. In embodiments, R4 is independently - N(CH3)(H). In embodiments, R4 is independently -C(0)0CH3. In embodiments, R4 is independently - 0C(0)N(CH3)(H). In embodiments, R4 is independently -N(H)C(0)N(CH3)(H). In embodiments, R4 is independently -N(H)C(0)0CH3. In embodiments, R4 is independently -N(H)S(0)2CH3. In embodiments, R4 is independently -C(0)CH3. In embodiments, R4 is independently -S(0)CH3. In embodiments, R4 is independently - 0C(0)CH3. In embodiments, R4 is independently -C(0)N(CH3)(H). In embodiments, R4 is independently - C(0)C(0)N(CH3)(H). In embodiments, R4 is independently -N(H)C(0)CH3. In embodiments, R4 is independently - S(0)2CH3. In embodiments, R4 is independently -S(0)2N(CH3)(H)-. In embodiments, R4 is independently S(=0)(=NH)N(CH3)(H). In embodiments, R4 is independently -CH2C(0)N(CH3)(H). In embodiments, R4 is independently -CH2N(H)C(0)CH3. In embodiments, R4 is independently -CH2S(0)2CH3. In embodiments, R4 is independently and -CH2S(0)2N(CH3)(H). In embodiments, R4 is independently -0C(0)N(CH3)2. In embodiments, R4 is independently -N(H)C(0)N(CH3)2. In embodiments, R4 is independently -C(0)(CH3). In embodiments, R4 is independently -C(0)N(CH3)2. In embodiments, R4 is independently -C(0)C(0)N(CH3)2. In embodiments, R4 is independently -N(H)C(0)(CH3). In embodiments, R4 is independently -S(0)2N(CH3)2. In embodiments, R4 is independently S(=0)(=NH)N(CH3)2. In embodiments, R4 is independently -CH2C(0)N(CH3)2. In embodiments, R4 is independently and -CH2S(0)2N(CH3)2. In embodiments, R4 is independently -CH3. In embodiments, R4 is independently -CF3. In embodiments, R4 is independently -CHF2. In embodiments, R4 is independently -CFH2. In embodiments, R4 is independently ethyl. In embodiments, R4 is independently propyl. In embodiments, R4 is independently isopropyl. In embodiments, R4 is independently butyl. In embodiments, R4 is independently tert- butyl.
[00256] In embodiments, R4 is capable of forming a covalent bond with the 12th amino acid of a G12D KRas mutant. In embodiments, R4 is capable of forming a covalent bond with the 12th amino acid of a G12C KRas mutant. In embodiments, R4 is capable of forming a covalent bond with the 12th amino acid of a G12S KRas mutant. In embodiments, R4 is capable of forming a covalent bond with the 13th amino acid of a G13D KRas mutant. In embodiments, R4 is capable of forming a covalent bond with the 13th amino acid of a G13C KRas mutant. In embodiments, R4 is capable of forming a covalent bond with the 13th amino acid of a G13S KRas mutant.
[00257] In embodiments, R4 is selected from the group consisting
where each Ra is independently hydrogen, Ci-
6alkyl, carboxy, Ci-6carboalkoxy, phenyl, C2-7carboalkyl, Rc-(C(Rb)2)z-, Rc-(C(Rb)2)w-M-(C(Rb)2)r, (Rd)(Re)CH-M- (C(Rb)2)r, or Het-J3-(C(Rb)2)r-; each Rb is independently hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-7carboalkyl, C2-7carboxyalkyl, phenyl, or phenyl optionally substituted with one or more halogen, Ci- 6alkoxy, trifluoromethyl, amino, Ci-3alkylamino, C2-6dialkylamino, nitro, azido, halomethyl, C2-7alkoxymethyl, C2- 7alkanoyloxymethyl, Ci-6alkylthio, hydroxy, carboxyl, C2-7carboalkoxy, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, Ci-6alkanoylamino, or Ci-6alkyl; eaehRc is independently -NRbRb or -ORb; Rd and Re are each, independently, -(C(Rb)2)r-NRbRb, or -(C(Rb)2)r-ORb; each J1 is independently hydrogen, chlorine, fluorine, or bromine; J2 is Ci-6alkyl or hydrogen; each M is independently -N(Rb)-, -0-, -N[(C(Rb)2)w-NRbRb]-, or - N[(C(Rb)2)w-ORb]-; each J3 is independently -N(Rb)-, -0-, or a bond; each Het is independently a heterocycle, optionally mono- or di-substituted on carbon or nitrogen with Rb and optionally mono-substituted on carbon with - CEflORh; wherein the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2, 3 -triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran, and tetrahydropyran; each r is independently 1-4; each w is independently 2-4; x is 0-1; y is 0-4, and each z is independently 1-6; wherein the sum of x+y is 2-4.
[00258] In embodiments, R4 is independently selected from the group consisting of hydrogen, hydroxyl, C1-C6 alkoxy, and C1-C6 alkyl, or two Rb are optionally join to form heterocycle having 3-12 ring atoms or C3-C6 cycloalkyl. In embodiments, R4 is independently selected from the group consisting of
[00259] In embodiments, R4is independently -C(0)N(R12)(R13), -N(R14)C(0)R15, or -C(0)R15. In embodiments, R4 is independently -C(0)N(R12)(R13). In embodiments, R4 is independently -N(R14)C(0)R15. In embodiments, R4 is independently -C(0)R15. one, two, or three R20f, -C(0)R15 wherein R15 is C2-6alkenyl optionally substituted with one, two, or three R20f, - C(0)R15 wherein R15 is C2-6alkynyl optionally substituted with one, two, or three R20f, -C(0)R15 wherein R15 is C3- 6cycloalkyl optionally substituted with one, two, or three R20f, -C(0)R15 wherein R15 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20f, -C(0)R15 wherein R15 is C6-ioaryl optionally substituted with one, two, or three R20f, and -C(0)R15 wherein R15 is Ci-dictcroaryl optionally substituted with one, two, or three R20f. [00261] In embodiments, R4 is independently -C(0)NH(R12) and R12 is independently Ci-dictcroaryl. wherein Ci- ihctcroaiyl is optionally substituted with one, two, or three R20d. In embodiments, R4 is independently - C(0)NH(R12) and R12 is independently Ci-shctcroan l. wherein Ci-shctcroaiy l is optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)NH(R12) and R12 is independently Ci-ihctcroaryl.
[00262] In embodiments, R12 is independently Cialkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently C2alkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cialkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cialkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cialkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cialkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently C2alkenyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cialkcnyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cialkcnyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cialkcnyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cealkenyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently C2alkynyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cialkynyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cialkynyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Csalkynyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cealkynyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cihaloalkyl. In embodiments, R12 is independently Cihaloalkyl.
In embodiments, R12 is independently Cihaloalkyl. In embodiments, R12 is independently Cihaloalkyl. In embodiments, R12 is independently Cshaloalkyl. In embodiments, R12 is independently Cehaloalkyl.
[00263] In embodiments, R12 is independently Cscycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cicycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cscycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cecycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently C7cycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cscycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cscycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Ciocycloalkyl optionally substituted with one, two, or three R20d.
[00264] In embodiments, R12 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cdictcrocycloalkyl optionally substituted with one, two, or three R20d.
In embodiments, R12 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cdictcrocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently C-hetcrocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cearyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently C-aryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Csaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Csaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cioaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cnaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cnaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cihctcroaiyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cihctcroaiyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cihctcroaiy l optionally substituted with one, two, or three R20d. In embodiments, R12 is independently C die tcro aryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Ceheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently C 7 he tcro aryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Csheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cihctcroaiy l optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cioheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently Cnheteroaryl optionally substituted with one, two, or three R20d.
[00265] In embodiments, R12 is independently 3 membered cycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 4 membered cycloalkyl optionally substituted with one, two, or three
R20d. In embodiments, R12 is independently 5 membered cycloalkyl optionally substituted with one, two, or three
R20d. In embodiments, R12 is independently 6 membered cycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 7 membered cycloalkyl optionally substituted with one, two, or three
R20d. In embodiments, R12 is independently 8 membered cycloalkyl optionally substituted with one, two, or three
R20d. In embodiments, R12 is independently 9 membered cycloalkyl optionally substituted with one, two, or three
R20d. In embodiments, R12 is independently 10 membered cycloalkyl optionally substituted with one, two, or three
R20d.
[00266] In embodiments, R12 is independently 3 membered heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 4 membered heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 5 membered heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 6 membered heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 7 membered heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 8 membered heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 9 membered heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 10 membered heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 6 membered aryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 7 membered aryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 8 membered aryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 9 membered aryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 10 membered aryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 11 membered aryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 12 membered aryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 5 membered heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 6 membered heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 7 membered heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 8 membered heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 9 membered heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 10 membered heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 11 membered heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12 is independently 12 membered heteroaryl optionally substituted with one, two, or three R20d.
[00267] In embodiments, R15 is independently Cialkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C2alkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cialkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cialkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Csalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cealkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C2alkenyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Ci alkenyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C4alkenyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Csalkcnyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cealkenyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C2alkynyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cialkynyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C4alkynyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Csalkynyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cealkynyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cihaloalkyl. In embodiments, R15 is independently Cihaloalkyl.
In embodiments, R15 is independently Cihaloalkyl. In embodiments, R15 is independently Cihaloalkyl. In embodiments, R15 is independently Cshaloalkyl. In embodiments, R15 is independently Cehaloalkyl.
[00268] In embodiments, R15 is independently Cscycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cicycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cscycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cecycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C7cycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cscycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cscycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Ciocycloalkyl optionally substituted with one, two, or three R20f.
[00269] In embodiments, R15 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R20f.
In embodiments, R15 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cdictcrocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C-hetcrocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cearyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C-aiyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Csaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Csaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cioaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cnaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cearyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cihctcroaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cihctcroaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cihctcroaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cshctcroarvl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Ceheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C-hetcroarvl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Csheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cdictcroarvl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cioheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Cnheteroaryl optionally substituted with one, two, or three R20f.
[00270] In embodiments, R15 is independently 3 membered cycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 4 membered cycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 5 membered cycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 6 membered cycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 7 membered cycloalkyl optionally substituted with one, two, or three
R20f. In embodiments, R15 is independently 8 membered cycloalkyl optionally substituted with one, two, or three
R20f. In embodiments, R15 is independently 9 membered cycloalkyl optionally substituted with one, two, or three
R20f. In embodiments, R15 is independently 10 membered cycloalkyl optionally substituted with one, two, or three
R20f.
[00271] In embodiments, R15 is independently 3 membered heterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 4 membered heterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 5 membered heterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 6 membered heterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 7 membered heterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 8 membered heterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 9 membered heterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 10 membered heterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 6 membered aryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 7 membered aryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 8 membered aryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 9 membered aryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 10 membered aryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 11 membered aryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 12 membered aryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 5 membered heteroaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 6 membered heteroaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 7 membered heteroaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 8 membered heteroaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 9 membered heteroaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 10 membered heteroaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 11 membered heteroaryl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently 12 membered heteroaryl optionally substituted with one, two, or three R20f.
[00272] In embodiments, R4 is independently -C(0)R15 and R15 is independently selected from C2-6alkenyl, C2- 6alkynyl, C2-s>heterocycloalkyl, and C’l-yhctcroarvl. wherein C2-6alkenyl, C2-6alkynyl, C2-s>heterocycloalkyl, and Ci- yhctcroarvl are optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently C2alkenyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Cialkcnyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Cialkcnyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Csalkcnyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Cealkenyl optionally substituted with one, two, or three R20f.
[00273] In embodiments, R4 is independently -C(0)R15 and R15 is independently C2alkynyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Cialkynyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Cialkynyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently - C(0)R15 and R15 is independently Csalkynyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Cealkynyl optionally substituted with one, two, or three R20f. [00274] In embodiments, R4 is independently -C(0)R15 and R15 is independently Cohctcrocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently - C(0)R15 and R15 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently C-hctcrocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20f.
[00275] In embodiments, R4 is independently -C(0)R15 and R15 is independently Ciheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Ciheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Ciheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Ciheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Cshctcroarvl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Ceheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Ciheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Csheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -C(0)R15 and R15 is independently Ceheteroaryl optionally substituted with one, two, or three R20f.
[00276] In embodiments, R4 is independently -NHC(0)R15 and R15 is independently selected from C2-6alkenyl, C2- 6alkynyl, C2-9heterocycloalkyl, and C’l-dictcroarvl. wherein C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, and Ci- eheteroaryl are optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently C2alkenyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Cialkcnyl optionally substituted with one, two, or three R20f.
In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Cialkcnyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Csalkcnyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Cealkenyl optionally substituted with one, two, or three R20f.
[00277] In embodiments, R4 is independently -NHC(0)R15 and R15 is independently C2alkynyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Csalkynyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Cialkynyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Csalkynyl optionally substituted with one, two, or three R20f.
In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Cealkynyl optionally substituted with one, two, or three R20f. [00278] In embodiments, R4 is independently -NHC(0)R15 and R15 is independently C2heterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently C3heterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently - NHC(0)R15 and R15 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Cshctcrocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently - NHC(0)R15 and R15 is independently C7heterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Cdictcrocycloalkyl optionally substituted with one, two, or three R20f.
[00279] In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Ciheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently C2heteroaryl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Cihctcroarvl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Ciheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Cshctcroarvl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Ceheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently C7heteroaryl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Csheteroaryl optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -NHC(0)R15 and R15 is independently Csheteroaryl optionally substituted with one, two, or three R20f. 7carboalkyl, Rc-(C(Rb)2)z-, Rc-(C(Rb)2)w-M-(C(Rb)2)r-, (Rd)(Re)CH-M-(C(Rb)2)r-, or Het-J3-(C(Rb)2)r-; eachRb is independently hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-7carboalkyl, C2-7carboxyalkyl, phenyl, or phenyl optionally substituted with one or more halogen, Ci-6alkoxy, trifluoromethyl, amino, Ci- 3alkylamino, C2-6dialkylamino, nitro, azido, halomethyl, C2-7alkoxymethyl, C2-7alkanoyloxymethyl, Ci-6alkylthio, hydroxy, carboxyl, C2-7carboalkoxy, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, Ci-6alkanoylamino, or Ci-6alkyl; each Rc is independently -NRbRb or -ORb; Rd and Re are each, independently, - (C(Rb)2)r-NRbRb, or -(C(Rb)2)r-ORb; each J1 is independently hydrogen, chlorine, fluorine, or bromine; J2 is Ci-6alkyl or hydrogen; each M is independently -N(Rb)-, -0-, -N[(C(Rb)2)w-NRbRb]-, or -N[(C(Rb)2)w-ORb]-; each J3 is independently -N(Rb)-, -0-, or a bond; each Het is independently a heterocycle, optionally mono- or di-substituted on carbon or nitrogen with Rb and optionally mono-substituted on carbon with -CH2ORb; wherein the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S- dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran, and tetrahydropyran; each r is independently 1-4; each w is independently 2-4; x is 0-1; y is 0-4, and each z is independently 1-6; wherein the sum of x+y is 2-4.
[00281] In embodiments, R4 is capable of forming a covalent bond with a Ras amino acid sidechain. In embodiments, R4 is capable of forming a covalent bond with a KRas amino acid. In embodiments, R4 is capable of forming a covalent bond with the 12th amino acid of a human KRas protein. In embodiments, R4 is capable of forming a covalent bond with the 12th amino acid of a mutant KRas protein selected from KRas G12D, KRas G12C, and KRas G12S. In embodiments, R4 is capable of forming a covalent bond with the 13th amino acid of a human KRas protein. In embodiments, R4 is capable of forming a covalent bond with the 13th amino acid of a mutant KRas protein selected from KRas G13D, KRas G13C, and KRas G13S.
[00282] In embodiments, R4 is selected from
[00283] In embodiments, R4 is selected from
[00284] In embodiments, R15 is independently C2-6alkenyl optionally substituted with one, two, or three
R20f. In embodiments, R15 is independently C2-6alkenyl optionally substituted with one, two, or three halogen. In embodiments, R15 is independently C2-6alkenyl optionally substituted with one, two, or three F. In embodiments,
R15 is independently C2-6alkenyl optionally substituted with -OR21. In embodiments, R15 is independently C2- 6alkenyl optionally substituted with -N(R22)(R23). In embodiments, R15 is independently C2-6alkenyl optionally substituted with C2-9heterocycloalkyl. In embodiments, R15 is independently C2-6alkenyl optionally substituted with Ci-5heteroaryl optionally substituted with one, two, or three Ci-6alkyl. In embodiments, R15 is independently C2- 6alkenyl optionally substituted with Ci-shctcroarvl optionally substituted with methyl. In embodiments, R15 is independently C2-6alkenyl optionally substituted with -CN. In embodiments, R15 is independently C2-6alkenyl optionally substituted with Ci-shctcroarvl optionally substituted with -N(R24)C(0)R25. In embodiments, R15 is independently C2-6alkenyl optionally substituted with Ci- hctcroarvl and/or CN. In embodiments, R15 is independently C2-6alkenyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C2-6alkenyl optionally substituted with one, two, or three halogen. In embodiments, R15 is independently C2-6alkenyl optionally substituted with one, two, or three F. In embodiments, R15 is independently C2-6alkenyl optionally substituted with -OR21. In embodiments, R15 is independently C2-6alkenyl optionally substituted with -N(R22)(R23). In embodiments, R15 is independently C2-6alkenyl optionally substituted with C2-9heterocycloalkyl. In embodiments, R15 is independently C2-6alkenyl optionally substituted with Ci-shctcroarvl optionally substituted with one, two, or three Ci-6alkyl. In embodiments, R15 is independently C2-6alkenyl optionally substituted with Ci-shctcroarvl optionally substituted with methyl. In embodiments, R15 is independently C2-6alkenyl optionally substituted with - CN. In embodiments, R15 is independently C2-6alkenyl optionally substituted with Ci-shctcroarvl optionally substituted with -N(R24)C(0)R25. In embodiments, R15 is independently C2-6alkenyl optionally substituted with - C(0)N(R22)(R23). In embodiments, R15 is independently C2-6alkenyl substituted with Cl and optionally substituted with one or two R20f. In embodiments, R15 is independently C2-6alkynyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C2-6alkynyl optionally substituted with one, two, or three halogen. In embodiments, R15 is independently C2-6alkynyl optionally substituted with one, two, or three F. In embodiments, R15 is independently C2-6alkynyl optionally substituted with -OR21. In embodiments, R15 is independently C2- 6alkynyl optionally substituted with -N(R22)(R23). In embodiments, R15 is independently C2-6alkynyl optionally substituted with C2-9heterocycloalkyl. In embodiments, R15 is independently C2-6alkynyl optionally substituted with Ci-sheteroaryl optionally substituted with one, two, or three Ci-6alkyl. In embodiments, R15 is independently C2- 6alkynyl optionally substituted with Ci-shctcroarvl optionally substituted with methyl. In embodiments, R15 is independently C2-6alkynyl optionally substituted with -CN. In embodiments, R15 is independently C2-6alkynyl optionally substituted with Ci-sheteroaryl optionally substituted with -N(R24)C(0)R25. In embodiments, R15 is independently C2-6alkynyl optionally substituted with Ci-sheteroaryl and/or CN. In embodiments, R15 is independently C2-6alkynyl optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C2-6alkynyl optionally substituted with one, two, or three halogen. In embodiments, R15 is independently C2- 6alkynyl optionally substituted with one, two, or three F. In embodiments, R15 is independently C2-6alkynyl optionally substituted with -OR21. In embodiments, R15 is independently C2-6alkynyl optionally substituted with - N(R22)(R23). In embodiments, R15 is independently C2-6alkynyl optionally substituted with C2-s>heterocycloalkyl. In embodiments, R15 is independently C2-6alkynyl optionally substituted with C’l-shctcroarvl optionally substituted with one, two, or three Ci-6alkyl. In embodiments, R15 is independently C2-6alkynyl optionally substituted with Ci- sheteroaryl optionally substituted with methyl. In embodiments, R15 is independently C2-6alkynyl optionally substituted with -CN. In embodiments, R15 is independently C2-6alkynyl optionally substituted with C’l-shctcroarvl optionally substituted with -N(R24)C(0)R25. In embodiments, R15 is independently C2-6alkynyl optionally substituted with -C(0)N(R22)(R23). In embodiments, R15 is independently C2-6alkynyl substituted with Cl and optionally substituted with one or two R20f. In embodiments, R15 is independently C3-scycloalkyl, optionally substituted with one, two, or three R20f. In embodiments, R15 is independently C3-scycloalkyl, optionally substituted with Ci-6alkyl optionally substituted with one, two, or three halogen. In embodiments, R15 is independently C3- scycloalkyl, optionally substituted with Ci-6alkyl optionally substituted with one, two, or three F. In embodiments, R15 is independently Ci-shctcrocycloalkyl. optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Ci-shctcrocycloalkyl. optionally substituted with Ci-6alkyl optionally substituted with one, two, or three halogen. In embodiments, R15 is independently Ci-shctcrocycloalkyl. optionally substituted with Ci-6alkyl optionally substituted with one, two, or three F. In embodiments, R15 is independently Ci-6alkyl, optionally substituted with one, two, or three R20f. In embodiments, R15 is independently Ci-6alkyl, substituted with Cl and optionally substituted with one, two, or three R20f. In embodiments, R4 is independently -CN.
[00285] In embodiments, L2 is independently a bond, -C(0)NH-, -NHC(O)-, or -C(O)-; and R5 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, -CFF-Cs-ncycloalkyl, Ci- liheterocycloalkyl, -CFF-Ci-nheterocycloalkyl, Gs-naryl, -CH2-C6-i2aryl, -CFF-Ci-nheteroaryl, Ci-nheteroaryl, - OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, - S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein the Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, -CH2-C3-i2cycloalkyl, Ci-iiheterocycloalkyl, -CH2-Ci-nheterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, Ci-nheteroaryl are optionally substituted with one, two, or three R20a.
[00286] In embodiments, L2 is independently -C(O)-; and R5 is independently a Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, -CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CFF-Ci-nheterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, - CH2-Ci-nheteroaryl, or Ci-nheteroaryl, wherein the Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, -CH2-C3- ncycloalkyl, Ci-nheterocycloalkyl, -CFF-Ci-nheterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a.
[00287] In embodiments, L2 is independently -C(O)-; and R5 is independently a C3-i2cycloalkyl, Ci- liheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, and Ci- nheteroaryl are optionally substituted with one, two, or three R20a. [00288] In embodiments, L2 is independently a bond, -C(0)NH-, -NHC(O)-, or -C(O)-; L2 is independently bonded to a carbon atom of R5; and R5 is independently selected from -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- ncycloalkyl, C6-i2aryl, and Ci-nheteroaryl, wherein Chalky 1, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, Gs-naryl, and Ci-iiheteroaryl, are optionally substituted with one, two, or three R20a.
[00289] In embodiments, L2 is independently -C(O)-; L2 is independently bonded to a carbon atom of R5; and R5 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, C6-i2aryl, and Ci-nheteroaryl, wherein the Chalky 1, C2-6alkenyl, C2-6alkynyl, C3-i2cycloalkyl, Gs-naryl, and Ci-nheteroaryl, are optionally substituted with one, two, or three R20a.
[00290] In embodiments, L2 is independently -C(O)-; L2 is independently bonded to a carbon atom of R5; and R5 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and 5-6 membered heteroaryl, wherein the Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20a. In embodiments, L2 is independently -C(O)-; R5 is independently a heteroaryl having the formula: ; R5a is independently O, S, CH, C(R20a), N, NH, or N(R20a); R5 comprises 0-3 independent R20a; and 0-4 R5a are independently N, NH, or N(R20a). In embodiments, L2 is independently -C(O)-; and R5 is independently a heteroaryl having the formula: ; R5a is independently CH, C(R20a), N, NH, or N(R20a); R5 comprises 0-3 independent R20a; and 0-4 R5a are independently N,
NH, or N(R20a). In embodiments, L2 is independently -C(O)-; R5 is independently ; R5a is independently CH, C(R20a), CH(R20a), QH, C(R20a)2, N, NH, or N(R20a); R5 comprises 0-3 independent R20a; and 0-4 R5a are independently N, NH, or N(R20a).
[00291] In embodiments, L2 is independently -C(O)-; and R5 is independently C3-iocycloalkyl, wherein C3- locycloalkyl is independently optionally substituted with one, two, or three R20a. In embodiments, L2 is independently -C(O)-; and R5 is independently cyclopropyl, wherein cyclopropyl is independently optionally substituted with one, two, or three F. In embodiments, L2 is independently -C(O)-; and R5 is independently cyclopropyl, wherein cyclopropyl is independently optionally substituted with one, two, or three CN. In embodiments, L2 is independently -C(O)-; and R5 is independently cyclopropyl, wherein cyclopropyl is independently optionally substituted with one, two, or three halogen.
[00292] In embodiments, R5 is independently hydrogen. In embodiments, R5 is independently halogen. In embodiments, R5 is independently R5 is independently oxo. In embodiments, R5 is independently -CN. In embodiments, R5 is independently Ci-6alkyl. In embodiments, R5 is independently C2-6alkenyl. In embodiments, R5 is independently C2-6alkynyl. In embodiments, R5 is independently Ci-6haloalkyl. In embodiments, R5 is independently C3-i2cycloalkyl. In embodiments, R5 is independently -CH2-C3-i2cycloalkyl. In embodiments, R5 is independently Ci-nheterocycloalkyl. In embodiments, R5 is independently -QH-Ci-nheterocycloalkyl. In embodiments, R5 is independently C6-i2aryl. In embodiments, R5 is independently -CH2-C6-i2aryl. In embodiments, R5 is independently -Cfh-Ci-nheteroaryl. In embodiments, R5 is independently Ci-nheteroaryl. In embodiments,
R5 is independently -OR12. In embodiments, R5 is independently -SR12. In embodiments, R5 is independently - N(R12)(R13). In embodiments, R5 is independently -C(0)0R12. In embodiments, R5 is independently - 0C(0)N(R12)(R13). In embodiments, R5 is independently -N(R15)C(0)N(R12)(R13). In embodiments, R5 is independently -N(R15)C(0)0R15. In embodiments, R5 is independently -N(R15)S(0)2R15. In embodiments, R5 is independently -C(0)R15. In embodiments, R5 is independently -S(0)R15. In embodiments, R5 is independently - 0C(0)R15. In embodiments, R5 is independently -C(0)N(R12)(R13). In embodiments, R5 is independently - C(0)C(0)N(R12)(R13). In embodiments, R5 is independently -N(R15)C(0)R15. In embodiments, R5 is independently -S(0)2R15. In embodiments, R5 is independently -S(0)2N(R12)(R13)-. In embodiments, R5 is independently S(=0)(=NH)N(R12)(R13). In embodiments, R5 is independently -CH2C(0)N(R12)(R13). In embodiments, R5 is independently -CH2N(R15)C(0)R15. In embodiments, R5 is independently -CH2S(0)2R15. In embodiments, R5 is independently and -CH2S(0)2N(R12)(R13). In embodiments, R5 is independently Ci-6alkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C2-6alkenyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C2-6alkynyl optionally substituted with one, two, or three R20a.
In embodiments, R5 is independently Ci-6haloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C3-i2cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently -CH2-C3-i2cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Ci-nheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently -Cfh-Ci-nheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C6-i2aryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently -CH2-C6-i2aryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently -Cfh-Ci-nheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cmheteroaryl optionally substituted with one, two, or three R20a.
[00293] In additional embodiments of the subject compound, R5 is independently selected from hydrogen, halogen, oxo, -CN, Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), and -C(0)R12, wherein Ci-6alkyl, C2-6alkenyl, and C2-6alkynyl, are optionally substituted with one, two, or three R20a. In embodiments of the subject compound, R5 is independently hydrogen. In further embodiments of the subject compound, R5 is independently halogen. In some embodiments of the subject compound, R5 is independently oxo. In some embodiments of the subject compound, R5 is independently -CN. In additional embodiments of the subject compound, R5 is independently Ci-6alkyl. In embodiments of the subject compound, R5 is independently C2- 6alkenyl. In some embodiments of the subject compound, R5 is independently C2-6alkynyl. In further embodiments of the subject compound, R5 is independently -OR12. In select embodiments of the subject compound, R5 is independently -N(R12)(R13). In additional embodiments of the subject compound, R5 is independently -C(0)0R12.
In embodiments of the subject compound, R5 is independently -0C(0)N(R12)(R13). In some embodiments of the subject compound, R5 is independently -C(0)R12. In select embodiments of the subject compound, R5 is independently -NH2. In further embodiments of the subject compound, R5 is independently -C(0)0H. In additional embodiments of the subject compound, R5 is independently -0C(0)NH2. In embodiments of the subject compound, R5 is independently -C(0)CH3.
[00294] In embodiments, R5 is independently Cialkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C2alkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cialkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cialkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Csalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cealkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C2alkenyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cialkcnyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cialkcnyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Csalkcnyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cealkenyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C2alkynyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cialkynyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cialkynyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Chalky m l optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cealkynyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cihaloalkyl. In embodiments, R5 is independently C2haloalkyl. In embodiments, R5 is independently Cihaloalkyl. In embodiments, R5 is independently Cihaloalkyl. In embodiments, R5 is independently Cshaloalkyl. In embodiments, R5 is independently Cehaloalkyl.
[00295] In embodiments, R5 is independently Cicycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cicycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cscycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cecycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C7cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cscycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cscycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Ciocycloalkyl optionally substituted with one, two, or three R20a.
[00296] In embodiments, R5 is independently C2heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cshetcrocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C-hetcrocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20a.
[00297] In embodiments, R5 is independently Cearyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C-arvl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Csaryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Csaryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cioaryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cnaryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cearyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C2heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cihctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cihctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cshctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Ceheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently C-hctcroaiy l optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Csheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cdictcroaiyl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cioheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently Cnheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R5 is independently -OH. In embodiments, R5 is independently -SH. In embodiments, R5 is independently -NH2. In embodiments, R5 is independently -C(0)0H. In embodiments, R5 is independently - 0C(0)NH2. In embodiments, R5 is independently -N(H)C(0)NH2. In embodiments, R5 is independently - N(H)C(0)0H. In embodiments, R5 is independently -N(H)S(0)2CH . In embodiments, R5 is independently - C(0)H. In embodiments, R5 is independently -S(0)CH . In embodiments, R5 is independently -0C(0)CH3. In embodiments, R5 is independently -C(0)NH2. In embodiments, R5 is independently -C(0)C(0)NH2. In embodiments, R5 is independently -N(H)C(0)H. In embodiments, R5 is independently -S(0)2CH3. In embodiments, R5 is independently -S(0)2NH2-. In embodiments, R5 is independently S(=0)(=NH)NH2. In embodiments, R5 is independently -CH2C(0)NH2. In embodiments, R5 is independently -CH2N(H)C(0)CH3. In embodiments, R5 is independently -CH2S(0)2CH3. In embodiments, R5 is independently and -CH2S(0)2NH2.
[00298] In embodiments, R5 is independently -OCH3. In embodiments, R5 is independently -SCH3. In embodiments, R5 is independently -N(CH3)(H). In embodiments, R5 is independently -C(0)0CH3. In embodiments, R5 is independently -0C(0)N(CH3)(H). In embodiments, R5 is independently -N(H)C(0)N(CH3)(H). In embodiments, R5 is independently -N(H)C(0)0CH3. In embodiments, R5 is independently -N(H)S(0)2CH3. In embodiments, R5 is independently -C(0)CH3. In embodiments, R5 is independently -S(0)CH3. In embodiments, R5 is independently -0C(0)CH3. In embodiments, R5 is independently -C(0)N(CH3)(H). In embodiments, R5 is independently -C(0)C(0)N(CH3)(H). In embodiments, R5 is independently -N(H)C(0)CH3. In embodiments, R5 is independently -S(0)2CH3. In embodiments, R5 is independently -S(0)2N(CH3)(H)-. In embodiments, R5 is independently S(=0)(=NH)N(CH3)(H). In embodiments, R5 is independently -CH2C(0)N(CH3)(H). In embodiments, R5 is independently -CH2N(H)C(0)CH3. In embodiments, R5 is independently -CH2S(0)2CH3. In embodiments, R5 is independently and -CH2S(0)2N(CH3)(H).
[00299] In embodiments, R5 is independently -0C(0)N(CH3)2. In embodiments, R5 is independently - N(H)C(0)N(CH3)2. In embodiments, R5 is independently -C(0)(CH3). In embodiments, R5 is independently - C(0)N(CH3)2. In embodiments, R5 is independently -C(0)C(0)N(CH3)2. In embodiments, R5 is independently - N(H)C(0)(CH3). In embodiments, R5 is independently -S(0)2N(CH3)2. In embodiments, R5 is independently S(=0)(=NH)N(CH3)2. In embodiments, R5 is independently -CH2C(0)N(CH3)2. In embodiments, R5 is independently and -CH2S(0)2N(CH3)2.
[00300] In embodiments, R5 is independently -CH3. In embodiments, R5 is independently -CF3. In embodiments, R5 is independently -CHF2. In embodiments, R5 is independently -CFH2. In embodiments, R5 is independently ethyl. In embodiments, R5 is independently propyl. In embodiments, R5 is independently isopropyl. In embodiments, R5 is independently butyl. In embodiments, R5 is independently tert-butyl.
[00301] In embodiments, R6 is independently halogen. In embodiments, R6 is independently R6 is independently oxo. In embodiments, R6 is independently -CN. In embodiments, R6 is independently Ci-6alkyl. In embodiments, R6 is independently C2-6alkenyl. In embodiments, R6 is independently C2-6alkynyl. In embodiments, R6 is independently Ci-6haloalkyl. In embodiments, R6 is independently C3-i2cycloalkyl. In embodiments, R6 is independently -CH2-C3-i2cycloalkyl. In embodiments, R6 is independently Ci-nheterocycloalkyl. In embodiments, R6 is independently -Cfh-Ci-nheterocycloalkyl. In embodiments, R6 is independently C6-i2aryl. In embodiments,
R6 is independently -CH2-C6-i2aryl. In embodiments, R6 is independently -Cfh-Ci-nheteroaryl. In embodiments, R6 is independently Ci-nheteroaryl. In embodiments, R6 is independently -OR12. In embodiments, R6 is independently -SR12. In embodiments, R6 is independently -N(R12)(R13). In embodiments, R6 is independently -C(0)0R12. In embodiments, R6 is independently -0C(0)N(R12)(R13). In embodiments, R6 is independently - N(R16)C(0)N(R12)(R13). In embodiments, R6 is independently -N(R16)C(0)0R15. In embodiments, R6 is independently -N(R16)S(0)2R15. In embodiments, R6 is independently -C(0)R15. In embodiments, R6 is independently -S(0)R15. In embodiments, R6 is independently -0C(0)R15. In embodiments, R6 is independently - C(0)N(R12)(R13). In embodiments, R6 is independently -C(0)C(0)N(R12)(R13). In embodiments, R6 is independently -N(R16)C(0)R15. In embodiments, R6 is independently -S/CfhR15. In embodiments, R6 is independently -S(0)2N(R12)(R13)-. In embodiments, R6 is independently S(=0)(=NH)N(R12)(R13). In embodiments, R6 is independently -CH2C(0)N(R12)(R13). In embodiments, R6 is independently -CH2N(R16)C(0)R15. In embodiments, R6 is independently -CH2S(0)2R15. In embodiments, R6 is independently and -CH2S(0)2N(R12)(R13). In embodiments, R6 is independently Ci-6alkyl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently C2-6alkenyl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently C2-6alkynyl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently Ci-6haloalkyl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently C3- ncycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently -CH2-C3- ncycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently Ci- liheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently -CH2-C1- liheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently C6-i2aryl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently -CH2-C6-i2aryl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently -Cfh-Ci-nheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R6 is independently Ci-nheteroaryl optionally substituted with one, two, or three R20a.
[00302] In additional embodiments of the subject compound, R1 is independently hydrogen. In select embodiments of the compound, R1 is independently Ci-6alkyl optionally substituted with one, two, or three R20a. In embodiments of the compound, R1 is independently methyl optionally substituted with one or two R20a. In further embodiments of the compound, R1 is independently methyl. In some embodiments of the compound, R1 is independently ethyl optionally substituted with one, two, or three R20a. In embodiments of the compound, R1 is independently ethyl. In some embodiments of the compound, R1 is independently propyl optionally substituted with one, two, or three R20a. In embodiments of the compound, R1 is independently propyl. In some embodiments, R1 is independently -CH2-C2- dictcrocycloalkyl optionally substituted with one, two, or three R20a. In some embodiments, R1 is independently - CH2-(monocyclic C2-8heterocycloalkyl) optionally substituted with one, two, or three R20a. In some embodiments,
R1 is independently -CH2-(monocyclic C3-5heterocycloalkyl) optionally substituted with one, two, or three R20a. In some embodiments, R1 is independently -CH2-(spirocyclic C2-nheterocycloalkyl) optionally substituted with one, two, or three R20a. In some embodiments, R1 is independently -CH2-(spirocyclic C3-iiheterocycloalkyl) optionally substituted with one, two, or three R20a. In some embodiments, R1 is independently -CH2-(fused C2- liheterocycloalkyl) optionally substituted with one, two, or three R20a. In some embodiments, R1 is independently - CH2-(spirocyclic Ce-sheterocycloalkyl) optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Ci-6alkyl. In embodiments, R1 is independently C2-6alkenyl. In embodiments, R1 is independently C2- 6alkynyl. In embodiments, R1 is independently C3-iocycloalkyl. In embodiments, R1 is independently -CH2-C3- locycloalkyl. In embodiments, R1 is independently C2-9heterocycloalkyl. In embodiments, R1 is independently - CH2-C2-9heterocycloalkyl. In embodiments, R1 is independently C6-ioaryl. In embodiments, R1 is independently - CH2-C6-ioaryl. In embodiments, R1 is independently -CEb-Ci-gheteroaryl. In embodiments, R1 is independently Ci- gheteroaryl. In embodiments, R1 is independently Ci-6alkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C2-6alkenyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C2-6alkynyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C3-iocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C3-iocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C2-9heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C6-ioaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently - CH2-C6-ioaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C1- gheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Ci-gheteroaryl optionally substituted with one, two, or three R20a.
[00303] In embodiments, R1 is independently Ci-6alkyl. In embodiments, R1 is independently C2-6alkenyl. In embodiments, R1 is independently C2-6alkynyl. In embodiments, R1 is independently Ci-6haloalkyl. In embodiments, R1 is independently C3-i2cycloalkyl. In embodiments, R1 is independently -CH2-C3-i2cycloalkyl. In embodiments, R1 is independently Ci-nheterocycloalkyl. In embodiments, R1 is independently -CH2-C1- liheterocycloalkyl. In embodiments, R1 is independently C6-i2aryl. In embodiments, R1 is independently -CH2-C6- naryl. In embodiments, R1 is independently -CEC-Ci-nheteroaryl. In embodiments, R1 is independently Ci- nheteroaryl.
[00304] In embodiments, R1 is independently Ci-6alkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C2-6alkenyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C2-6alkynyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Ci-6haloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C3-i2cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C3- ncycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Ci- liheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C1- liheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C6-i2aryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C6-i2aryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -Qk-Ci-nheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Ci-nheteroaryl optionally substituted with one, two, or three R20a.
[00305] In embodiments, R1 is independently Cialkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C2alkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C ialky l optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cialkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cialkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cealkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C2alkenyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cialkcnyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cialkcnyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Csalkcnyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cealkenyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C2alkynyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cialkynyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cialkynyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Csalkynyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cealkynyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cihaloalkyl. In embodiments, R1 is independently Cihaloalkyl. In embodiments, R1 is independently Cihaloalkyl. In embodiments, R1 is independently Cihaloalkyl. In embodiments, R1 is independently Cihaloalkyl. In embodiments, R1 is independently Cehaloalkyl.
[00306] In embodiments, R1 is independently Ci cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cicycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cscycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cecycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C7cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cscycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cscycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Ciocycloalkyl optionally substituted with one, two, or three R20a.
[00307] In embodiments, R1 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cdictcrocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cvheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20a.
[00308] In embodiments, R1 is independently Cearyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C-arvl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Csaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Csaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cioaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cnaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cearyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cihctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cihctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cihctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cihctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Ceheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently C-hetcroarvl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Csheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cihctcroarvl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cioheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently Cnheteroaryl optionally substituted with one, two, or three
R20a.
[00309] In embodiments, R1 is independently -CH2-C3cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C4cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CFF-Cscycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C6cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C7cycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CFF-Cscycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CFF-Cgcycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-Ciocycloalkyl optionally substituted with one, two, or three R20a.
[00310] In embodiments, R1 is independently -CH2-C2heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C3heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C4heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CFF-Csheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C6heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C7heterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CFF-Csheterocycloalkyl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CFF-Csiheterocycloalkyl optionally substituted with one, two, or three R20a.
[00311] In embodiments, R1 is independently -CH2-C6aryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C7aryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CFF-Csaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C9aryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-Cioaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-Cnaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-Ci2aryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C2heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C3heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C4heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CFF-Csheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C6heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-C7heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CFF-Csheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-Cs>heteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-Cioheteroaryl optionally substituted with one, two, or three R20a. In embodiments, R1 is independently -CH2-Cnheteroaryl optionally substituted with one, two, or three R20a.
[00312] In embodiments, R1 is independently -CH3. In embodiments, R1 is independently -CF3. In embodiments, R1 is independently -CHF2. In embodiments, R1 is independently -CFH2. In embodiments, R1 is independently ethyl. In embodiments, R1 is independently propyl. In embodiments, R1 is independently isopropyl. In embodiments, R1 is independently butyl. In embodiments, R1 is independently tert-butyl. [00313] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 p is an integer from 0 to 12;
X1 is selected from CH2, C(R4)(R6), C=N-OR4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), O, S, S(O), S(=0)(=NR4), S(0)2N(R4), N(R4)S(0)N(R4), N(R4)S(0)2N(R4), S(0)N(R4), 0C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0, C(R4)(R4)OC(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(R4), C(R4)(R4)S(0), C(R4)(R4)S(0)C(R4)(R4), C(R4)(R4)S(0)2C(R4)(R4), C(R4)(R4)S(=0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(R4)(R4)N(R4)C(0)N(R4), C(R4)(R4)S(0)2, C=NN(R4)(R4)C(R4)(R4), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R4)(R4), S(0)N(R4)C(R4)(R4), and 0C(0)N(R4)C(R4)(R4);
X2 is selected from N, C, C(R6), C(R4), CH, N(R4), N(R4), N(R6), O, S, S(O), C(H)(R6), C(R4)2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2; and X3 is selected from N, C, C(R6), and C(R4). [00314] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is p is an integer from 0 to 12;
X1 is selected from CH2, C(R4)(R6), C=N-OR4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), O, S, S(O), S(=0)(=NR4), S(0)2N(R4), N(R4)S(0)N(R4), N(R4)S(0)2N(R4), S(0)N(R4), 0C(0)N(R4), N(R4)C(0)N(R4), S(0)¾ CH2C(R4)(R6), CH2C(R4)(R6)CH2, C(R4)(R6)C(R4)(R6)C(R4)(R6),
independently an integer from 0 to 12.
[00324] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is
[00325] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7
[00326] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
[00327] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl are optionally substituted with one, two, or three R20g. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen and halogen. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen and fluoro. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is hydrogen. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is fluoro.
[00328] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from hydrogen, Ci-6alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl, wherein Ci-6alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c independently selected from halogen, Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from hydrogen, methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from hydrogen, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments, R8 is selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-yhctcroan l are optionally substituted with one, two, or three R20c. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from Ci-6alkyl, C3-iocycloalkyl, and C2-s>heterocycloalkyl, wherein Ci-6alkyl, C3-iocycloalkyl, and C2-s>heterocycloalkyl are optionally substituted with one, two, or three R20c independently selected from halogen, Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
[00329] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen or CN. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is CN.
[00330] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L1 is a bond. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L1 is selected from a Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -C(O)-, -NHC(O)-, -C(0)NH-,
CH2O, CH2NH, and CH2.
[00331] In embodiments, L1 is a bond. In embodiments, L1 is Ci-Cealkyl. In embodiments, L1 is C2-C6alkenyl. In embodiments, L1 is C2-C6alkynyl. In embodiments, L1 is -0-. In embodiments, L1 is -N(R14)-. In embodiments, L1 is -C(O)-. In embodiments, L1 is -N(R14)C(0)-. In embodiments, L1 is -C(0)N(R14)-. In embodiments, L1 is -S-. In embodiments, L1 is -S(0)2-. In embodiments, L1 is -S(O)-. In embodiments, L1 is -S(0)2N(R14)-. In embodiments, L1 is -S(0)N(R14)-. In embodiments, L1 is -N(R14)S(0)-. In embodiments, L1 is -N(R14)S(0)2-. In embodiments, L1 is -OCON(R14)-. In embodiments, L1 is - N(R14)C(0)0-. In embodiments, L1 is N(Rle). In embodiments, L1 is C(0)N(Rlc). In embodiments, L1 is S(0)2N(R1c). In embodiments, L1 is S(0)N(Rlc). In embodiments, L1 is C(Rlf)(Rlg)0. In embodiments, L1 is C(Rlf)(Rlg)N(Rlc). In embodiments, L1 is C(Rlf)(Rlg). In embodiments, L1 is -N(H)-. In embodiments, L1 is -N(H)C(0)-. In embodiments, L1 is -C(0)N(H)-. In embodiments, L1 is -S(0)2N(H)-. In embodiments, L1 is -S(0)N(H)-. In embodiments, L1 is -N(H)S(0)-. In embodiments, L1 is -N(H)S(0)2-.
In embodiments, L1 is -OCON(H)-. In embodiments, L1 is -N(H)C(0)0-. In embodiments, L1 is -N(H)-.
In embodiments, L1 is -C(0)N(H)-. In embodiments, L1 is -S(0)2N(H)-. In embodiments, L1 is - S(0)N(H)-. In embodiments, L1 is -CH2O-. In embodiments, L1 is -CH2N(H)-. In embodiments, L1 is -
CH2-.
[00332] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
R19 is a monocyclic ring. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a bicyclic ring system. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a polycyclic ring system. In embodiments of the
I II
B,x9 subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is: X6
Q1, Q3, and Q5 are independently N or C(Rld);
Q4 and Q6 are independently O, S, C(Rla)(Rlb), or N(Rlc);
X4, X5, X6, X9, X10, X11, and X12 are independently selected from C(Rla) or N;
X7 and X8 are independently selected from C(Rla), C(Rla)(Rlb), N, or N(Rlc); each Rla, Rlb, Rld, and Rlh are each independently selected from hydrogen, halogen, -CN, CYr, alkyl. CY (Jialoalkyl. CYr, alkenyl. CYr,alkynyl. C3-iocycloalkyl, C2-9heterocycloalkyl, Ce-ioaryl, Ci-9heteroaryl, - OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), - N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), - C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), - CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci_ (,alkyl. CYr, alkenyl. CYr,alkynyl. C3-iocycloalkyl, C2-9heterocycloalkyl, Ce-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R201; or Rla and Rlb bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a Ce-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, CYioaryl ring, 5-12 membered heteroaryl ring, or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlh and one of Rla, Rlb, Rlc, and Rld bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a Ce-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a CYioaryl ring, a 5-12 membered heteroaryl ring, and C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; and each Rlc is independently selected from hydrogen, CYr,alkyl. CYr, alkenyl. CYr,alkynyl. C3-iocycloalkyl, C2. 9heterocycloalkyl, Ce-ioaryl, Ci-9heteroaryl, wherein CYr, alkyl. CYr, alkenyl. CYr,alkynyl. C3- locycloalkyl, C2-9heterocycloalkyl, Ce-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R201.
[00333] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
[00334] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R2 is selected from
[00335] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, each R5 is independently selected from:
[00336] In an aspect is provided a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(0), S(0), or S(0)2; V is C(R16) or N;
R10 is -L7-R7; V is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -
S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein Ci-C6alkyl, C2-C6alkenyl, and C2-C6alkynyl, are optionally substituted with one, two, or three R20a;
R7 is a 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl are optionally substituted with one or more R1, one or more R4, or one or more R6; two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3- i2cycloalkyl. Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R1 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3- i2cycloalkyl. -CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CH2-Ci-nheterocycloalkyl, C6-i2aryl, -CH2-C6- i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3-i2cycloalkyl, -CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CH2-Ci-nheterocycloalkyl, C6-i2aryl, -CH2- C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R4 is independently selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-yhctcroan l. -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20a;
R6 is -L2-R5; each L2 is independently selected from a bond, G-Galkyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, - S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, - N(R14)C(0)0-, and -N(R14)C(0)N(R14)-; each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20c;
R17 is -G-R19;
L1 is selected from a bond, G-Galkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, - C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, - OCON(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg); Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-s>heterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. -OR12, -SR12, -N(R12)(R13), - C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-dictcroarvl are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-dictcroarvl. wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201
R19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3- ncycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20g;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, - CH2S(0)2N(R12)(R13), -(Ci-C6alkyl)-R12b, -(C2-6alkenyl)-R12b, -(C2-6alkynyl)-R12b, -0-R12a, -N(R14)-R12b, - S-R12b, -(C3-iocycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-ioaryl)-R12b, or -(Ci-9heteroaryl)-R12b, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2- yhctcrocycloalkvl. -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20b; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-CI- gheteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-CI- gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R201 are each independently selected from halogen, -CN, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2. gheterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, Ci-gheteroaryl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), - 0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-CI- gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-yhctcroan l: each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; and indicates a single or double bond such that all valences are satisfied.
[00337] In an aspect is provided a compound of Formula (IF), or a pharmaceutically acceptable salt or solvate thereof: Formula (IF); wherein
W is C(O), S(O), or S(0)2;
V is C(R16) or N;
R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -
S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R20a;
R7 is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6; two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3- i2cycloalkyl. Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R1 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3- i2cycloalkyl. -CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CH2-Ci-nheterocycloalkyl, C6-i2aryl, -CH2-C6- i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3-i2cycloalkyl, -CH2-C3-i2cycloalkyl, Ci-nheterocycloalkyl, -CH2-Ci-nheterocycloalkyl, C6-i2aryl, -CH2- C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R4 is independently selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroaiyl. -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, Gs- ioaryl, and Ci-yhctcroan l are optionally substituted with one, two, or three R20a;
R6 is -L2-R5; each L2 is independently selected from a bond, Ci-Cealkyl, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, - S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, - N(R14)C(0)0-, and -N(R14)C(0)N(R14)-; each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. dictcrocycloalkyl. C6-ioaryl, Ci-yhctcroan l. -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20c;
R17 is -lA-R19;
L1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, - C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, - OCON(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg);
Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), - C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,- ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201
R19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3- i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, Gs-
R16
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, - CH2S(0)2N(R12)(R13), -(Ci-C6alkyl)-R12b, -(C2.6alkenyl)-R12b, -(C2.6alkynyl)-R12b, -0-R12a, -N(R14)-R12b, - S-R12b, -(C3-iocycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-ioaryl)-R12b, or -(Ci-9heteroaryl)-R12b, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2. gheterocycloalkyl, -C(R12c)2-C2-9heterocyeloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R20d;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2. gheterocycloalkyl, -C(R12c)2-C2-9heterocyeloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R20d;
R12c is independently selected from hydrogen and R20k;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20b; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-CI- gheteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, R201, and R20k are each independently selected from halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-ioaryl, -CFF-G-ioaryl, -CH2-Ci-9heteroaryl, Ci-gheteroaryl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), - 0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CFF-G-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; and indicates a single or double bond such that all valences are satisfied.
[00338] In some embodiments of Formula (IF), or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the a 4- 12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6; wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a. [00339] In an aspect is provided a compound of Formula (I”), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O), S(O), or S(0)2;
V is C(R17) and J is C(R16), or V is C(R17) and J is N, or J is C(R17) and V is C(R16), or J is C(R17) and V is N;
R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -
S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, and 2 to 4 membered heteroalkylene linker are unsubstituted or optionally substituted;
R7 is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are unsubstituted or optionally substituted;
R8 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. dictcrocycloalkyl. C6-ioaryl, Ci-dictcroarvl. -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-yhctcroan l are unsubstituted or optionally substituted;
R17 is -G-R19;
L1 is selected from a bond, G-Galkyl, C2-C6alkenyl, C2-Galkynyl, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, - C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, - OCON(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg);
Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), - C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4- 7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are unsubstituted or optionally substituted;
Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. loaryl, and Ci-<jhctcroaiyl. wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted;
R19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the G- ncycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are unsubstituted or optionally substituted;
R16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, G- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G- ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, - CH2S(0)2N(R12)(R13), -(Ci-C6alkyl)-R12b, -(C2-6alkenyl)-R12b, -(C2-6alkynyl)-R12b, -0-R12a, -N(R14)-R12b, - S-R12b, -(C3-iocycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-ioaryl)-R12b, or -(Ci-9heteroaryl)-R12b, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- gheteroaryl are unsubstituted or optionally substituted;
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-G-iocycloalkyl, G- gheterocycloalkyl, -C(R12c)2-G-9heterocyeloalkyl, C6-ioaryl, -C(R12c)2-G-ioaryl, -C(R12c)2-G-9heteroaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl are unsubstituted or optionally substituted;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2- gheterocycloalkyl, -C(R12c)2-C2-9heterocyeloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl are unsubstituted or optionally substituted;
R12c is selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1. 9heteroaryl, Ci-sheteroaiyl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted; eachR21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-yhctcroarvl: each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-siheteroaryl;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; or R12 and R13, together with the nitrogen to which they are attached, form an unsubstituted or optionally substituted C2-9heterocycloalkyl ring; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G- ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted; indicates a single or double bond such that all valences are satisfied.
[00340] In some embodiments of Formula (I”), or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the a 4- 12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted or unsubstituted.
[00341] In an aspect is provided a compound of Formula (II”), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O), S(O), or S(0)2;
V is C(R16) or N;
R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -
S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, and 2 to 4 membered heteroalkylene linker are unsubstituted or optionally substituted;
R7 is a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are unsubstituted or optionally substituted;
R8 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. dictcrocycloalkyl. C6-ioaryl, Ci-dictcroarvl. -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-yhctcroan l are unsubstituted or optionally substituted;
R17 is -G-R19;
L1 is selected from a bond, G-Galkyl, C2-C6alkenyl, C2-Galkynyl, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, - C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, - OCON(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg);
Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), - C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4- 7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are unsubstituted or optionally substituted;
Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. loaryl, and Ci-<jhctcroaiyl. wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted;
R19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the G- ncycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are unsubstituted or optionally substituted;
R16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, G- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G- ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, - CH2S(0)2N(R12)(R13), -(Ci-C6alkyl)-R12b, -(C2-6alkenyl)-R12b, -(C2-6alkynyl)-R12b, -0-R12a, -N(R14)-R12b, - S-R12b, -(C3-iocycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-ioaryl)-R12b, or -(Ci-9heteroaryl)-R12b, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- gheteroaryl are unsubstituted or optionally substituted;
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-G-iocycloalkyl, G- gheterocycloalkyl, -C(R12c)2-G-9heterocyeloalkyl, C6-ioaryl, -C(R12c)2-G-ioaryl, -C(R12c)2-G-9heteroaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl are unsubstituted or optionally substituted;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2- gheterocycloalkyl, -C(R12c)2-C2-9heterocyeloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl are unsubstituted or optionally substituted;
R12c is selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1. 9heteroaryl, Ci-sheteroaiyl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted; eachR21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-yhctcroan l: each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; or R12 and R13, together with the nitrogen to which they are attached, form an unsubstituted or optionally substituted C2-9heterocycloalkyl ring; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G- ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are unsubstituted or optionally substituted; indicates a single or double bond such that all valences are satisfied.
[00342] In some embodiments of Formula (II”), or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4- 12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the a 4- 12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted or unsubstituted.
[00343] In an aspect is provided a compound of Formula (1-1), or a pharmaceutically acceptable salt or solvate thereof: wherein W is C(O), S(O), or S(0)2;
V is C(R17) and J is C(R16), or V is C(R17) and J is N, or J is C(R17) and V is C(R16), or J is C(R17) and V is N;
R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -
S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R20a;
R7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6; wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one, two, or three R20a; each R1 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3- i2cycloalkyl. -CH2-C3-i2cycloalkyl, C2-nheterocycloalkyl, -CH2-C2-nheterocycloalkyl, C6-i2aryl, -CH2-C6- i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3-i2cycloalkyl, -CH2-C3-i2cycloalkyl, C2-nheterocycloalkyl, -CH2-C2-nheterocycloalkyl, C6-i2aryl, -CH2- C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R4 is independently selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, C2-9heterocycloalkyl, C6-i2aryl, Ci-nheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R12, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R12, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, G,. i2aryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a;
R6 is -L2-R5; each L2 is independently selected from a bond, G-Galkyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, - S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, - N(R14)C(0)0-, and -N(R14)C(0)N(R14)-; each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, G- i2aryl, Ci-nheteroaiyl, -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), - C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), - CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20c;
R17 is -L!-R19;
L1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, - C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, - OCON(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg);
Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-i2aryl, Ci-nheteroaryl, -OR12, -SR12, -N(R12)(R13), - C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, naryl, Ci-nheteroaryl, wherein Chalky 1, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, CV,. naryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R201;
R19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3- ncycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, C2-9heterocycloalkyl, Gs-naryl, Ci-nheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, CV,. naryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-i2aryl, Ci-nheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, G,- S-R12b, -(C3-iocycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-ioaryl)-R12b, or -(Ci-9heteroaryl)-R12b, wherein said Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d;
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2- gheterocycloalkyl, -C(R12c)2-C2-9heterocyeloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2- gheterocycloalkyl, -C(R12c)2-C2-9heterocyeloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d;
R12c is independently selected from hydrogen and R20k;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-i2aryl, Ci-nheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, G,. naryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20b; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, G- naryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, G- gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, R201, and R20k are each independently selected from halogen, oxo, - CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, Ci-nheteroaryl, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, Gs-naryl, -CH2-C6- i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25; eachR21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2. dictcrocycloalkyl. C6-i2aryl, and Ci-nheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2. dictcrocycloalkyl. C6-i2aryl, and Ci-nheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2. siheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl; and indicates a single or double bond such that all valences are satisfied.
[00344] In an aspect is provided a compound of Formula (II-l), or a pharmaceutically acceptable salt or solvate thereof: Formula (II-l); wherein
W is C(O), S(O), or S(0)2;
V is C(R16) or N;
R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -
S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R20a;
R7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6; two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl, wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one, two, or three R20a; each R1 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3- ncycloalkyl, -CH2-C3-i2cycloalkyl, C2-iiheterocycloalkyl, -CH2-C2-iiheterocycloalkyl, C6-i2aryl, -CH2-C6- naryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6haloalkyl, C3-i2cycloalkyl, -CH2-C3-i2cycloalkyl, C2-iiheterocycloalkyl, -CH2-C2-iiheterocycloalkyl, C6-i2aryl, -CH2- C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a; each R4 is independently selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, C2-9heterocycloalkyl, C6-i2aryl, Ci-nheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R12, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R12, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, CV,. naryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a;
R6 is -L2-R5; each L2 is independently selected from a bond, Ci-Cealkyl, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, - S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, - N(R14)C(0)0-, and -N(R14)C(0)N(R14)-; each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, i2aryl, Ci-nheteroaiyl, -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), - C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), - CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20c;
R17 is -lA-R19;
L1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, - C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, - OCON(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg);
Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, Gs-naryl, Ci-nheteroaryl, -OR12, -SR12, -N(R12)(R13), - C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, - S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201; Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, naryl, Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, CV,. naryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R201;
R19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3- ncycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, C2-9heterocycloalkyl, C6-i2aryl, Ci-nheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, CV,. naryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-i2aryl, Ci-nheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, CV,.
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2- gheterocycloalkyl, -C(R12c)2-C2-9heterocyeloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R20d;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2- gheterocycloalkyl, -C(R12c)2-C2-9heterocyeloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -C(R12c)2-C3-iocycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-ioaryl, -C(R12c)2-C6-ioaryl, -C(R12c)2-Ci-9heteroaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R20d;
R12c is independently selected from hydrogen and R20k;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-i2aryl, Ci-nheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, Gs- i2aryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20b; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-CI- nheteroaryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-CI- nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, G,. i2aryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2. gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, R201, and R20k is independently selected from halogen, oxo, -CN, G- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2. gheterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, Ci-nheteroaryl, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, G- locycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-G- i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, G- gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, G- gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2. gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl; and indicates a single or double bond such that all valences are satisfied.
[00345] In embodiments of Formula 1-1, one R4 is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein; [00346] In embodiments of Formula II-l, one R4 is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein;
[00347] In an aspect is provided a compound of Formula (I-G), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O); V is C(R17) and J is C(R16);
R10 is -L7-R7;
L7 is a bond, -0-, or -N(R14)-;
R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more R4, and optionally substituted with one or more R6; each R4 is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-i2aiyl, Ci-nheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R12, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R12, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, CV,. naryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a; one R4 is optionally independently an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein;
R6 is -L2-R5; each L2 is independently selected from a bond and -C(O)-; each R5 is independently hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein; each R5 is independently selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, C2-9heterocycloalkyl, Gs-naryl, Ci-nheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R12, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R12, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, CV,. naryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20a;
R8 is selected from -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, and -C(0)R12, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c;
R17 is -LCR19; L1 is a bond;
R19 is selected from a C6-i2aryl and C2-i2heteroaryl, wherein the C6-i2aryl and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6 cycloalkyl, Cz-sheterocycloalkyl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -C(0)R12, -C(0)N(R12)(R13), and -N(R14)C(0)R12, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, and C2-5heterocycloalkyl, are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen and halogen;
R2 is -0-R12a;
R12a is -C(R12c)2-C2-9heterocycloalkyl, wherein -C(R12c)2-C2-9heterocyeloalkyl is optionally substituted with one, two, or three R20d;
R12c is independently selected from hydrogen and Ci-3alkyl;
X is C(R3) orN;
R3 is selected from hydrogen and -CN; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, CV,. naryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20c, R20d, R20e, R20f, and R201 is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, Ci-nheteroaryl, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6- naryl, -CEC-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25; eachR21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, Gs-naryl, and Ci-nheteroaryl; and indicates a single or double bond such that all valences are satisfied.
[00348] In an aspect is provided a compound of Formula (1-1”), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O); V is C(R17) and J is C(R16);
R10 is -L7-R7;
L7 is a bond, -0-, or -N(R14)-;
R7 is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl each comprises one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl are each optionally substituted with one or more R4;
R4 are independently selected from halogen, oxo, -CN, -C(0)R12, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, C2-9heterocycloalkyl, and -OR12, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20a;
R8 is selected from Ci-6alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl, wherein Ci-6alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c;
R17 is -LriR19;
L1 is a bond;
R19 is selected from a C6-i2aryl and 9-10 membered heteroaryl, wherein the C6-i2aryl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, -OH, - NH2, wherein Ci-6alkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen and halogen;
R2 is -0-R12a;
R12a is -C(R12C)2-(5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d;
R12c is independently selected from hydrogen and methyl;
X is N; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, G,. naryl, and Ci-nheteroaryl, wherein Chalky 1, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20c, R20d, R20e, R20f, and R201 is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CFF-Ci-nheteroaryl, Ci-nheteroaryl, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-G- naryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25; eachR21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, G-naryl, and Ci-nheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, G-naryl, and Ci-nheteroaryl; and indicates a single or double bond such that all valences are satisfied.
[00349] In an aspect is provided a compound of Formula (1-1”), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O); V is C(R17) and J is C(R16); R10 is -L7-R7; L7 is a bond, -0-, or -N(R14)-;
R7 is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl each comprises one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl are each substituted with one or more R4;
R4 are independently selected from halogen, oxo, -CN, -C(0)R12, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, C2-9heterocycloalkyl, and -OR12, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20a;
R8 is selected from Ci-6alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl, wherein Ci-6alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c;
R17 is -LriR19;
L1 is a bond;
R19 is selected from a C6-i2aryl and 9-10 membered heteroaryl, wherein the C6-i2aryl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, -OH, - NH2, wherein Ci-6alkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen and halogen;
R2 is -0-R12a;
R12a is -C(R12C)2-(5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d;
R12c is independently selected from hydrogen and methyl;
X is N; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, Gs-naryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and CM ihctcroan l. wherein Chalky 1, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and C1-1 ihctcroan l are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, CV,. naryl, and Ci-nheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20c, R20d, R20e, R20f, and R201 is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -QH-Cs-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, Ci-nheteroaryl, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3- locycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6- i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2. gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2. gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2. gheterocycloalkyl, C6-i2aryl, and Ci-nheteroaryl; and indicates a single or double bond such that all valences are satisfied.
[00350] In embodiments, R4is independently -C(0)N(R12)(R13), -N(R14)C(0)R12, or -C(0)R12. In embodiments, R4 is independently -C(0)N(R12)(R13). In embodiments, R4 is independently -N(R14)C(0)R12. In embodiments, R4 is independently -C(0)R12.
[00351] In embodiments, R4 is independently -C(0)NH(R12) and R12 is independently Ci-gheteroaryl, wherein Ci- gheteroaryl is optionally substituted with one, two, or three R20d. In embodiments, R4 is independently - C(0)NH(R12) and R12 is independently Ci-shctcroan l. wherein Ci-shctcroarvl is optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)NH(R12) and R12 is independently C’l-shctcroarvl.
[00352] In embodiments, R4 is independently -C(0)R12 and R12 is independently selected from C2-6alkenyl, C2. 6alkynyl, C2-9heterocycloalkyl, and Ci-gheteroaryl, wherein C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, and Ci- gheteroaryl are optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is C2alkenyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently - C(0)R12 and R12 is Cialkcnyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is Cialkcnyl optionally substituted with one, two, or three R20d. In embodiments, R4 is -C(0)R12 and R12 is Cialkcnyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is Gialkenyl optionally substituted with one, two, or three R20d.
[00353] In embodiments, R4 is independently -C(0)R12 and R12 is independently C2alkynyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Cialkynyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Cialkynyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently - C(0)R12 and R12 is independently Cialkynyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Cealkynyl optionally substituted with one, two, or three R20d. [00354] In embodiments, R4 is independently -C(0)R12 and R12 is independently C2heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently C3heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently - C(0)R12 and R12 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Cshctcrocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently C-hctcrocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R20d.
[00355] In embodiments, R4 is independently -C(0)R12 and R12 is independently Ciheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Ciheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Ciheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Ciheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Cshctcroarvl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Ceheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Ciheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Csheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -C(0)R12 and R12 is independently Ceheteroaryl optionally substituted with one, two, or three R20d.
[00356] In embodiments, R4 is independently -NHC(0)R12 and R12 is independently selected from C2-6alkenyl, C2- 6alkynyl, C2-9heterocycloalkyl, and C’l-dictcroarvl. wherein C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, and Ci- eheteroaryl are optionally substituted with one, two, or three R20d. In embodiments, R4 is independently - NHC(0)R12 and R12 is independently C2alkenyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Cialkcnyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Cialkcnyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Cialkcnyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Cealkenyl optionally substituted with one, two, or three R20d.
[00357] In embodiments, R4 is independently -NHC(0)R12 and R12 is independently C2alkynyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently C3alkynyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Cialkynyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Csalkynyl optionally substituted with one, two, or three R20d.
In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Gialkynyl optionally substituted with one, two, or three R20d.
[00358] In embodiments, R4 is independently -NHC(0)R12 and R12 is independently C2heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently - NHC(0)R12 and R12 is independently C ihctcrocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Ceheterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently - NHC(0)R12 and R12 is independently C7heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Csheterocycloalkyl optionally substituted with one, two, or three R20d.
[00359] In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Ciheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently C2heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Cdictcroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Ciheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Cdictcroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Ceheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently C7heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Csheteroaryl optionally substituted with one, two, or three R20d. In embodiments, R4 is independently -NHC(0)R12 and R12 is independently Csheteroaryl optionally substituted with one, two, or three R20d.
[00360] In an aspect is provided a compound of Formula (I-G"). or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O); V is C(R17) and J is C(R16);
R10 is -L7-R7;
L7 is a bond;
R7 is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl each comprises one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl are each optionally substituted with one or more R4;
R4 is independently selected from halogen; Ci-6alkyl, wherein Ci-6alkyl is optionally substituted with one, two, or three R20a; and -C(0)R15, wherein said R15 is independently selected from Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f; R8 is selected from Ci-4alkyl and C3-4cycloalkyl, wherein Ci-4alkyl and C3-4cycloalkyl are optionally substituted with one, two, or three R20c;
R17 is -L!-R19;
L1 is a bond;
R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, C2-3alkynyl, -OH, - NH2, wherein Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, and C2-3alkynyl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen and F;
R2 is -0-R12a;
R12a is -C(R12C)2-(5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d;
R12c is independently selected from hydrogen and methyl;
X is N; and each R20a, R20c, R20d, R20e, R20f, and R201 is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -QH-Cs-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2- dictcrocycloalkyl. C6-i2aryl, -CH2-C6-i2aryl, -QH-Ci-nheteroaryl, Ci-nheteroaryl, -OH, -OCH3, -NH2, - N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00361] In an aspect is provided a compound of Formula (I-G”), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O); V is C(R17) and J is C(R16);
R10 is -L7-R7;
L7 is a bond;
R7 is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl each comprises one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl are each substituted with one or more R4;
R4 is independently selected from halogen; Ci-6alkyl, wherein Ci-6alkyl is optionally substituted with one, two, or three R20a; and -C(0)R15, wherein said R15 is independently selected from Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f;
R8 is selected from Ci-4alkyl and C3-4cycloalkyl, wherein Ci-4alkyl and C3-4cycloalkyl are optionally substituted with one, two, or three R20c;
R17 is -LriR19;
L1 is a bond;
R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, C2-3alkynyl, -OH, - NH2, wherein Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, and C2-3alkynyl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen and F;
R2 is -0-R12a;
R12a is -C(R12C)2-(5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d;
R12c is independently selected from hydrogen and methyl;
X is N; and each R20a, R20c, R20d, R20e, R20f, and R201 is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -QH-Cs-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, Ci-iiheteroaryl, -OH, -OCH3, -NH2, - N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-iocycloalkyl, -QH-Cs-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -QH-Ci-iiheteroaryl, and Ci-iiheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00362] In an aspect is provided a compound of Formula (1-3), or a pharmaceutically acceptable salt or solvate thereof: Formula (1-3); wherein R7 is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl each comprises one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl are each substituted with one or more R4;
R4 is independently selected from halogen; Ci-6alkyl, wherein Ci-6alkyl is optionally substituted with one, two, or three R20a; and -C(0)R15, wherein said R15 is independently selected from Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f;
R8 is selected from cyclopropyl, fluoro-substituted cyclopropyl, methyl, ethyl, n-propyl, -CH2CH2CN, and - CH2CH2CH2CN; each R20a and R20f are independently selected from halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, -CFF-Cs-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6- i2aryl, -CH2-Ci-nheteroaiyl, Ci-nheteroaryl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, - NHC(0)H, -C(0)H, and -C(0)CH , wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OH, -OCH3, -NH2, - N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00363] In an aspect is provided a compound of Formula (1-4), or a pharmaceutically acceptable salt or solvate thereof: Formula (1-4); wherein
R7 is a 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, or 7-12 membered bridged bicyclic heterocycloalkyl, wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl each comprises one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl, 7-12 membered fused bicyclic heterocycloalkyl, 7-12 membered spirocyclic bicyclic heterocycloalkyl, and 7-12 membered bridged bicyclic heterocycloalkyl are each optionally substituted with one or more R4;
R4 is independently selected from -C(0)R15, wherein said R15 is independently selected from Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f; halogen; and Ci-6alkyl, wherein Ci-6alkyl is optionally substituted with one, two, or three R20a;
R8 is selected from cyclopropyl, fluoro-substituted cyclopropyl, methyl, ethyl, n-propyl, -CH2CH2CN, and - CH2CH2CH2CN; each R20a and R20f are independently selected from halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- locycloalkyl, -CH2-C3-iocycloalkyl, C2-s>heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2- Ci-iiheteroaryl, Ci-iiheteroaiyl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and - C(0)CH , wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci.6alkoxy, Ci-6haloalkoxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and - C(0)CH3.
[00364] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is C(R3). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, X is N. [00365] In an aspect is provided a compound of Formula (I-G"). or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O); V is C(R17) and J is C(R16); R10 is -L7-R7; L7 is a bond;
R7 is a 5-7 membered monocyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 5-7 membered monocyclic heterocycloalkyl is optionally substituted with one or more R4;
R4 is independently selected from 1) -C(0)R15, wherein said R15 is independently selected from Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f; 2) halogen; and 3) Ci-6alkyl optionally substituted with one, two, or three R20a;
R8 is selected from Ci-4alkyl and cyclopropyl, wherein Ci-4alkyl and cyclopropyl are optionally substituted with one, two, or three R20c;
X is N; and each R20a, R20c, and R20f is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6- i2aryl, -CH2-Ci-nheteroaiyl, Ci-nheteroaryl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, - NHC(0)H, -C(0)H, and -C(0)CH , wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OH, -OCH3, -NH2, - N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00366] In an aspect is provided a compound of Formula (I-G”), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O); V is C(R17) and J is C(R16); R10 is -L7-R7; L7 is a bond;
R7 is a 7-12 membered fused bicyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 7-12 membered fused bicyclic heterocycloalkyl is optionally substituted with one or more R4;
R4 is independently selected from 1) -C(0)R15, wherein said R15 is independently selected from Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f; 2) halogen; and 3) Ci-6alkyl optionally substituted with one, two, or three R20a;
R8 is selected from Ci-4alkyl and cyclopropyl, wherein Ci-4alkyl and cyclopropyl are optionally substituted with one, two, or three R20c;
R16 is selected from hydrogen and F;
X is N; and each R20a, R20c, and R20f is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-s>heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6- i2aryl, -CH2-Ci-nheteroaiyl, Ci-nheteroaiyl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, - NHC(0)H, -C(0)H, and -C(0)CH3, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OH, -OCH3, -NH2, - N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00367] In an aspect is provided a compound of Formula (I-G”), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O); V is C(R17) and J is C(R16); R10 is -L7-R7; L7 is a bond;
R7 is a 7-10 membered spirocyclic bicyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 7-10 membered spirocyclic bicyclic heterocycloalkyl is optionally substituted with one or more
R4;
R4 is independently selected from 1) -C(0)R15, wherein said R15 is independently selected from Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f; 2) halogen; and 3) Ci-6alkyl optionally substituted with one, two, or three R20a;
R8 is selected from Ci-4alkyl and cyclopropyl, wherein Ci-4alkyl and cyclopropyl are optionally substituted with one, two, or three R20c;
R16 is selected from hydrogen and F;
X is N; and each R20a, R20c, and R20f is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6- i2aryl, -CH2-Ci-nheteroaiyl, Ci-nheteroaiyl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)OH, -C(0)NH2, - NHC(0)H, -C(0)H, and -C(0)CH , wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OH, -OCH3, -NH2, - N(CH3)2, -C(0)OH, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00368] In an aspect is provided a compound of Formula (I-G”), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O); V is C(R17) and J is C(R16); R10 is -L7-R7; L7 is a bond;
R7 is a 7-10 membered bridged bicyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 7-10 membered bridged bicyclic heterocycloalkyl is optionally substituted with one or more
R4;
R4 is independently selected from 1) -C(0)R15, wherein said R15 is independently selected from Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f; 2) halogen; and 3) Ci-6alkyl optionally substituted with one, two, or three R20a;
R8 is selected from Ci-4alkyl and cyclopropyl, wherein Ci-4alkyl and cyclopropyl are optionally substituted with one, two, or three R20c;
X is N; and each R20a, R20c, and R20f is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-s>heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6- i2aryl, -CH2-Ci-nheteroaiyl, Ci-nheteroaiyl, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, - NHC(0)H, -C(0)H, and -C(0)CH3, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3- locycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-C1- nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OH, -OCH3, -NH2, - N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00369] In an aspect is provided a compound of Formula (I-G”), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O); V is C(R17) and J is C(R16); R10 is -L7-R7; L7 is a bond;
R7 is a 5-8 membered monocyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 5-8 membered monocyclic heterocycloalkyl is optionally substituted with one or more R4;
R4 is independently selected from 1) -C(0)R15, wherein said R15 is independently selected from Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f; 2) halogen; and 3) Ci-6alkyl optionally substituted with one, two, or three R20a;
R8 is selected from Ci-4alkyl and cyclopropyl, wherein Ci-4alkyl and cyclopropyl are optionally substituted with one, two, or three R20c;
R17 is -I^-R19; L1 is a bond;
R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, C2-3alkynyl, -OH, - NH2, wherein Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, and C2-3alkynyl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen and F;
R2 is -0-R12a; R12a is -C(R12c)2-(5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d; R12c is independently selected from hydrogen and methyl;
X is N; and each R20a, R20c, R20d, R20e, R20f, and R201 is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -QH-Cs-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2- dictcrocycloalkyl. C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, Ci-nheteroaryl, -OH, -OCH3, -NH2, - N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00370] In an aspect is provided a compound of Formula (I-G”), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O); V is C(R17) and J is C(R16); R10 is -L7-R7; L7 is a bond;
R7 is a 7-12 membered fused bicyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 7-12 membered fused bicyclic heterocycloalkyl is optionally substituted with one or more R4;
R4 is independently selected from 1) -C(0)R15, wherein said R15 is independently selected from Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f; 2) halogen; and 3) Ci-6alkyl optionally substituted with one, two, or three R20a;
R8 is selected from Ci-4alkyl and cyclopropyl, wherein Ci-4alkyl and cyclopropyl are optionally substituted with one, two, or three R20c;
R17 is -I^-R19; L1 is a bond;
R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, C2-3alkynyl, -OH, - NH2, wherein Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, and C2-3alkynyl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen and F;
R2 is -0-R12a; R12a is -C(R12c)2-(5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d; R12c is independently selected from hydrogen and methyl;
X is N; and each R20a, R20c, R20d, R20e, R20f, and R201 is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -QH-Cs-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2- dictcrocycloalkyl. Gs-naryl, -CH2-C6-i2aryl, -QH-Ci-nheteroaryl, Ci-nheteroaryl, -OH, -OCH3, -NH2, - N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)0H, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00371] In an aspect is provided a compound of Formula (I-G”), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O); V is C(R17) and J is C(R16); R10 is -L7-R7; L7 is a bond;
R7 is a 7-10 membered spirocyclic bicyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 7-10 membered spirocyclic bicyclic heterocycloalkyl is optionally substituted with one or more
R4;
R4 is independently selected from 1) -C(0)R15, wherein said R15 is independently selected from Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f; 2) halogen; and 3) Ci-6alkyl optionally substituted with one, two, or three R20a;
R8 is selected from Ci-4alkyl and cyclopropyl, wherein Ci-4alkyl and cyclopropyl are optionally substituted with one, two, or three R20c;
R17 is -LriR19; L1 is a bond;
R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, C2-3alkynyl, -OH, - NH2, wherein Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, and C2-3alkynyl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen and F;
R2 is -0-R12a; R12a is -C(R12c)2-(5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d; R12c is independently selected from hydrogen and methyl;
X is N; and each R20a, R20c, R20d, R20e, R20f, and R201 is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -QH-Cs-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2- dictcrocycloalkyl. Gs-naryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, Ci-nheteroaryl, -OH, -OCH3, -NH2, - N(CH3)2, -C(0)OH, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)OH, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3.
[00372] In an aspect is provided a compound of Formula (I-G”), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O); V is C(R17) and J is C(R16); R10 is -L7-R7; L7 is a bond;
R7 is a 7-10 membered bridged bicyclic heterocycloalkyl, comprising one or more ring nitrogen atoms and wherein the 7-10 membered bridged bicyclic heterocycloalkyl is optionally substituted with one or more
R4;
R4 is independently selected from 1) -C(0)R15, wherein said R15 is independently selected from Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one, two, or three R20f; 2) halogen; and 3) Ci-6alkyl optionally substituted with one, two, or three R20a;
R8 is selected from Ci-4alkyl and cyclopropyl, wherein Ci-4alkyl and cyclopropyl are optionally substituted with one, two, or three R20c;
R17 is -LriR19; L1 is a bond;
R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, C2-3alkynyl, -OH, - NH2, wherein Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, and C2-3alkynyl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen and F;
R2 is -0-R12a; R12a is -C(R12c)2-(5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d; R12c is independently selected from hydrogen and methyl;
X is N; and each R20a, R20c, R20d, R20e, R20f, and R201 is independently selected from halogen, oxo, -CN, Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -QH-Cs-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2- dictcrocycloalkyl. Gs-naryl, -CH2-C6-i2aryl, -QH-Ci-nheteroaryl, Ci-nheteroaryl, -OH, -OCH3, -NH2, - N(CH3)2, -C(0)OH, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i2aryl, -CH2-C6-i2aryl, -CH2-Ci-nheteroaryl, and Ci-nheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OH, -OCH3, -NH2, -N(CH3)2, -C(0)OH, -C(0)NH2, -NHC(0)H, -C(0)H, and -C(0)CH3. [00373] In an aspect is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein
W is C(O);
V is C(R17) and J is C(R16);
R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, - N(R14)S(0)-, -N(R14)S(0)2-, Ci-Cealkyl, C2-C6alkenyl, or C2-Cealkynyl, wherein Ci-Cealkyl, C2-C6alkenyl, and C2-C6alkynyl, are optionally substituted with one, two, or three R20a;
R7 is a 6-10 membered nitrogen containing heterocycloalkyl, wherein the 6-10 membered nitrogen containing heterocycloalkyl is substituted with one or more R4; each R4 is independently selected from CN, Ci-6alkyl, C2-6alkenyl, C2-9heterocycloalkyl, -C(0)0R12, and -C(0)R15, wherein Ci-6alkyl, C2-6alkenyl, and C2-9heterocycloalkyl, are optionally substituted with one, two, or three R20a;
R8 is selected from Ci-6alkyl and C3-6cycloalkyl, wherein Ci-6alkyl and C3-6cycloalkyl are optionally substituted with one, two, or three R20c;
R17 is -L!-R19;
L1 is a bond;
R19 is a fused bicyclic 9-10 membered heterocycloalkyl substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, and -N(R12)(R13);
R16 is halogen;
R2 is selected from -(Ci-C6alkyl)-R12b, -0-R12a, and -(C2-9heterocycloalkyl)-R12b, wherein said Ci-6alkyl and C2. gheterocycloalkyl are optionally substituted with one, two, or three R20d;
R12a is selected from -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, and C6-ioaryl, wherein - CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, and C6-ioaryl are optionally substituted with one, two, or three R20d;
R12b is independently selected from hydrogen and C2-9heterocycloalkyl, wherein C2-9heterocycloalkyl is optionally substituted with one, two, or three R20d;
X is N; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-
6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-sdieteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20c, R20d, R20e, and R20f are each independently selected from halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, - CH2-C6-ioaryl, -CHz-Cwheteroaiyl, C^heteroaiyl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CEh-Ci-gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25; eachR21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-gheteroaryl; and indicates a single or double bond such that all valences are satisfied.
[00374] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is C(R16). In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, V is N.
[00375] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
W is C(O). In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(O). In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, W is S(0)2.
[00376] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the
[00377] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is a bond. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L7 is -NH-.
[00378] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R1, one or more R4, or one or more R6; and wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci- liheterocycloalkyl, C6-i2aryl, or Ci-iiheteroaryl, wherein the C3-i2cycloalkyl, Ci-iiheterocycloalkyl, C6-i2aryl, or Ci- nheteroaryl are optionally substituted with one, two, or three R20a. [00379] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, p is an integer from 0 to 12;
X1 is selected from CH2, C(R4)(R6), C=N-OR4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), O, S, S(O), S(=0)(=NR4), S(0)2N(R4), N(R4)S(0)N(R4), N(R4)S(0)2N(R4), S(0)N(R4), 0C(0)N(R4), CH2C=NN(R4)(R4), C(R4)(R4)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0, C(R4)(R4)OC(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(R4), C(R4)(R4)S(0), C(R4)(R4)S(0)C(R4)(R4), C(R4)(R4)S(0)2C(R4)(R4), C(R4)(R4)S(=0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(R4)(R4)N(R4)C(0)N(R4), C(R4)(R4)S(0)2, C=NN(R4)(R4)C(R4)(R4), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R4)(R4), S(0)N(R4)C(R4)(R4), and 0C(0)N(R4)C(R4)(R4);
X2 is selected from N, C, C(R6), C(R4), CH, N(R4), N(R4), N(R6), O, S, S(O), C(H)(R6), C(R4)2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2; and X3 is selected from N, C, C(R6), and C(R4). [00380] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7
[00381] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7
[00382] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
[00383] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7
[00384] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen, halogen, -CN, Ci^alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl are optionally substituted with one, two, or three R20g. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen and halogen. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is independently selected from hydrogen and fluoro.
[00385] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
R8 is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from hydrogen, Ci-6alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl, wherein Ci-6alkyl, C3- locycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c independently selected from halogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from hydrogen, methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from hydrogen, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In embodiments, R8 is , and -CH2S(0)2N(R12)(R13), wherein Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20c. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from Ci-6alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl, wherein Ci-6alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c independently selected from halogen, Chalky 1, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is methyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cyclopropyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cyclobutyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is oxetanyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is fluoro-substituted cyclopropyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is fluoro-substituted methyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is fluoro- substituted ethyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is CN-substituted cyclopropyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is CN-substituted methyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is CN-substituted ethyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is CN-substituted n-propyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is CN-substituted n-butyl.
[00386] In embodiments, R8 is independently selected from
[00387] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen or CN. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R3 is hydrogen.
[00388] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L1 is a bond. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L1 is selected from a Ci-Cealkyl, C -C alkenyl, C -C alkynyl, -C(O)-, -NHC(O)-, -C(0)NH-, CH20, CH2NH, and CH2.
[00389] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic ring. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a bicyclic ring system. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a polycyclic ring system. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is:
Q4 and Q6 are independently O, S, C(Rla)(Rlb), or N(Rlc);
X4, X5, X6, X9, X10, X11, and X12 are independently selected from C(Rla) or N;
X7 and X8 are independently selected from C(Rla), C(Rla)(Rlb), N, or N(Rlc); each Rla, Rlb, Rld, and Rlh are each independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-
6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-yhctcroan l. -OR12, - SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), - CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C^alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201; or Rla and Rlb bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3- locycloalkyl ring are optionally substituted with one, two, or three R201; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6-ioaryl ring, 5-12 membered heteroaryl ring, or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlh and one of Rla, Rlb, Rlc, and Rld bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, and C3- locycloalkyl ring are optionally substituted with one, two, or three R201; and each Rlc is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201. [00390] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R is:
[00391] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R2 is selected from
[00392] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, each R5 is independently selected from:
[00393] In some embodiments of the subject compound, L7 is a bond. In embodiments of the subject compound, L7 is -N(R14)-. In iurther embodiments of the subject compound, L7 is Ci-Cealkyl. In additional embodiments of the subject compound, L7 is methylene. In some embodiments of the subject compound, L7 is ethylene.
[00394] In embodiments of the subject compound, R7 is a 3-12 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R1, one or more R4, or one or more R6. In some embodiments of the subject compound, R7 is a 3-12 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R1. In additional embodiments of the subject compound, R7 is a 3-12 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R4. In further embodiments of the subject compound, R7 is a 3-12 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R6.
[00395] In some embodiments of the subject compound, R7 is a 6-9 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R1, one or more R4, or one or more R6. In embodiments of the subject compound, R7 is a 6-9 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R1. In some embodiments of the subject compound, R7 is a 6-9 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R4. In additional embodiments of the subject compound,
R7 is a 6-9 membered nitrogen containing heterocycloalkyl optionally substituted with one or more R6. In some embodiments of the subject compound, R7 is an unsubstituted 6-9 membered nitrogen containing heterocycloalkyl. [00396] In further embodiments of the subject compound, R7 is a 5-12 membered nitrogen containing heteroaryl optionally substituted with one or more R1, one or more R4, or one or more R6. In embodiments of the subject compound, R7 is a 5-12 membered nitrogen containing heteroaryl optionally substituted with one or more R1. In some embodiments of the subject compound, R7 is a 5-12 membered nitrogen containing heteroaryl optionally substituted with one or more R4. In additional embodiments of the subject compound, R7 is a 5-12 membered nitrogen containing heteroaryl optionally substituted with one or more R6. In embodiments of the subject compound, R7 is an unsubstituted 5-12 membered nitrogen containing heteroaryl.
[00397] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R1, one or more R4, or one or more R6. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R1. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R4. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R6. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4-9 membered heterocycloalkyl, wherein the 4-9 membered heterocycloalkyl is optionally substituted with one or more R1, one or more R4, or one or more R6. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4-9 membered heterocycloalkyl, wherein the 4-9 membered heterocycloalkyl is optionally substituted with one or more R1. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4-9 membered heterocycloalkyl, wherein the 4-9 membered heterocycloalkyl is optionally substituted with one or more R4. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a 4-9 membered heterocycloalkyl, wherein the 4-9 membered heterocycloalkyl is optionally substituted with one or more R6. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is an unsubstituted 3-12 membered heterocycloalkyl. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is an unsubstituted 4-9 membered heterocycloalkyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a monocyclic Ci-sheterocycloalkyl optionally substituted with one or more R1, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a monocyclic Ci-shctcroarvl optionally substituted with one or more R1, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a spirocyclic C2-iiheterocycloalkyl optionally substituted with one or more R1, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a lused C2-iiheterocycloalkyl optionally substituted with one or more R1, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a lused 6 to 12 membered aryl optionally substituted with one or more R1, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a lused 5 to 12 membered heteroaryl optionally substituted with one or more R1, one or more R4, or one or more R6.
[00398] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a monocyclic nitrogen containing Ci-sheterocycloalkyl optionally substituted with one or more R1, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a monocyclic nitrogen containing Ci- hctcroarvl optionally substituted with one or more R1, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a spirocyclic nitrogen containing C2-nheterocycloalkyl optionally substituted with one or more R1, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a lused nitrogen containing C2-nheterocycloalkyl optionally substituted with one or more R1, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a fused nitrogen containing C6-i2aryl, optionally substituted with one or more R1, one or more R4, or one or more R6. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is a fused nitrogen containing 5 to 12 membered heteroaryl optionally substituted with one or more R1, one or more R4, or one or more R6.
[00399] In additional embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to the same atom are joined to form a C3-i2cycloalkyl or Ci-nheterocycloalkyl, wherein the C3- ncycloalkyl and Ci-nheterocycloalkyl are optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3- ncycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a C3-5cycloalkyl, wherein the C3-5cycloalkyl is optionally substituted with one, two, or three R20a. In embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a C3- scycloalkyl. In further embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a C3-4cycloalkyl, wherein the C3-4cycloalkyl is optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a C3- 4cycloalkyl. In embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a 4 to 5 membered heterocycloalkyl, wherein the 4 to 5 membered heterocycloalkyl is optionally substituted with one, two, or three R20a. In additional embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a 4 to 5 membered heterocycloalkyl. In further embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a 4 membered heterocycloalkyl, wherein the 4 membered heterocycloalkyl is optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two R4 substitutents bonded to the same atom are joined to form a 4 membered heterocycloalkyl. In some embodiments of the subject compound, two substituents selected from R1 and R4 that are bonded to the same atom are joined to form a C3-i2cycloalkyl or Ci-nheterocycloalkyl, wherein the C3- ncycloalkyl and Ci-nheterocycloalkyl are optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two substituents selected from R4 that are bonded to the same atom are joined to form a C3-i2cycloalkyl or Ci-nheterocycloalkyl, wherein the C3-i2cycloalkyl and Ci-nheterocycloalkyl are optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two substituents selected from R1 and R6 that are bonded to the same atom are joined to form a C3-i2cycloalkyl or Ci-nheterocycloalkyl, wherein the C3-i2cycloalkyl and Ci-nheterocycloalkyl are optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two substituents selected from R4 and R6 that are bonded to the same atom are joined to form a C3-i2cycloalkyl or Ci-nheterocycloalkyl, wherein the C3-i2cycloalkyl and Ci- liheterocycloalkyl are optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two substituents selected from R1 and R4 that are bonded to adjacent atoms are joined to form a C3- ncycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two substituents selected from R1 and R4 that are bonded to adjacent atoms are joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl. In some embodiments of the subject compound, two R4 substituents that are bonded to adjacent atoms are joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, naryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Cmheteroaryl are optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two R4 substituents that are bonded to adjacent atoms are joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl. In some embodiments of the subject compound, two substituents selected from R1 and R6 that are bonded to adjacent atoms are joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two substituents selected from R1 and R6 that are bonded to adjacent atoms are joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl. In some embodiments of the subject compound, two substituents selected from R4 and R6 that are bonded to adjacent atoms are joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3- ncycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two substituents selected from R4 and R6 that are bonded to adjacent atoms are joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl.
[00400] In additional embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to the same atom are joined to form a C3-i2cycloalkyl or Ci-nheterocycloalkyl, wherein the C3- ncycloalkyl and Ci-nheterocycloalkyl are optionally substituted with one, two, or three R20a. In additional embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to the same atom are joined to form a C3-i2cycloalkyl or Ci-nheterocycloalkyl. In additional embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are joined to form a C3- ncycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a. In additional embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl. In some embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are joined to form a C3- ncycloalkyl, wherein the C3-i2cycloalkyl is optionally substituted with one, two, or three R20a. In additional embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are joined to form a C3-i2cycloalkyl. In further embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are joined to form a Ci-nheterocycloalkyl, wherein the Ci-nheterocycloalkyl is optionally substituted with one, two, or three R20a. In some embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are joined to form a Ci- nheterocycloalkyl. In additional embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are joined to form a C6-i2aryl, wherein the C6-i2aryl is optionally substituted with one, two, or three R20a. In embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are joined to form a C6-i2aryl. In additional embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are joined to form a Ci- nheteroaryl, wherein the Ci-nheteroaryl is optionally substituted with one, two, or three R20a. In additional embodiments of the subject compound, two substituents selected from R1, R4, and R6 that are bonded to adjacent atoms are joined to form a Ci-nheteroaryl.
[00401] In some embodiments of the subject compound, R1 is hydrogen.
[00402] In additional embodiments of the subject compound, R4 is independently selected from hydrogen, halogen, oxo, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), and - C(0)R15, wherein Ci-6alkyl, C2-6alkenyl, and C2-6alkynyl, are optionally substituted with one, two, or three R20a. In embodiments of the subject compound, R4 is independently hydrogen. In further embodiments of the subject compound, R4 is independently halogen. In some embodiments of the subject compound, R4 is independently oxo. In some embodiments of the subject compound, R4 is independently -CN. In additional embodiments of the subject compound, R4 is independently Ci-6alkyl. In embodiments of the subject compound, R4 is independently C2- 6alkenyl. In some embodiments of the subject compound, R4 is independently C2-6alkynyl. In further embodiments of the subject compound, R4 is independently -OR12. In select embodiments of the subject compound, R4 is independently -N(R12)(R13). In additional embodiments of the subject compound, R4 is independently -C(0)0R12.
In embodiments of the subject compound, R4 is independently -0C(0)N(R12)(R13). In some embodiments of the subject compound, R4 is independently -C(0)R15. In select embodiments of the subject compound, R4 is independently -NH2. In lurther embodiments of the subject compound, R4 is independently -C(0)0H. In additional embodiments of the subject compound, R4 is independently -0C(0)NH2. In embodiments of the subject compound, R4 is independently -C(0)CH .
[00403] In some embodiments of the subject compound, R6 is hydrogen.
[00404] In select embodiments of the subject compound, L2 is a bond. In additional embodiments of the subject compound, L2 is Ci-Cealkyl.
[00405] In further embodiments of the subject compound, R5 is independently hydrogen.
[00406] In embodiments of the subject compound, R8 is hydrogen. In some embodiments of the subject compound, R8 is Ci-6alkyl optionally substituted with one, two, or three R20c. In select embodiments of the subject compound, R8 is C2-6alkenyl optionally substituted with one, two, or three R20c. In additional embodiments of the subject compound, R8 is C2-6alkynyl optionally substituted with one, two, or three R20c. In some embodiments of the subject compound, R8 is C3-6cycloalkyl optionally substituted with one, two, or three R20c. In embodiments of the subject compound, R8 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20c. In further embodiments of the subject compound, R8 is Ci-6alkyl. In select embodiments of the subject compound, R8 is C2- 6alkenyl. In additional embodiments of the subject compound, R8 is C2-6alkynyl. In some embodiments of the subject compound, R8 is C3-6cycloalkyl. In embodiments of the subject compound, R8 is C2-9heterocycloalkyl. [00407] In select embodiments of the subject compound, L1 is a bond. In lurther embodiments of the subject compound, L1 is Ci-Cealkyl. In additional embodiments of the subject compound, L1 is -C(O)-. In some embodiments of the subject compound, L1 is C(Rlf)(Rlg)0. In embodiments of the subject compound, L1 is CH20. [00408] In select embodiments of the subject compound, R19 is a C3-i2cycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In additional embodiments of the subject compound, R19 is a C2- liheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In further embodiments of the subject compound, R19 is a C6-i2aryl optionally substituted with one, two, three, four, five, six, or seven R11.
In some embodiments of the subject compound, R19 is a C2-i2heteroaryl optionally substituted with one, two, three, four, five, six, or seven R11. In embodiments of the subject compound, R19 is a C3-i2cycloalkyl. In select embodiments of the subject compound, R19 is a C2-nheterocycloalkyl. In additional embodiments of the subject compound, R19 is a C6-i2aryl. In some embodiments of the subject compound, R19 is a C2-i2heteroaryl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic C3-9cycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic Ci-sheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic phenyl optionally substituted with one, two, three, four, or five R11. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic Ci- ictcroaryl optionally substituted with one, two, three, four, or five R11. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a spirocyclic Cs-ncycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a spirocyclic C2-nheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a fused C4-i2cycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In lurther embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a fused C2- liheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a fused C6-i2aryl, optionally substituted with one, two, three, four, five, six, or seven R11. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a fused 5 to 12 membered heteroaryl optionally substituted with one, two, three, four, five, six, or seven R11.
[00409] In further embodiments of the subject compound, R16 is hydrogen. In embodiments of the subject compound, R16 is halogen. In select embodiments of the subject compound, R16 is Ci-6alkyl. In some embodiments of the subject compound, R16 is -OR12.
[00410] In additional embodiments of the subject compound, R2 is -0-R12a.
[00411] In select embodiments of the subject compound, R12a is Ci-6alkyl optionally substituted with one, two, or three R20d. In embodiments of the subject compound, R12a is methylene optionally substituted with one or two R20d. In further embodiments of the subject compound, R12a is methylene. In some embodiments of the subject compound, R12a is ethylene optionally substituted with one, two, or three R20d. In embodiments of the subject compound, R12a is ethylene. In some embodiments of the subject compound, R12a is propylene optionally substituted with one, two, or three R20d. In embodiments of the subject compound, R12a is propylene. In some embodiments, R12a is -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three R20d. In some embodiments, R12a is - CH2-(monocyclic C2-8heterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12a is -CH2-(monocyclic C3-5heterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12a is -CH2-(spirocyclic C2-nheterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12a is -CH2-(spirocyclic C3-iiheterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12a is -CH2-(fused C2-nheterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12a is -CH2-(spirocyclic Ce-sheterocycloalkyl) optionally substituted with one, two, or three R20d.
[00412] In select embodiments of the compound, R12a is Ci-6alkyl optionally substituted with one, two, or three R20d. In embodiments of the compound, R12a is methylene optionally substituted with one or two R20d. In further embodiments of the compound, R12a is methylene. In some embodiments of the compound, R12a is ethylene optionally substituted with one, two, or three R20d. In embodiments of the compound, R12a is ethylene. In some embodiments of the compound, R12a is propylene optionally substituted with one, two, or three R20d. In embodiments of the compound, R12a is propylene. In some embodiments, R12a is -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three R20d. In some embodiments, R12a is -CH2-(monocyclic C2. sheterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12a is -CH2- (monocyclic Ci-shctcrocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12a is -CH2-(spirocyclic C2-nheterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12a is -CH2-(spirocyclic C3-iiheterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12a is -CH2-(fused C2-nheterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12a is -CH2-(spirocyclic Ce-sheterocycloalkyl) optionally substituted with one, two, or three R20d. [00413] In embodiments, R12a is Ci-6alkyl. In embodiments, R12a is C2-6alkenyl. In embodiments, R12a is C2. 6alkynyl. In embodiments, R12a is C3-iocycloalkyl. In embodiments, R12a is -CH2-C3-iocycloalkyl. In embodiments, R12a is C2-9heterocycloalkyl. In embodiments, R12a is -CH2-C2-9heterocycloalkyl. In embodiments, R12a is C6-ioaryl. In embodiments, R12a is -CH2-C6-ioaryl. In embodiments, R12a is -CH2-Ci-9heteroaryl. In embodiments, R12a is Ci- gheteroaryl.
[00414] In embodiments, R12a is Ci-6alkyl optionally substituted with one, two, or three R20d. In embodiments, R12a is C2-6alkenyl optionally substituted with one, two, or three R20d. In embodiments, R12a is C2-6alkynyl optionally substituted with one, two, or three R20d. In embodiments, R12a is C3-10cycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12a is -CH2-C3-iocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12a is C2-9heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12a is -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12a is Ce- ioaryl optionally substituted with one, two, or three R20d. In embodiments, R12a is -CH2-C6-ioaryl optionally substituted with one, two, or three R20d. In embodiments, R12a is -CH2-Ci-9heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12a is Ci-gheteroaryl optionally substituted with one, two, or three R20d. [00415] In additional embodiments of the subject compound, R12b is hydrogen. In select embodiments of the compound, R12b is C1-6alkyl optionally substituted with one, two, or three R20d. In embodiments of the compound, R12b is methylene optionally substituted with one or two R20d. In further embodiments of the compound, R12b is methylene. In some embodiments of the compound, R12b is ethylene optionally substituted with one, two, or three R20d. In embodiments of the compound, R12b is ethylene. In some embodiments of the compound, R12b is propylene optionally substituted with one, two, or three R20d. In embodiments of the compound, R12b is propylene. In some embodiments, R12b is -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three R20d. In some embodiments, R12b is -CH2-(monocyclic C2-8heterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12b is -CH2-(monocyclic C3-5heterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12b is -CH2-(spirocyclic C2-nheterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12b is -CH2-(spirocyclic C3-iiheterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12b is -CH2-(fused C2-iiheterocycloalkyl) optionally substituted with one, two, or three R20d. In some embodiments, R12b is -CH2-(spirocyclic Ce-sheterocycloalkyl) optionally substituted with one, two, or three R20d.
[00416] In embodiments, R12b is Ci-6alkyl. In embodiments, R12b is C2-6alkenyl. In embodiments, R12b is C2- 6alkynyl. In embodiments, R12b is C3-iocycloalkyl. In embodiments, R12b is -CH2-C3-iocycloalkyl. In embodiments, R12b is C2-9heterocycloalkyl. In embodiments, R12b is -CH2-C2-9heterocycloalkyl. In embodiments, R12b is C6-ioaryl. In embodiments, R12b is -CH2-C6-ioaryl. In embodiments, R12b is -CH2-Ci-9heteroaryl. In embodiments, R12b is Ci- gheteroaryl.
[00417] In embodiments, R12b is Ci-6alkyl optionally substituted with one, two, or three R20d. In embodiments,
R12b is C2-6alkenyl optionally substituted with one, two, or three R20d. In embodiments, R12b is C2-6alkynyl optionally substituted with one, two, or three R20d. In embodiments, R12b is C3-iocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12b is -CH2-C3-iocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12b is C2-9heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12b is -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three R20d. In embodiments, R12b is ioaryl optionally substituted with one, two, or three R20d. In embodiments, R12b is -CH2-C6-ioaryl optionally substituted with one, two, or three R20d. In embodiments, R12b is -CH2-Ci-9heteroaryl optionally substituted with one, two, or three R20d. In embodiments, R12b is Ci-gheteroaryl optionally substituted with one, two, or three R20d. [00418] In further embodiments of the subject compound, X is C(R3). In select embodiments of the subject compound, X is N.
[00419] In some embodiments of the subject compound, R3 is hydrogen. In embodiments of the subject compound, R3 is -CN. In embodiments of the subject compound, R3 is Ci-6alkyl. In additional embodiments of the subject compound, R3 is methyl. In embodiments, R3 is Ci-6alkyl optionally substituted with one, two, or three R20b. In embodiments, R3 is C2-6alkenyl optionally substituted with one, two, or three R20b. In embodiments, R3 is C2- 6alkynyl optionally substituted with one, two, or three R20a. In embodiments, R3 is C3-iocycloalkyl optionally substituted with one, two, or three R20b. In embodiments, R3 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20b. In embodiments, R3 is C6-ioaryl optionally substituted with one, two, or three R20b. In embodiments, R3 is Ci-gheteroaryl optionally substituted with one, two, or three R20b. In embodiments, R3 is -OR12. In embodiments, R3 is -C(0)0R12. In embodiments, R3 is -0C(0)N(R12)(R13). In embodiments, R3 is -C(0)R15. In embodiments, R3 is halogen. In embodiments, R3 is -N(R12)(R13). In embodiments, R3 is -NH2.
[00420] In further embodiments of the subject compound, each R12 is independently selected from hydrogen, Ci- 6alkyl, and C3-6cycloalkyl. In some embodiments of the subject compound, each R12 is independently selected from hydrogen or Ci-6alkyl. In embodiments of the subject compound, R12 is independently hydrogen. In select embodiments of the subject compound, each R13 is independently selected from hydrogen and Ci-4alkyl. In some embodiments of the subject compound, each R14 is independently selected from hydrogen and Ci-4alkyl. In additional embodiments of the subject compound, each R15 is independently Ci-4alkyl. [00421] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IA1) wherein R2, R8,
R10, R16 and R17 are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IA2) wherein R2, R8, R10, R16 and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IA3) wherein R2, R8, R10, R16 and R17 are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IA4) wherein R2, R8, R10, and R17 are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula
(IA5) wherein R2, R8, R10, and R17 are as described herein. In further embodiments of the subject compound or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IA6) wherein R2, R8, R10, and R17 are as described herein. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IA7) wherein R2, R3, R8, R10, R16 and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IA8) wherein R2, R3,
R8, R10, R16 and R17 are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IA9) wherein R2, R3, R8, R10, R16 and R17 are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IA10) wherein R2, R3, R8, R10, and R17 are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IA11) wherein R2, R3,
R8, R10, and R17 are as described herein. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IA12) wherein R2, R3, R8, R10, R16 and R17 are as described herein. [00422] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IIA1) wherein R2, R8, R10, R16 and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IIA2) wherein R2, R8,
R10, R16 and R17 are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IIA3) wherein R2, R8, R10, R16 and R17 are as described herein. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IIA4) wherein R2, R8, R10, and R17 are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IIA5) wherein R2, R8,
R10, and R17 are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IIA6) wherein R2, R8, R10, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IIA7) wherein R2, R3, R8, R10, R16 and R17 are as described herein. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IIA8) wherein R2, R3, R8, R10, R16 and
R17 are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula
(IIA9) wherein R2, R3, R8, R10, R16 and R17 are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IIA10) wherein R2, R3, R8, R10, and R17 are as described herein. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IIA11) wherein R2, R3, R8, R10, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IIA12) wherein R2, R3, R8, R10, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (IV) wherein R8, W, R16, and R17 are as described herein.
In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (V) wherein R8, W, R16, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (VI) wherein R8,
W, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure
Formula (VII) wherein R8, W, R3, R16, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or Formula (VIII) wherein R8, W, R3, R16, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure o Formula (IX) wherein R8, W, R3, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (X) wherein
R16 and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (XI) wherein R16 and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or Formula (XII) wherein R17 is as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (XIII) wherein R3, R16, and R17 are as described herein.
In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (XIV) wherein R3, R16, and R17 are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure Formula (XV) wherein
R3 and R17 are as described herein.
[00423] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the stmcture o Formula (XVI) wherein R16 and R10 are as described herein. In embodiments of Formula (XVI), R16 is F and R10 is a 10 membered spirocyclic bicyclic heterocycloalkyl substituted with one R6 and optionally substituted with one, two, or three R4. In embodiments of Formula (XVI), R16 is F and R10 is a 10 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R4. In embodiments of Formula (XVI), R16 is F and R10 is a 11 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R4. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or embodiments of Formula (XVII), R16 is F and R10 is a 10 membered spirocyclic bicyclic heterocycloalkyl substituted with one R6 and optionally substituted with one, two, or three R4. In embodiments of Formula (XVII), R16 is F and R10 is a 10 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R4. In embodiments of Formula (XVII), R16 is F and R10 is a 11 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R4. In embodiments of the subject compound, or a pharmaceutically acceptable
(XVIII) wherein R16 and R10 are as described herein. In embodiments of Formula (XVIII), R16 is F and R10 is a 10 membered spirocyclic bicyclic heterocycloalkyl substituted with one R6 and optionally substituted with one, two, or three R4. In embodiments of Formula (XVIII), R16 is F and R10 is a 10 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R4. In embodiments of Formula (XVIII), R16 is F and R10 is a 11 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R4. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, the compound has the structure or embodiments of Formula (XIX), R16 is F and R10 is a 10 membered spirocyclic bicyclic heterocycloalkyl substituted with one R6 and optionally substituted with one, two, or three R4. In embodiments of Formula (XIX), R16 is F and R10 is a 10 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R4. In embodiments of Formula (XIX), R16 is F and R10 is a 11 membered fused bicyclic heterocycloalkyl optionally substituted with one, two, or three R4. [00424] In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, X3, R4, and p are as described herein. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, wherein
X1, X2, X3, R4, and p are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X2, X3, R4, and p are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is wherein X2, X3, R4, and p are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X2, X3, R4, and p are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, X3, R4, and p are as described herein. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is wherein X1, X2, R4, and p are as described herein.
[00425] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is wherein X1, X2, X3, R4, and p are as described herein. In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2,
X3, R4, and p are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X2, X3, R4, and p are as described herein. In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is wherein X2, X3, R4, and p are as described herein. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X2, X3, R4, and p are as described herein. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, X3, R4, and p are as described herein. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R7 is wherein X1, X2, R4, and p are as described herein.
[00426] In further embodiments of the subject compound, p is an integer from 0 to 4. In embodiments of the subject compound, p is 0. In select embodiments of the subject compound, p is 1. In some embodiments of the subject compound, p is 2. In embodiments of the subject compound, p is 3. In additional embodiments of the subject compound, p is 4.
[00427] In embodiments of the subject compound, X1 is selected from CH2, C(R4)(R6), CH2C(R4)(R6), CH2C(R4)(R6)CH2, C(R4)(R6)C(R4)(R6)C(R4)(R6), C(R4)(R6)N(R4), C(R4)(R6)N(R6), C(R4)(R6)0, C(R4)(R6)OC(R4)(R6), C(R4)(R6)S, C(R4)(R6)SC(R4)(R6), C(R4)(R4), CH2C(R4)(R4), CH2C(R4)(R4)CH2, C(R4)(R4)C(R4)(R6)C(R4)(R4), C(R4)(R4)C(R4)(R4)C(R4)(R4), C(R4)(R4)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0, C(R4)(R4)OC(R4)(R4), C(R4)(R4)S, and C(R4)(R4)SC(R4)(R4).
[00428] In further embodiments of the subject compound, X1 is CH2. In some embodiments of the subject compound, X1 is C(R4)(R6). In select embodiments of the subject compound, X1 is CH2C(R4)(R6). In additional embodiments of the subject compound, X1 is CH2C(R4)(R6)CH2. In embodiments of the subject compound, X1 is C(R4)(R6)C(R4)(R6)C(R4)(R6). In select embodiments of the subject compound, X1 is C(R4)(R6)N(R4). In further embodiments of the subject compound, X1 is C(R4)(R6)N(R6). In some embodiments of the subject compound, X1 is C(R4)(R6)0. In select embodiments of the subject compound, X1 is C(R4)(R6)OC(R4)(R6). In embodiments of the subject compound, X1 is C(R4)(R6)S. In additional embodiments of the subject compound, X1 is C(R4)(R6)SC(R4)(R6). In embodiments of the subject compound, X1 is C(R4)(R4). In further embodiments of the subject compound, X1 is CH2C(R4)(R4). In select embodiments of the subject compound, X1 is CH2C(R4)(R4)CH2.
In embodiments of the subject compound, X1 is C(R4)(R4)C(R4)(R6)C(R4)(R4). In some embodiments of the subject compound, X1 is C(R4)(R4)C(R4)(R4)C(R4)(R4). In embodiments of the subject compound, X1 is C(R4)(R4)C(0)N(R4). In additional embodiments of the subject compound, X1 is C(R4)(R4)N(R4). In further embodiments of the subject compound, X1 is C(R4)(R4)N(R6). fn embodiments of the subject compound, X1 is C(R4)(R4)0. fn some embodiments of the subject compound, X1 is C(R4)(R4)OC(R4)(R4). fn select embodiments of the subject compound, X1 is C(R4)(R4)S. In some embodiments of the subject compound, X1 is C(R4)(R4)SC(R4)(R4).
[00429] In select embodiments of the subject compound, X2 is N. In embodiments of the subject compound, X2 is C. In further embodiments of the subject compound, X2 is C(R6). In additional embodiments of the subject compound, X2 is C(R4). In some embodiments of the subject compound, X2 is CH. In select embodiments of the subject compound, X2 is N(R'). In embodiments of the subject compound, X2 is N(R4). In select embodiments of the subject compound, X2 is N(R6). In iurther embodiments of the subject compound, X2 is O. In additional embodiments of the subject compound, X2 is S. In some embodiments of the subject compound, X2 is S(O). In embodiments of the subject compound, X2 is C(H)(R6). In embodiments of the subject compound, X2 is C(R4)2. In embodiments of the subject compound, X2 is CH2. In select embodiments of the subject compound, X2 is C(R4)(R6). In further embodiments of the subject compound, X2 is S(=0)(=NR4). In embodiments of the subject compound, X2 is S(0)2.
[00430] In additional embodiments of the subject compound, X3 is N. In some embodiments of the subject compound, X3 is C. In select embodiments of the subject compound, X3 is C(R6). In select embodiments of the subject compound, X3 is C(R4).
[00431] In embodiments of the subject compound, wherein R4 and p are as described herein.
In further embodiments of the subject compound, wherein R4 and p are as described herein.
In some embodiments of the subject compound, wherein R4 and p are as described herein. In additional embodiments of the subject compound, wherein R4 and p are as described herein.
In select embodiments of the subject compound, wherein R4 and p are as described herein. In embodiments of the subject compound, wherein R4 and p are as described herein. In some embodiments of the subject compound, wherein R4 and p are as described herein. In further embodiments of the subject compound, wherein R4 and p are as described herein. In some embodiments of the subject compound, wherein R4 and p are as described herein. In select embodiments of the subject compound, wherein R4 and p are as described herein. In embodiments of the subject compound, wherein R4 and p are as described herein. In additional embodiments of the subject compound, wherein R4 and p are as described herein. In some embodiments of the subject compound, wherein R4 and p are as described herein. In further embodiments of the subject compound, wherein R4 and p are as described herein. In some embodiments of the subject compound, wherein R4 and p are as described herein. In embodiments of the subject compound, R7 is -L^h/ wherein R4 and p are as described herein.
In select embodiments of the subject compound, wherein R4 and p are as described herein. In some embodiments of the subject compound, R 7 -L/w wherein R4 and p are as described herein. In additional embodiments of the subject compound, wherein R4 and p are as described herein. In further embodiments of the subject compound, R7 is wherein R4 and p are as described herein.
In embodiments of the subject compound, R7 is wherein R4 and p are as described herein. In some embodiments of the subject compound, R7 is wherein R4 and p are as described herein. In
N select embodiments of the subject compound, R7 is wherein R4 and p are as described herein. In some embodiments of the subject compound, wherein R4 and p are as described herein.
[00432] In some embodiments of the subject compound, embodiments of the subject compound, , n additional embodiments of the subject compound, select embodiments of the subject compound, some embodiments of the subject compound, embodiments of the subject compound, embodiments of the subject compound, further embodiments of the subject compound, R7 is
H
-N,
0 N
. In select embodiments of the subject compound, R7 is In additional embodiments of the subject compound, R7 is . In some embodiments of the subject compound, R7 is . In embodiments of the subject compound, some embodiments of the subject compound, further embodiments of the subject compound, select embodiments of the subject compound,
R7 is . In some embodiments of the subject compound, additional embodiments of the . In some embodiments of the subject compound, further embodiments of the subject compound, R7 is . , . In some embodiments of the subject compound, R7 is . In embodiments of the subject compound, R7 is . In embodiments of the subject compound, additional embodiments of the subject compound, R7 is . In iurther embodiments of the subject compound, [00433] In select embodiments of the subject compound, wherein R4 and p are as described herein. In embodiments of the subject compound, wherein R4 and p are as described herein.
In some embodiments of the subject compound, wherein R4 and p are as described herein. In some embodiments of the subject compound, wherein R4 and p are as described herein. In select embodiments of the subject compound, wherein R4 and p are as described herein. In further embodiments of the subject compound, wherein R4 and p are as described herein. In embodiments of the subject compound, wherein R4 and p are as described herein. In additional embodiments of the subject compound, wherein R4 and p are as described herein.
In some embodiments of the subject compound, wherein R4 and p are as described herein. In embodiments of the subject compound, wherein R4 and p are as described herein. In select embodiments of the subject compound, wherein R4 and p are as described herein. In embodiments of the subject compound, wherein R4 and p are as described herein. In further embodiments of the subject compound, wherein R4 and p are as described herein.
In some embodiments of the subject compound, R 1 10 0 i ics, wherein R4 and p are as described herein.
In additional embodiments of the subject compound, wherein R4 and p are as described herein. In some embodiments of the subject compound, R10 is ^ wherein R4 and p are as described herein. In embodiments of the subject compound, wherein R4 and p are as described herein.
L T-(R4)P N
In select embodiments of the subject compound, R10 is wherein R4 and p are as described herein. In further embodiments of the subject compound, wherein R4 and p are as described herein. In some embodiments of the subject compound, R10 is wherein R4 and p are as described herein. In some embodiments of the subject compound, R10 is wherein R4 and p are as described herein. In ~(R4)p embodiments of the subject compound, R10 is wherein R4 and p are as described herein. In P
N I additional embodiments of the subject compound, R10 is ""V” wherein R4 and p are as described herein. In select embodiments of the subject compound, wherein R4 and p are as described herein.
[00434] In further embodiments of the subject compound, some embodiments of the subject compound, embodiments of the subject compound, embodiments of the subject compound, select embodiments of the subject compound, additional embodiments of the subject compound, n further embodiments of the subject compound, R10 is , n some embodiments of the subject compound,
H H
.N, .N,
0 N 0 N
I
R10 is I . In some embodiments of the subject compound, R10 is . In select embodiments of the subject compound, R10 is . In some embodiments of the subject compound, R is . In embodiments of the subject compound, n further embodiments of the subject compound, R10 is , n some embodiments of the . In select embodiments of the subject compound, embodiments of the subject compound, some embodiments of the subject compound, R 10 , . In embodiments of the subject compound, R10 is . , . In embodiments of the subject compound, R10 is . In select embodiments of the subject compound, R10 is . In some embodiments of the subject compound, R10 i In further embodiments of the subject compound, ,
[00435] In embodiments of the subject compound, R10 is . In select embodiments of the subject compound, [00436] In embodiments, R10 is independently selected from
[00437] In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is hydrogen. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is halogen. In lurther embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R16 is fluoro.
[00438] In embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is hydrogen. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is methyl. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cyclopropyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cyclobutyl. In additional embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is oxetanyl.
[00439] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is methyl optionally substituted with one, two, or three R20c. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cyclopropyl optionally substituted with one, two, or three R20c. In select embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cyclobutyl optionally substituted with one, two, or three R20c. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is oxetanyl optionally substituted with one, two, or three R20c. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is -CN. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is - CH2CN. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof,
R8 is -CH2CH2CN. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is -CH2CH2CH2CN. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is -CH2CH2CH2CH2CN. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is -(Ci-C6alkyl)-CN. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cylopropyl optionally substituted with one, two, or three R20c. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cylopropyl substituted with CN. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is cylopropyl substituted with -(Ci-C6alkyl)-CN. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is Ci- Cehaloalkyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is Ci-C2haloalkyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is Ci-Cealkyl. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is-(Ci-C6alkyl)-C(0)NH2. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is-(Ci-C6alkyl)-(C3-C6cycloalkyl). In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R8 is-(Ci-C2alkyl)-(C3- Cicycloalkyl). In embodiments, R8 is hydrogen. In embodiments, R8 is halogen. In embodiments, R8 is -CN. In embodiments, R8 is Ci-6alkyl. In embodiments, R8 is C2-6alkenyl. In embodiments, R8 is C2-6alkynyl. In embodiments, R8 is C3-6cycloalkyl. In embodiments, R8 is C2-9heterocycloalkyl. In embodiments, R8 is C6-ioaryl. In embodiments, R8 is C’l-dictcroaiyl. In embodiments, R8 is -OR12. In embodiments, R8 is -SR12. In embodiments, R8 is -N(H)(R12) . In embodiments, R8 is -C(0)0R12. In embodiments, R8 is -0C(0)N(R12)(R13) . In embodiments, R8 is -N(R14)C(0)N(R12)(R13) . In embodiments, R8 is -N(R14)C(0)0R15. In embodiments, R8 is -N(R14)S(0)2R15. In embodiments, R8 is -C(0)R15. In embodiments, R8 is -S(0)R15. In embodiments, R8 is -0C(0)R15. In embodiments, R8 is -C(0)N(R12)(R13) . In embodiments, R8 is -C(0)C(0)N(R12)(R13) . In embodiments, R8 is - N(R14)C(0)R15. In embodiments, R8 is -S(0)2R15. In embodiments, R8 is -S(0)2N(R12)(R13)- . In embodiments, R8 is S(=0)(=NH)N(R12)(R13) . In embodiments, R8 is -CH2C(0)N(R12)(R13) . In embodiments, R8 is - CH2N(R14)C(0)R15. In embodiments, R8 is -CH2S(0)2R15. In embodiments, R8 is -CH2S(0)2N(R12)(R13). In embodiments, R8 is Ci-6alkyl optionally substituted with one, two, or three R20c. In embodiments, R8 is C2-6alkenyl optionally substituted with one, two, or three R20c. In embodiments, R8 is C2-6alkynyl optionally substituted with one, two, or three R20c. In embodiments, R8 is C3-6cycloalkyl optionally substituted with one, two, or three R20c. In embodiments, R8 is C2-9heterocycloalkyl optionally substituted with one, two, or three R20c. In embodiments, R8 is C6-ioaryl optionally substituted with one, two, or three R20c. In embodiments, R8 is Ci-gheteroaryl optionally substituted with one, two, or three R20c.
[00440] In some embodiments, L1 is a bond. In some embodiments, L1 is Ci-Cealkyl. In some embodiments, L1 is C2-C6alkenyl. In some embodiments, L1 is C2-C6alkynyl. In some embodiments, L1 is -0-. In some embodiments, L1 is -N(R14)-. In some embodiments, L1 is -C(O)-. In some embodiments, L1 is -N(R14)C(0)-. In some embodiments, L1 is -C(0)N(R14)-. In some embodiments, L1 is -S-. In some embodiments, L1 is -S(0)2-. In some embodiments, L1 is -S(O)-. In some embodiments, L1 is -S(0)2N(R14)-. In some embodiments, L1 is -S(0)N(R14)-. In some embodiments, L1 is -N(R14)S(0)- . In some embodiments, L1 is -N(R14)S(0)2-. In some embodiments, L1 is -OCON(R14)-. In some embodiments, L1 is -N(R14)C(0)0-. In some embodiments, L1 is N(Rle) . In some embodiments, L1 is C(0)N(Rlc). In some embodiments, L1 is S(0)2N(Rlc). In some embodiments, L1 is S(0)N(Rlc)
. In some embodiments, L1 is C(Rlf)(Rlg)0. In some embodiments, L1 is C(Rlf)(Rlg)N(Rlc). In some embodiments, L1 is C(Rlf)(Rlg). In some embodiments, L1 is -NH-. In some embodiments, L1 is -NHC(O)-. In some embodiments, L1 is -C(0)NH-. In some embodiments, L1 is -S(0)2NH-. In some embodiments, L1 is -S(0)NH-. In some embodiments, L1 is -NHS(O)- . In some embodiments, L1 is -NHS(0)2-. In some embodiments, L1 is - OCONH-. In some embodiments, L1 is -NHC(0)0-. In some embodiments, L1 is CH20. In some embodiments, L1 is CH2NH. In some embodiments, L1 is CH2. In some embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, L1 is selected from a Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -
C(O)-, -NHC(O)-, -C(0)NH-, CH20, CH2NH, and CH2.
[00441] In embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is:
Q1, Q3, and Q5 are independently N or C(Rld);
Q4 and Q6 are independently O, S, C(Rla)(Rlb), or N(Rlc);
X4, X5, X6, X9, X10, X11, X12, and X16 are independently selected from C(Rla) or N;
X7 and X8 are independently selected from C(Rla), C(Rla)(Rlb), N, or N(Rlc);
X13 is selected from a bond, C(O), C(Rla)(Rlb), C(0)C(Rla)(Rlb), C(Rla)(Rlb)C(Rla)(Rlb), C(Rla)(Rlb)N(Rlc), and N(Rlc);
X14 and X15 are independently selected from a bond, C(O), C(Rla)(Rlb), and N(Rlc); each Rla, Rlb, Rld, Rlf, Rlg, and Rlh are each independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-yhctcroan l. -OR12, - SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, - S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, - CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-yhctcroan l are optionally substituted with one, two, or three R201; or Rla and Rlb bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6-ioaryl ring, 5-12 membered heteroaryl ring, or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlh and one of Rla, Rlb, Rlc, and Rld bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, and C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201; and each Rlc is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, Ci-dictcroarvl. wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, and Cj-dictcroaryl are optionally substituted with one, two, or three R201.
[00442] In embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is:
Q1, Q3, and Q5 are independently N or C(Rld);
Q4 and Q6 are independently O, S, C(Rla)(Rlb), or N(Rlc);
X4, X5, X6, X9, X10, X11, and X12 are independently selected from C(Rla) or N;
X7 and X8 are independently selected from C(Rla), C(Rla)(Rlb), N, or N(Rlc);
X13 is selected from a bond, C(O), C(Rla)(Rlb), C(0)C(Rla)(Rlb), C(Rla)(Rlb)C(Rla)(Rlb), C(Rla)(Rlb)N(Rlc), and N(Rlc);
X14 and X15 are independently selected from a bond, C(O), C(Rla)(Rlb), and N(Rlc); each Rla, Rlb, Rld, Rlf, Rlg, and Rlh are each independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroaryl. -OR12, - SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, - S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, - CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and C’l-dictcroani are optionally substitirted with one, two, or three R201; or Rla and Rlb bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6-ioaryl ring, 5-12 membered heteroaryl ring, or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlh and one of Rla, Rlb, Rlc, and Rld bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, and C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201; and each Rlc is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2. . C6-ioaryl, Ci-dictcroan l. wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2. C6-ioaryl, and Ci-dictcroaiyl are optionally substituted with one, two, or three R201.
[00443] In embodiments, Rlh is selected from hydrogen, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, - N(R12)(R13), -C(0)OR12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -C(0)R15, -OC(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -CH2C(0)N(R12)(R13), and -CH2N(R14)C(0)R15, wherein Ci-6alkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted with one, two, or three R201.
[00444] In embodiments, Rlh is selected from hydrogen and -N(R12)(R13). In embodiments, Rlh is hydrogen. In embodiments, Rlh is -N(R12)(R13). In embodiments, Rlh is -NH2.
[00445] In embodiments, Rld is independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2. 6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroan l. -OR12, -SR12, -N(R12)(R13), - C(0)OR12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20a. In embodiments, Rld is independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci- 9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)OR12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), - N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -OC(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), - CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20a. In embodiments, Rld is independently selected from hydrogen, -CN, Ci-6alkyl, and Ci-6haloalkyl, wherein Ci-6alkyl is optionally substituted with one, two, or three R201. In embodiments, Rld is independently hydrogen. In embodiments, Rld is independently -CN. [00446] In some embodiments, R19 is selected from: [00448] In some embodiments, R19 is selected from:
[00450] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic ring. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a bicyclic ring system. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a polycyclic ring system.
[00451] In select embodiments of the compound, R19 is a C3-i2cycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In additional embodiments of the compound, R19 is a C2-iiheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In further embodiments of the compound, R19 is a naryl optionally substituted with one, two, three, four, five, six, or seven R11. In some embodiments of the compound, R19 is a C2-i2heteroaryl optionally substituted with one, two, three, four, five, six, or seven R11. In embodiments of the compound, R19 is a C3-i2cycloalkyl. In select embodiments of the compound, R19 is a C2- liheterocycloalkyl. In additional embodiments of the compound, R19 is a C6-i2aryl. In some embodiments of the compound, R19 is a C2-i2heteroaryl. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic C3-s>cycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic Ci-sheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In additional embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic phenyl optionally substituted with one, two, three, four, or five R11. In further embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a monocyclic Ci-shctcroarvl optionally substituted with one, two, three, four, or five R11. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a spirocyclic Cs-ncycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a spirocyclic C2-iiheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In additional embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a fused Cs-ncycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In lurther embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a fused C2- liheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In further embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a fused C6-i2aryl, optionally substituted with one, two, three, four, five, six, or seven R11. In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is a fused 5 to 12 membered heteroaryl optionally substituted with one, two, three, four, five, six, or seven R11.
embodiments, embodiments, R19 is , , . , . In embodiments, embodiments, R19 is
[00453] In some embodiments, some embodiments, some embodiments, , some embodiments, R19 is . , . In some embodiments,
F . In some embodiments, R19 is F . In some embodiments, R19 is
F In some embodiments, R19 is F . In some embodiments, R19 is . , n some em o mens, s
. In some embodiments, R19 is CN In some embodiments, R19 is
[00454] In some embodiments of the compound, or a pharmaceutically acceptable salt or solvate thereof, R19 is:
[00455] In embodiments of the subject compound, R19 is wherein X4, X5, X6, X9, and X10 are as described herein. In embodiments of the subject compound, R19 is wherein X4, X5, X6, X9, X10,
X11, and X12 are as described herein. In embodiments of the subject compound, R19 is wherein X4, X5, X6, Q1, and Rlh are as described herein. In embodiments of the subject compound, R19 is wherein X4, X5, X6, Q1, and Rlh are as described herein. In embodiments of the subject compound, R 1199 i ics , w„hhoerroemin anU D lh . and R111 are as described herein. In embodiments of the subject compound, R19 is wherein X9, X10, X11, Q3, Q4, and Rlh are as described herein. In embodiments of the subject compound, R 1199 i ics, wherein X7, X8, X12, Q3, Q4, and Rlh are as described herein. In embodiments of the subject compound, wherein X7, X8, Q3, Q4, and Rlh are as described herein. In embodiments of the subject compound, R19 is , , , , , embodiments of the subject compound, wherein Q3, Q4, Q5, Q6, and Rlh are as described herein. In embodiments of the subject compound, wherein X4, X5, X6, Q3, and Q4 are as described herein. In embodiments of the subject compound, wherein X4, X5, X6, Q3, and Q4 are as described herein. In embodiments of the subject compound, wherein, Q3, Q4, Q5, Q6, and Rlh are as described herein. In embodiments of the subject compound, R19 is wherein, Q3, Q4, X13, X14, X15, Rla and Rlh are as described herein.
[00456] In embodiments of the subject compound, some embodiments of the subject compound, further embodiments of the subject compound, subject compound, select embodiments of the subject compound,
. In some embodiments of the subject compound, additional embodiments of the subject compound, embodiments of the subject compound, R19 is , further embodiments of the subject compound, R19 is . In select embodiments of the subject
H compound, R19 is . p ,
H
In embodiments of the subject compound, R19 is 3 . In some embodiments of the subject
, , , ,
embodiments of the compound, embodiments of the compound, R19 is
[00457] In embodiments R19 is selected from
[00459] In some embodiments, R19 is selected from:
[00461] In embodiments, R17 is a fused bicyclic C i icycloalkyl. In embodiments, R17 is a fused bicyclic C2- liheterocycloalkyl. In embodiments, R17 is a fused bicyclic C7-i2aryl. In embodiments, R17 is a fused bicyclic C2- nheteroaryl.
[00462] In embodiments, R17 is a fused bicyclic Cs-ncycloalkyl substituted with one, two, three, four, five, six, or seven R11. In embodiments, R17 is a fused bicyclic C2-nheterocycloalkyl substituted with one, two, three, four, five, six, or seven R11. In embodiments, R17 is a fused bicyclic C7-i2aryl substituted with one, two, three, four, five, six, or seven R11. In embodiments, R17 is a fused bicyclic C2-i2heteroaryl substituted with one, two, three, four, five, six, or seven R11.
[00463] In embodiments, R17 is a fused bicyclic Cs-ncycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In embodiments, R17 is a fused bicyclic C2-nheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In embodiments, R17 is a fused bicyclic C7-i2aryl optionally substituted with one, two, three, four, five, six, or seven R11. In embodiments, R17 is a fused bicyclic C2-i2heteroaryl optionally substituted with one, two, three, four, five, six, or seven R11.
[00464] In embodiments, R17 is a C3-i2cycloalkyl. In embodiments, R17 is a C2-iiheterocycloalkyl. In embodiments, R17 is a C6-i2aryl. In embodiments, R17 is a C2-i2heteroaryl.
[00465] In embodiments, R17 is a C3-i2cycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In embodiments, R17 is a C2-iiheterocycloalkyl optionally substituted with one, two, three, four, five, six, or seven R11. In embodiments, R17 is a C6-i2aryl optionally substituted with one, two, three, four, five, six, or seven R11. In embodiments, R17 is a C2-i2heteroaryl optionally substituted with one, two, three, four, five, six, or seven R11. [00466] In embodiments, R17 is a C3-i2cycloalkyl substituted with one, two, three, four, five, six, or seven R11. In embodiments, R17 is a C2-nheterocycloalkyl substituted with one, two, three, four, five, six, or seven R11. In embodiments, R17 is a C6-i2aryl substituted with one, two, three, four, five, six, or seven R11. In embodiments, R17 is a C2-i2heteroaryl substituted with one, two, three, four, five, six, or seven R11.
[00467] In embodiments, R11 is independently hydrogen. In embodiments, R11 is independently halogen. In embodiments, R11 is independently oxo. In embodiments, R11 is independently -CN. In embodiments, R11 is independently Ci-6alkyl. In embodiments, R11 is independently C2-6alkenyl. In embodiments, R11 is independently C2- 6alkynyl. In embodiments, R11 is independently C3-iocycloalkyl. In embodiments, R11 is independently C2- dictcrocycloalkyl. In embodiments, R11 is independently C6-ioaryl. In embodiments, R11 is independently Ci- dictcroaryl.
[00468] In embodiments, R11 is independently Ci-6alkyl optionally substituted with one, two, or three R201. In embodiments, R11 is independently C2-6alkenyl optionally substituted with one, two, or three R201. In embodiments, R11 is independently C2-6alkynyl optionally substituted with one, two, or three R201. In embodiments, R11 is independently C3-iocycloalkyl optionally substituted with one, two, or three R201. In embodiments, R11 is independently C2-9heterocycloalkyl optionally substituted with one, two, or three R201. In embodiments, R11 is independently C6-ioaryl optionally substituted with one, two, or three R201. In embodiments, R11 is independently Ci- dictcroaryl optionally substituted with one, two, or three R201.
[00469] In embodiments, R11 is independently -OR12. In embodiments, R11 is independently -SR12. In embodiments, R11 is independently -N(R12)(R13) . In embodiments, R11 is independently -C(0)OR12. In embodiments, R11 is independently -0C(0)N(R12)(R13) . In embodiments, R11 is independently - N(R14)C(0)N(R12)(R13) . In embodiments, R11 is independently -N(R14)C(0)0R15. In embodiments, R11 is independently -N(R14)S(0)2R15. In embodiments, R11 is independently -C(0)R15. In embodiments, R11 is independently -S(0)R15. In embodiments, R11 is independently -OC(0)R15. In embodiments, R11 is independently -C(0)N(R12)(R13) . In embodiments, R11 is independently -C(0)C(0)N(R12)(R13) . In embodiments, R11 is independently -N(R14)C(0)R15. In embodiments, R11 is independently -S(0)2R15. In embodiments, R11 is independently -S(0)2N(R12)(R13) . In embodiments, R11 is independently S(=0)(=NH)N(R12)(R13) . In embodiments, R11 is independently -CH2C(0)N(R12)(R13) . In embodiments, R11 is independently -CH2N(R14)C(0)R15. In embodiments, R11 is independently -CH2S(0)2R15. In embodiments, R11 is independently -CH2S(0)2N(R12)(R13). [00470] In embodiments of the subject compound, wherein X4, X5, X6, X9, and X10 are as described herein. In embodiments of the subject compound, wherein X4, X5, X6, X9, X10,
X11, and X12 are as described herein. In embodiments of the subject compound, wherein X4, X5, X6, Q1, and Rlh are as described herein. In embodiments of the subject compound, R17 is , , , , , , embodiments of the subject compound, wherein X9, X10, X11, Q3, Q4, and R111 are as described herein. In embodiments of the subject compound, R 17 i ics wherein X7, X8, X12, Q3,
Q4, and Rlh are as described herein. In embodiments of the subject compound, wherein X7, X8, Q3, Q4, and Rlh are as described herein. In embodiments of the subject compound, R17 is , , , , , embodiments of the subject compound, wherein Q3, Q4, Q5, Q6, and Rlh are as described herein. In embodiments of the subject compound, wherein X4, X5, X6, Q3, and Q4 are as described herein. In embodiments of the subject compound, wherein X4, X5, X6, Q3, and Q4 are as described herein. In embodiments of the subject compound, wherein, Q3,
Q4, Q5, Q6, and Rlh are as described herein. In embodiments of the subject compound, R17 is wherein, Q3, Q4, X13, X14, X15, Rla and Rlh are as described herein. In embodiments of the subject compound, wherein, Q3, Q4, X13, X14, X15, X16, Rla and R111 are as described herein.
[00471] In some embodiments of the subject compound, select embodiments of the
subject compound, select embodiments of the subject compound, further embodiments of the subject compound, some embodiments of the subject
M
X
O compound, embodiments of the subject compound, R 17 v . In some embodiments of the subject compound, additional embodiments of the subject compound, R17 is . In select embodiments of the subject compound, R17 is
H2Ng ziN . In iurther embodiments of the subject compound, R17 is . In
H2N -N embodiments of the subject compound, R17 is CF 3 . In some embodiments of the subject compound, , CF3
In additional embodiments of the subject compound, R17 is . In select embodiments of the subject compound, ,
In further embodiments of the subject compound, some embodiments of the subject compound, R17 is In embodiments of the subject compound, R17 is . In some embodiments of the compound, R17 is In some embodiments of the compound, R17 is . In some embodiments of the compound, R17 is In some embodiments of the compound, R17 is In some embodiments of the compound, R17 is In some embodiments of the compound, R17 is . In some embodiments of the compound, R17 is In some embodiments of the compound, R17 is In some embodiments of the
embodiments of the compound, embodiments of the compound, R17 is
[00472] In some embodiments, R17 is selected from:
[00475] In embodiments, R2 is . In embodiments, R2 is . In embodiments, R2 is
«" TL
N — r
/ . In embodiments, R2 is . In embodiments, R2 is . In embodiments, , . In embodiments, R2 is . In additional embodiments of the subject compound, R . In embodiments of the subject compound, select embodiments of the subject compound, R2 is I In further embodiments of the subject compound, R2 is . In some embodiments of the subject compound, R2 some embodiments of the subject compound, R2 is . In embodiments of the subject compound, additional embodiments of the subject compound, R2 is . In select embodiments of the subject compound, n further embodiments of the subject compound, some embodiments of the subject compound, R2 is embodiments of the subject compound, R2 is . In some embodiments of the subject compound, additional embodiments of the subject compound, select embodiments of the subject compound, R2 is , .
. In some embodiments of the subject compound, embodiments of the subject compound, R2 is . In additional embodiments of the subject compound, select embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is . In iurther embodiments of the subject compound, R2 is . In some embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is F . In additional embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is . In select embodiments of the subject . p , . In some embodiments of the subject compound, embodiments of the subject compound, R2 is °Ύ
. In additional embodiments of the subject compound, R2 is In select embodiments of the subject compound, R2 is . In further embodiments of the subject
N- compound, R2 is / . In some embodiments of the subject compound, R2 is
In embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is . In additional embodiments of the subject compound, R2 is in select embodiments of the subject compound, R2 is 0 ^ . In further embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is . In some embodiments of the subject compound, some embodiments of the subject compound, In additional embodiments of the subject compound, select embodiments of the subject compound, R2 is p , . In further embodiments of the subject compound, R2 is . In some embodiments of the subject compound, R2 is H . In embodiments of the subject compound, R2 is . In additional embodiments of the subject compound, R2 is . In embodiments of the subject
O
N compound, R2 is I . In select embodiments of the subject compound, R2 is
In further embodiments of the subject compound, R2 is . In some embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 i
In embodiments of the subject compound, R2 is . In additional embodiments of the subject compound, R2 is . In select embodiments of the subject compound, R2 is . In further embodiments of the subject compound, R2 is . In some embodiments of the subject compound, some embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is . In additional embodiments of the subject compound, select embodiments of the subject compound, R2 is . In further embodiments of the subject compound, R2 is . In some embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is
F . p , . In additional embodiments of the subject compound, R2 is . In select embodiments of the subject compound, R2 is In further embodiments of the subject compound. R2 is . In embodiments of the subject compound, R2 is . In some embodiments of the subject compound, R2 is . In some embodiments of the subject compound, R2 is . In select embodiments of the subject compound, R2 is . In additional embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is . In further embodiments of the subject compound, R2 is . In some embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is . In select embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is . In some embodiments of the subject compound, R2 is . In further 0 O embodiments of the subject compound, R2 is . In additional embodiments of the subject compound, R2 is . p ,
In embodiments of the subject compound, R2 is O in select embodiments of the subject compound,
^ cN
R2 is ^ . In some embodiments of the subject compound, R2 is . Iniurther 3 embodiments of the subject compound, R2 is / . In some embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is . In additional embodiments of the subject compound, R2 is ^ — OH . In select embodiments of the subject compound, R2 is
. In some embodiments of the subject compound, R2 is In further embodiments of the subject compound, R2 is . In embodiments of the subject compound, R2 is . In embodiments of the subject compound, select embodiments of the subject compound, embodiments, R2 is
In embodiments, R2 is independently selected from
[00476] In further embodiments of the subject compound, or a pharmaceutically acceptable salt or solvate thereof, R5 is hydrogen.
[00477] In some embodiments, R20a is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In some embodiments, R20a is independently selected from halogen, - CN, Ci-ealkyl, -OR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)R25, and -0C(0)R25, wherein Ci-6alkyl is optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci- ehaloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In some embodiments, R20d is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, Ce-ioaiyl, Ci-9heteroaryl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In some embodiments, R20d is independently selected from halogen, -CN, Ci-6alkyl, -OR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)R25, and -0C(0)R25, wherein Ci-6alkyl is optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, - SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25. In some embodiments, R20f is independently selected from halogen, -CN, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, - N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci- ehaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In some embodiments, independently selected from halogen, -CN, Ci-6alkyl, -OR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)R25, and -0C(0)R25, wherein Ci-6alkyl is optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00478] In embodiments, R20a is independently halogen. In embodiments, R20a is independently oxo. In embodiments, R20a is independently -CN. In embodiments, R20a is independently Ci-6alkyl. In embodiments, R20a is independently C2-6alkenyl. In embodiments, R20a is independently C2-6alkynyl. In embodiments, R20a is independently C3-6cycloalkyl. In embodiments, R20a is independently -CH2-C3-6cycloalkyl. In embodiments, R20a is independently C2-9heterocycloalkyl. In embodiments, R20a is independently -CH2-C2-9heterocycloalkyl. In embodiments, R20a is independently C6-ioaryl. In embodiments, R20a is independently -CH2-C6-ioaryl. In embodiments, R20a is independently -CH2-Ci-9heteroaryl. In embodiments, R20a is independently Ci-gheteroaryl. In embodiments, R20a is independently -OR21. In embodiments, R20a is independently -SR21. In embodiments, R20a is independently -N(R22)(R23) . In embodiments, R20a is independently -C(0)0R22. In embodiments, R20a is independently -C(0)N(R22)(R23) . In embodiments, R20a is independently -C(0)C(0)N(R22)(R23) . In embodiments, R20a is independently -0C(0)N(R22)(R23) . In embodiments, R20a is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R20a is independently -N(R24)C(0)0R25. In embodiments, R20a is independently -N(R24)C(0)R25. In embodiments, R20a is independently -N(R24)S(0)2R25. In embodiments, R20a is independently -C(0)R25. In embodiments, R20a is independently -S(0)2R25. In embodiments, R20a is independently -S(0)2N(R22)(R23) . In embodiments, R20a is independently -0CH2C(0)0R22. In embodiments, R20a is independently -0C(0)R25. In embodiments, R20a is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C5-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Ci-gheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00479] In embodiments, R20a is independently halogen. In embodiments, R20a is independently oxo. In embodiments, R20a is independently -CN. In embodiments, R20a is independently Ci-6alkyl. In embodiments, R20a is independently C2-6alkenyl. In embodiments, R20a is independently C2-6alkynyl. In embodiments, R20a is independently C3-6cycloalkyl. In embodiments, R20a is independently -CH2-C3-6cycloalkyl. In embodiments, R20a is independently C2-9heterocycloalkyl. In embodiments, R20a is independently -CH2-C2-9heterocycloalkyl. In embodiments, R20a is independently C5-ioaryl. In embodiments, R20a is independently -CH2-C6-ioaryl. In embodiments, R20a is independently -CH2-Ci-9heteroaryl. In embodiments, R20a is independently Ci-gheteroaryl. In embodiments, R20a is independently -OR21. In embodiments, R20a is independently -SR21. In embodiments, R20a is independently -N(R22)(R23) . In embodiments, R20a is independently -C(0)0R22. In embodiments, R20a is independently -C(0)N(R22)(R23) . In embodiments, R20a is independently -C(0)C(0)N(R22)(R23) . In embodiments, R20a is independently -0C(0)N(R22)(R23) . In embodiments, R20a is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R20a is independently -N(R24)C(0)0R25. In embodiments, R20a is independently -N(R24)C(0)R25. In embodiments, R20a is independently -N(R24)S(0)2R25. In embodiments, R20a is independently -C(0)R25. In embodiments, R20a is independently -S(0)2R25. In embodiments, R20a is independently -S(0)2N(R22)(R23) . In embodiments, R20a is independently -0CH2C(0)0R22. In embodiments, R20a is independently -0C(0)R25. In embodiments, R20a is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-G5-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Ci-dictcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00480] In further embodiments of the subject compound, R20a is independently halogen. In some embodiments of the subject compound, R20a is independently oxo. In some embodiments of the subject compound, R20a is independently -CN. In additional embodiments of the subject compound, R20a is independently Ci-6alkyl. In embodiments of the subject compound, R20a is independently C2-6alkenyl. In some embodiments of the subject compound, R20a is independently Chalky nyl. In further embodiments of the subject compound, R20a is independently -OR22. In select embodiments of the subject compound, R20a is independently -N(R22)(R23). In additional embodiments of the subject compound, R20a is independently -C(0)0R22. In embodiments of the subject compound, R20a is independently -0C(0)N(R22)(R23). In some embodiments of the subject compound, R20a is independently -C(0)R25. In select embodiments of the subject compound, R20a is independently -NH2. In further embodiments of the subject compound, R20a is independently -C(0)0H. In additional embodiments of the subject compound, R20a is independently -0C(0)NH2. In embodiments of the subject compound, R20a is independently - C(0)CH3.
[00481] In embodiments, R20a is independently halogen. In embodiments, R20a is independently oxo. In embodiments, R20a is independently -CN. In embodiments, R20a is independently Ci-6alkyl. In embodiments, R20a is independently C2-6alkenyl. In embodiments, R20a is independently C2-6alkynyl. In embodiments, R20a is independently Ci-6haloalkyl. In embodiments, R20a is independently C3-i2cycloalkyl. In embodiments, R20a is independently -CH2-C3-i2cycloalkyl. In embodiments, R20a is independently Ci-nheterocycloalkyl. In embodiments, R20a is independently -CH2-Ci-nheterocycloalkyl. In embodiments, R20a is independently C6-i2aryl. In embodiments, R20a is independently -CH2-C6-i2aryl. In embodiments, R20a is independently -CH2-Ci-nheteroaryl. In embodiments, R20a is independently Ci-nheteroaryl. In embodiments, R20a is independently -OR22. In embodiments, R20a is independently -SR22. In embodiments, R20a is independently -N(R22)(R23). In embodiments, R20a is independently -C(0)0R22. In embodiments, R20a is independently -0C(0)N(R22)(R23). In embodiments, R20a is independently -N(R24)C(0)N(R22)(R23). In embodiments, R20a is independently -N(R24)C(0)0R25. In embodiments, R20a is independently -N(R24)S(0)2R25. In embodiments, R20a is independently -C(0)R25. In embodiments, R20a is independently -S(0)R25. In embodiments, R20a is independently -0C(0)R25. In embodiments, R20a is independently -C(0)N(R22)(R23). In embodiments, R20a is independently -C(0)C(0)N(R22)(R23). In embodiments, R20a is independently -N(R24)C(0)R25. In embodiments, R20a is independently -S(0)2R25. In embodiments, R20a is independently -S(0)2N(R22)(R23)-. In embodiments, R20a is independently S(=0)(=NH)N(R22)(R23). In embodiments, R20a is independently -CH2C(0)N(R22)(R23). In embodiments, R20a is independently - CH2N(R24)C(0)R25. In embodiments, R20a is independently -CH2S(0)2R25. In embodiments, R20a is independently and -CH2S(0)2N(R22)(R23).
[00482] In embodiments, R20a is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Ci-6haloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C3-i2cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C3-i2cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Ci-nheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-Ci-nheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C6-i2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-G5-i2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-Ci-nheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Ci-nheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00483] In embodiments, R20a is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C2alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cialky l optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cealkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C2alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cialkcnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cialkcnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csalkcnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cealkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C2alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cialkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cialkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csalkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cealkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cihaloalkyl. In embodiments, R20a is independently C2haloalkyl. In embodiments, R20a is independently Cihaloalkyl. In embodiments, R20a is independently Cihaloalkyl. In embodiments, R20a is independently Cshaloalkyl. In embodiments, R20a is independently Cehaloalkyl.
[00484] In embodiments, R20a is independently Cicycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cicy cloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cecycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Gcycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Ciocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00485] In embodiments, R20a is independently C2heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, - SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cdictcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cihctcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Ceheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)iR2S. -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cearyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C-arvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cgaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cnaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Ci2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)iR2S. -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cihctcroan l optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cihctcroan l optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cshctcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Ceheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, C1-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently C-hctcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cioheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently Cnheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -OH. In embodiments, R20a is independently -SH. In embodiments, R20a is independently -NH2. In embodiments, R20a is independently -C(0)0H. In embodiments, R20a is independently -0C(0)NH2. In embodiments, R20a is independently -N(H)C(0)NH2. In embodiments, R20a is independently -N(H)C(0)0H. In embodiments, R20a is independently -N(H)S(0)2CH3. In embodiments, R20a is independently -C(0)H. In embodiments, R20a is independently -S(0)CH3. In embodiments, R20a is independently -0C(0)CH3. In embodiments, R20a is independently -C(0)NH2. In embodiments, R20a is independently -C(0)C(0)NH2. In embodiments, R20a is independently -N(H)C(0)H. In embodiments, R20a is independently -S(0)2CH3. In embodiments, R20a is independently -S(0)2NH2-. In embodiments, R20a is independently S(=0)(=NH)NH2. In embodiments, R20a is independently -CH2C(0)NH2. In embodiments, R20a is independently -CH2N(H)C(0)CH3. In embodiments, R20a is independently -CH2S(0)2CH3. In embodiments, R20a is independently and -CH2S(0)2NH2. In embodiments, R20a is independently -OCH3. In embodiments, R20a is independently -SCH3. In embodiments, R20a is independently -N(CH3)(H). In embodiments, R20a is independently - C(0)0CH3. In embodiments, R20a is independently -0C(0)N(CH3)(H). In embodiments, R20a is independently - N(H)C(0)N(CH3)(H). In embodiments, R20a is independently -N(H)C(0)0CH3. In embodiments, R20a is independently -N(H)S(0)2CH3. In embodiments, R20a is independently -C(0)CH3. In embodiments, R20a is independently -S(0)CH3. In embodiments, R20a is independently -0C(0)CH3. In embodiments, R20a is independently -C(0)N(CH3)(H). In embodiments, R20a is independently -C(0)C(0)N(CH3)(H). In embodiments, R20a is independently -N(H)C(0)CH3. In embodiments, R20a is independently -S(0)2CH3. In embodiments, R20a is independently -S(0)2N(CH3)(H)-. In embodiments, R20a is independently S(=0)(=NH)N(CH3)(H). In embodiments, R20a is independently -CH2C(0)N(CH3)(H). In embodiments, R20a is independently - CH2N(H)C(0)CH3. In embodiments, R20a is independently -CH2S(0)2CH3. In embodiments, R20a is independently and -CH2S(0)2N(CH3)(H). In embodiments, R20a is independently -0C(0)N(CH3)2. In embodiments, R20a is independently -N(H)C(0)N(CH3)2. In embodiments, R20a is independently -C(0)(CH3). In embodiments, R20a is independently -C(0)N(CH3)2. In embodiments, R20a is independently -C(0)C(0)N(CH3)2. In embodiments, R20a is independently -N(H)C(0)(CH3). In embodiments, R20a is independently -S(0)2N(CH3)2. In embodiments, R20a is independently S(=0)(=NH)N(CH3)2. In embodiments, R20a is independently -CH2C(0)N(CH3)2. In embodiments, R20a is independently and -CH2S(0)2N(CH3)2. In embodiments, R20a is independently -CH3. In embodiments, R20a is independently -CF3. In embodiments, R20a is independently -CHF2. In embodiments, R20a is independently - CFH2. In embodiments, R20a is independently ethyl. In embodiments, R20a is independently propyl. In embodiments, R20a is independently isopropyl. In embodiments, R20a is independently butyl. In embodiments, R20a is independently tert-butyl.
[00486] In embodiments, R20a is independently -CH2-C3cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, - SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CF[2-C4cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CFF-Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)iR2S. -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CEb-Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C9cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CEh-Ciocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00487] In embodiments, R20a is independently -CH2-C2heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, - OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CEC-Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently - CH 2 - Ci li c tc ro c > c 1 o a 1 k > 1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci- ehaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently - CEh-Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-ealkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, - N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C6heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CfC-Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00488] In embodiments, R20a is independently -CH2-C6aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C7aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-Csaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C9aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-Cioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-Cnaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-Ci2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C3heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C4heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CEC-Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-G5heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C7heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-C8heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CEC-Csiheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-Cioheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20a is independently -CH2-Cnheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00489] In embodiments, R20b is independently halogen. In embodiments, R20b is independently oxo. In embodiments, R20b is independently -CN. In embodiments, R20b is independently Ci-6alkyl. In embodiments, R20b is independently C2-6alkenyl. In embodiments, R20b is independently C2-6alkynyl. In embodiments, R20b is independently C3-6cycloalkyl. In embodiments, R20b is independently -CH2-C3-6cycloalkyl. In embodiments, R20b is independently C2-9heterocycloalkyl. In embodiments, R20b is independently -CH2-C2-9heterocycloalkyl. In embodiments, R20b is independently C6-ioaryl. In embodiments, R20b is independently -CfC-Ce-ioaryl. In embodiments, R20b is independently -CfC-Ci-gheteroaryl. In embodiments, R20b is independently Ci-gheteroaryl. In embodiments, R20b is independently -OR21. In embodiments, R20b is independently -SR21. In embodiments, R20b is independently -N(R22)(R23) . In embodiments, R20b is independently -C(0)0R22. In embodiments, R20b is independently -C(0)N(R22)(R23) . In embodiments, R20b is independently -C(0)C(0)N(R22)(R23) . In embodiments, R20b is independently -0C(0)N(R22)(R23) . In embodiments, R20b is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R20b is independently -N(R24)C(0)0R25. In embodiments, R20b is independently -N(R24)C(0)R25. In embodiments, R20b is independently -N(R24)S(0)2R25. In embodiments, R20b is independently -C(0)R25. In embodiments, R20b is independently -S(0)2R25. In embodiments, R20b is independently -S(0)2N(R22)(R23) . In embodiments, R20b is independently -0CH2C(0)0R22. In embodiments, R20b is independently -0C(0)R25. In embodiments, R20b is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20b is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20b is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20b is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20b is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20b is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20b is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20b is independently C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20b is independently -CH2-C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20b is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20b is independently Ci-dictcroaiyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00490] In embodiments, R20c is independently halogen. In embodiments, R20c is independently oxo. In embodiments, R20c is independently -CN. In embodiments, R20c is independently Ci-6alkyl. In embodiments, R20c is independently C2-6alkenyl. In embodiments, R20c is independently C2-6alkynyl. In embodiments, R20c is independently C3-6cycloalkyl. In embodiments, R20c is independently -CH2-C3-6cycloalkyl. In embodiments, R20c is independently C2-9heterocycloalkyl. In embodiments, R20c is independently -CH2-C2-9heterocycloalkyl. In embodiments, R20c is independently C6-ioaryl. In embodiments, R20c is independently -CH2-C6-ioaryl. In embodiments, R20c is independently -CH2-Ci-9heteroaryl. In embodiments, R20c is independently Ci-gheteroaryl. In embodiments, R20c is independently -OR21. In embodiments, R20c is independently -SR21. In embodiments, R20c is independently -N(R22)(R23) . In embodiments, R20c is independently -C(0)0R22. In embodiments, R20c is independently -C(0)N(R22)(R23) . In embodiments, R20c is independently -C(0)C(0)N(R22)(R23) . In embodiments, R20c is independently -0C(0)N(R22)(R23) . In embodiments, R20c is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R20c is independently -N(R24)C(0)0R25. In embodiments, R20c is independently -N(R24)C(0)R25. In embodiments, R20c is independently -N(R24)S(0)2R25. In embodiments, R20c is independently -C(0)R25. In embodiments, R20c is independently -S(0)2R25. In embodiments, R20c is independently -S(0)2N(R22)(R23) . In embodiments, R20c is independently -0CH2C(0)0R22. In embodiments, R20c is independently -0C(0)R25. In embodiments, R20c is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20c is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20c is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20c is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20c is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20c is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20c is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20c is independently C5-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20c is independently -CH2-G5-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20c is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20c is independently Ci-gheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00491] In embodiments, R20d is independently halogen. In embodiments, R20d is independently oxo. In embodiments, R20d is independently -CN. In embodiments, R20d is independently Ci-6alkyl. In embodiments, R20d is independently C2-6alkenyl. In embodiments, R20d is independently C2-6alkynyl. In embodiments, R20d is independently C3-6cycloalkyl. In embodiments, R20d is independently -CH2-C3-6cycloalkyl. In embodiments, R20d is independently C2-9heterocycloalkyl. In embodiments, R20d is independently -CH2-C2-9heterocycloalkyl. In embodiments, R20d is independently C6-ioaryl. In embodiments, R20d is independently -CH2-C6-ioaryl. In embodiments, R20d is independently -CH2-Ci-9heteroaryl. In embodiments, R20d is independently Ci-gheteroaryl. In embodiments, R20d is independently -OR21. In embodiments, R20d is independently -SR21. In embodiments, R20d is independently -N(R22)(R23) . In embodiments, R20d is independently -C(0)0R22. In embodiments, R20d is independently -C(0)N(R22)(R23) . In embodiments, R20d is independently -C(0)C(0)N(R22)(R23) . In embodiments, R20d is independently -0C(0)N(R22)(R23) . In embodiments, R20d is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R20d is independently -N(R24)C(0)0R25. In embodiments, R20d is independently -N(R24)C(0)R25. In embodiments, R20d is independently -N(R24)S(0)2R25. In embodiments, R20d is independently -C(0)R25. In embodiments, R20d is independently -S(0)2R25. In embodiments, R20d is independently -S(0)2N(R22)(R23) . In embodiments, R20d is independently -0CH2C(0)0R22. In embodiments, R20d is independently -0C(0)R25. In embodiments, R20d is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Ci-dictcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00492] In embodiments, R20d is independently halogen. In embodiments, R20d is independently oxo. In embodiments, R20d is independently -CN. In embodiments, R20d is independently Ci-6alkyl. In embodiments, R20d is independently C2-6alkenyl. In embodiments, R20d is independently C2-6alkynyl. In embodiments, R20d is independently C3-6cycloalkyl. In embodiments, R20d is independently -CH2-C3-6cycloalkyl. In embodiments, R20d is independently C2-9heterocycloalkyl. In embodiments, R20d is independently -CH2-C2-9heterocycloalkyl. In embodiments, R20d is independently C6-ioaryl. In embodiments, R20d is independently -CH2-C6-ioaryl. In embodiments, R20d is independently -CH2-Ci-9heteroaryl. In embodiments, R20d is independently Ci-gheteroaryl. In embodiments, R20d is independently -OR21. In embodiments, R20d is independently -SR21. In embodiments, R20d is independently -N(R22)(R23) . In embodiments, R20d is independently -C(0)0R22. In embodiments, R20d is independently -C(0)N(R22)(R23) . In embodiments, R20d is independently -C(0)C(0)N(R22)(R23) . In embodiments, R20d is independently -0C(0)N(R22)(R23) . In embodiments, R20d is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R20d is independently -N(R24)C(0)0R25. In embodiments, R20d is independently -N(R24)C(0)R25. In embodiments, R20d is independently -N(R24)S(0)2R25. In embodiments, R20d is independently -C(0)R25. In embodiments, R20d is independently -S(0)2R25. In embodiments, R20d is independently -S(0)2N(R22)(R23) . In embodiments, R20d is independently -0CH2C(0)0R22. In embodiments, R20d is independently -0C(0)R25. In embodiments, R20d is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Ci-gheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00493] In further embodiments of the subject compound, R20d is independently halogen. In some embodiments of the subject compound, R20d is independently oxo. In some embodiments of the subject compound, R20d is independently -CN. In additional embodiments of the subject compound, R20d is independently Ci-6alkyl. In embodiments of the subject compound, R20d is independently C2-6alkenyl. In some embodiments of the subject compound, R20d is independently Chalky nyl. In further embodiments of the subject compound, R20d is independently -OR22. In select embodiments of the subject compound, R20d is independently -N(R22)(R23). In additional embodiments of the subject compound, R20d is independently -C(0)0R22. In embodiments of the subject compound, R20d is independently -0C(0)N(R22)(R23). In some embodiments of the subject compound, R20d is independently -C(0)R25. In select embodiments of the subject compound, R20d is independently -NH2. In further embodiments of the subject compound, R20d is independently -C(0)0H. In additional embodiments of the subject compound, R20d is independently -0C(0)NH2. In embodiments of the subject compound, R20d is independently - C(0)CH3. [00494] In embodiments, R20d is independently halogen. In embodiments, R20d is independently oxo. In embodiments, R20d is independently -CN. In embodiments, R20d is independently Ci-6alkyl. In embodiments, R20d is independently C2-6alkenyl. In embodiments, R20d is independently C2-6alkynyl. In embodiments, R20d is independently Ci-6haloalkyl. In embodiments, R20d is independently C3-i2cycloalkyl. In embodiments, R20d is independently -CH2-C3-i2cycloalkyl. In embodiments, R20d is independently Ci-nheterocycloalkyl. In embodiments, R20d is independently -CEC-Ci-nheterocycloalkyl. In embodiments, R20d is independently C6-i2aryl. In embodiments, R20d is independently -CH2-C6-i2aryl. In embodiments, R20d is independently -CH2-Ci-nheteroaryl. In embodiments, R20d is independently Ci-nheteroaryl. In embodiments, R20d is independently -OR22. In embodiments, R20d is independently -SR22. In embodiments, R20d is independently -N(R22)(R23). In embodiments, R20d is independently -C(0)0R22. In embodiments, R20d is independently -0C(0)N(R22)(R23). In embodiments, R20d is independently -N(R24)C(0)N(R22)(R23). In embodiments, R20d is independently -N(R24)C(0)0R25. In embodiments, R20d is independently -N(R24)S(0)2R25. In embodiments, R20d is independently -C(0)R25. In embodiments, R20d is independently -S(0)R25. In embodiments, R20d is independently -0C(0)R25. In embodiments, R20d is independently -C(0)N(R22)(R23). In embodiments, R20d is independently -C(0)C(0)N(R22)(R23). In embodiments, R20d is independently -N(R24)C(0)R25. In embodiments, R20d is independently -S(0)2R25. In embodiments, R20d is independently -S(0)2N(R22)(R23)-. In embodiments, R20d is independently S(=0)(=NH)N(R22)(R23). In embodiments, R20d is independently -CH2C(0)N(R22)(R23). In embodiments, R20d is independently -CH2N(R24)C(0)R25. In embodiments, R20d is independently -CH2S(0)2R25. In embodiments, R20d is independently and -CH2S(0)2N(R22)(R23).
[00495] In embodiments, R20d is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Ci-6haloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C3-i2cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C3-i2cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Ci-nheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-Ci-nheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C6-i2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C6-i2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-Ci-nheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Ci-nheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00496] In embodiments, R20d is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C2alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Csalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cealkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C2alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cialkcnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cialkcnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Csalkcnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cealkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C2alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cialkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cialkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Csalkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cealkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cihaloalkyl. In embodiments, R20d is independently C2haloalkyl. In embodiments, R20d is independently Cihaloalkyl. In embodiments, R20d is independently Cihaloalkyl. In embodiments, R20d is independently Cshaloalkyl. In embodiments, R20d is independently Cehaloalkyl.
[00497] In embodiments, R20d is independently Cicycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cicycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cecycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Gjcycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Ciocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00498] In embodiments, R20d is independently C2heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, - SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cdictcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cihctcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cdictcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Ceheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cdictcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cearyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C-aiy l optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)iR2S. -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Csaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cyarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cnaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Ci2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cihctcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cihctcroaiy l optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cshctcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Ceheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently C-hctcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cioheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently Cnheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -OH. In embodiments, R20d is independently -SH. In embodiments, R20d is independently -NH2. In embodiments, R20d is independently -C(0)0H. In embodiments, R20d is independently -0C(0)NH2. In embodiments, R20d is independently -N(H)0(0)NH2. In embodiments, R20d is independently -N(H)C(0)0H. In embodiments, R20d is independently -N(H)S(0)2CH3. In embodiments, R20d is independently -C(0)H. In embodiments, R20d is independently -S(0)CH3. In embodiments, R20d is independently -0C(0)CH3. In embodiments, R20d is independently -C(0)NH2. In embodiments, R20d is independently -C(0)C(0)NH2. In embodiments, R20d is independently -N(H)C(0)H. In embodiments, R20d is independently -S(0)2CH3. In embodiments, R20d is independently -S(0)2NH2-. In embodiments, R20d is independently S(=0)(=NH)NH2. In embodiments, R20d is independently -CtRC(0)NHi. In embodiments, R20d is independently -CH2N(H)C(0)CH3. In embodiments, R20d is independently -CH2S(0)2CH3. In embodiments, R20d is independently and -CH2S(0)2NH2. In embodiments, R20d is independently -OCH3. In embodiments, R20d is independently -SCH3. In embodiments, R20d is independently -N(CH3)(H). In embodiments, R20d is independently - C(0)0CH3. In embodiments, R20d is independently -0C(0)N(CH3)(H). In embodiments, R20d is independently - N(H)C(0)N(CH3)(H). In embodiments, R20d is independently -N(H)C(0)0CH3. In embodiments, R20d is independently -N(H)S(0)2CH3. In embodiments, R20d is independently -C(0)CH3. In embodiments, R20d is independently -S(0)CH3. In embodiments, R20d is independently -0C(0)CH3. In embodiments, R20d is independently -C(0)N(CH3)(H). In embodiments, R20d is independently -C(0)C(0)N(CH3)(H). In embodiments, R20d is independently -N(H)C(0)CH3. In embodiments, R20d is independently -S(0)2CH3. In embodiments, R20d is independently -S(0)2N(CH3)(H)-. In embodiments, R20d is independently S(=0)(=NH)N(CH3)(H). In embodiments, R20d is independently -CH2C(0)N(CH3)(H). In embodiments, R20d is independently - CH2N(H)C(0)CH3. In embodiments, R20d is independently -CH2S(0)2CH3. In embodiments, R20d is independently and -CH2S(0)2N(CH3)(H). In embodiments, R20d is independently -0C(0)N(CH3)2. In embodiments, R20d is independently -N(H)C(0)N(CH3)2. In embodiments, R20d is independently -C(0)(CH3). In embodiments, R20d is independently -C(0)N(CH3)2. In embodiments, R20d is independently -C(0)C(0)N(CH3)2. In embodiments, R20d is independently -N(H)C(0)(CH3). In embodiments, R20d is independently -S(0)2N(CH3)2. In embodiments, R20d is independently S(=0)(=NH)N(CH3)2. In embodiments, R20d is independently -CH2C(0)N(CH3)2. In embodiments, R20d is independently and -CH2S(0)2N(CH3)2. In embodiments, R20d is independently -CH3. In embodiments, R20d is independently -CF3. In embodiments, R20d is independently -CHF2. In embodiments, R20d is independently - CFH2. In embodiments, R20d is independently ethyl. In embodiments, R20d is independently propyl. In embodiments, R20d is independently isopropyl. In embodiments, R20d is independently butyl. In embodiments, R20d is independently tert-butyl.
[00499] In embodiments, R20d is independently -CH2-C3cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, - SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CFF-Cicycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CFF-Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CFF-Cecycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C8cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CFF-Cgcycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-Ciocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00500] In embodiments, R20d is independently -CH2-C2heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, - OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C3heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CEh-Ciheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci- ehaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently - CEb-Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-ealkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, - N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C6heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CEC-Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CEC-Csiheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00501] In embodiments, R20d is independently -CH2-C6aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C7aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C8aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C9aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-Cioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-Cnaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-Ci2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C3heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CEC-Ciheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C5heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C6heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C7heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-C8heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CEC-Cgheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-Cioheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20d is independently -CH2-Cnheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00502] In embodiments, R20e is independently halogen. In embodiments, R20e is independently oxo. In embodiments, R20e is independently -CN. In embodiments, R20e is independently Ci-6alkyl. In embodiments, R20e is independently C2-6alkenyl. In embodiments, R20e is independently C2-6alkynyl. In embodiments, R20e is independently C3-6cycloalkyl. In embodiments, R20e is independently -CH2-C3-6cycloalkyl. In embodiments, R20e is independently C2-9heterocycloalkyl. In embodiments, R20e is independently -CH2-C2-9heterocycloalkyl. In embodiments, R20e is independently C6-ioaryl. In embodiments, R20e is independently -CH2-C6-ioaryl. In embodiments, R20e is independently -CH2-Ci-9heteroaryl. In embodiments, R20e is independently Ci-gheteroaryl. In embodiments, R20e is independently -OR21. In embodiments, R20e is independently -SR21. In embodiments, R20e is independently -N(R22)(R23) . In embodiments, R20e is independently -C(0)0R22. In embodiments, R20e is independently -C(0)N(R22)(R23) . In embodiments, R20e is independently -C(0)C(0)N(R22)(R23) . In embodiments, R20e is independently -0C(0)N(R22)(R23) . In embodiments, R20e is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R20e is independently -N(R24)C(0)0R25. In embodiments, R20e is independently -N(R24)C(0)R25. In embodiments, R20e is independently -N(R24)S(0)2R25. In embodiments, R20e is independently -C(0)R25. In embodiments, R20e is independently -S(0)2R25. In embodiments, R20e is independently -S(0)2N(R22)(R23) . In embodiments, R20e is independently -0CH2C(0)0R22. In embodiments, R20e is independently -0C(0)R25. In embodiments, R20e is independently C1-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20e is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20e is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20e is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20e is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20e is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20e is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20e is independently C5-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20e is independently -CH2-C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20e is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20e is independently Ci-gheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00503] In embodiments, R20f is independently halogen. In embodiments, R20f is independently oxo. In embodiments, R20f is independently -CN. In embodiments, R20f is independently Ci-6alkyl. In embodiments, R20f is independently C2-6alkenyl. In embodiments, R20f is independently C2-6alkynyl. In embodiments, R20f is independently C3-6cycloalkyl. In embodiments, R20f is independently -CH2-C3-6cycloalkyl. In embodiments, R20f is independently C2-9heterocycloalkyl. In embodiments, R20f is independently -CH2-C2-9heterocycloalkyl. In embodiments, R20f is independently C6-ioaryl. In embodiments, R20f is independently -CH2-C6-ioaryl. In embodiments, R20f is independently -CH2-Ci-9heteroaryl. In embodiments, R20f is independently Ci-gheteroaryl. In embodiments, R20f is independently -OR21. In embodiments, R20f is independently -SR21. In embodiments, R20f is independently -N(R22)(R23) . In embodiments, R20f is independently -C(0)0R22. In embodiments, R20f is independently -C(0)N(R22)(R23) . In embodiments, R20f is independently -C(0)C(0)N(R22)(R23) . In embodiments, R20f is independently -0C(0)N(R22)(R23) . In embodiments, R20f is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R20f is independently -N(R24)C(0)0R25. In embodiments, R20f is independently -N(R24)C(0)R25. In embodiments, R20f is independently -N(R24)S(0)2R25. In embodiments, R20f is independently -C(0)R25. In embodiments, R20f is independently -S(0)2R25. In embodiments, R20f is independently -S(0)2N(R22)(R23) . In embodiments, R20f is independently -0CH2C(0)0R22. In embodiments, R20f is independently -0C(0)R25. In embodiments, R20f is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Ci-dictcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00504] In embodiments, R20f is independently halogen. In embodiments, R20f is independently oxo. In embodiments, R20f is independently -CN. In embodiments, R20f is independently Ci-6alkyl. In embodiments, R20f is independently C2-6alkenyl. In embodiments, R20f is independently C2-6alkynyl. In embodiments, R20f is independently C3-6cycloalkyl. In embodiments, R20f is independently -CH2-C3-6cycloalkyl. In embodiments, R20f is independently C2-9heterocycloalkyl. In embodiments, R20f is independently -CH2-C2-9heterocycloalkyl. In embodiments, R20f is independently C6-ioaryl. In embodiments, R20f is independently -CH2-C6-ioaryl. In embodiments, R20f is independently -CH2-Ci-9heteroaryl. In embodiments, R20f is independently Ci-gheteroaryl. In embodiments, R20f is independently -OR21. In embodiments, R20f is independently -SR21. In embodiments, R20f is independently -N(R22)(R23) . In embodiments, R20f is independently -C(0)0R22. In embodiments, R20f is independently -C(0)N(R22)(R23) . In embodiments, R20f is independently -C(0)C(0)N(R22)(R23) . In embodiments, R20f is independently -0C(0)N(R22)(R23) . In embodiments, R20f is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R20f is independently -N(R24)C(0)0R25. In embodiments, R20f is independently -N(R24)C(0)R25. In embodiments, R20f is independently -N(R24)S(0)2R25. In embodiments, R20f is independently -C(0)R25. In embodiments, R20f is independently -S(0)2R25. In embodiments, R20f is independently -S(0)2N(R22)(R23) . In embodiments, R20f is independently -0CH2C(0)0R22. In embodiments, R20f is independently -0C(0)R25. In embodiments, R20f is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Ci-gheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00505] In further embodiments of the subject compound, R20f is independently halogen. In some embodiments of the subject compound, R20f is independently oxo. In some embodiments of the subject compound, R20f is independently -CN. In additional embodiments of the subject compound, R20f is independently Ci-6alkyl. In embodiments of the subject compound, R20f is independently C2-6alkenyl. In some embodiments of the subject compound, R20f is independently C2-6alkynyl. In further embodiments of the subject compound, R20f is independently -OR22. In select embodiments of the subject compound, R20f is independently -N(R22)(R23). In additional embodiments of the subject compound, R20f is independently -C(0)0R22. In embodiments of the subject compound, R20f is independently -0C(0)N(R22)(R23). In some embodiments of the subject compound, R20f is independently -C(0)R25. In select embodiments of the subject compound, R20f is independently -NH2. In further embodiments of the subject compound, R20f is independently -C(0)0H. In additional embodiments of the subject compound, R20f is independently -0C(0)NH2. In embodiments of the subject compound, R20f is independently - C(0)CH3.
[00506] In embodiments, R20f is independently halogen. In embodiments, R20f is independently oxo. In embodiments, R20f is independently -CN. In embodiments, R20f is independently Ci-6alkyl. In embodiments, R20f is independently C2-6alkenyl. In embodiments, R20f is independently C2-6alkynyl. In embodiments, R20f is independently Ci-6haloalkyl. In embodiments, R20f is independently C3-i2cycloalkyl. In embodiments, R20f is independently -CH2-C3-i2cycloalkyl. In embodiments, R20f is independently Ci-nheterocycloalkyl. In embodiments, R20f is independently -CH2-Ci-nheterocycloalkyl. In embodiments, R20f is independently C6-i2aryl. In embodiments, R20f is independently -CH2-C6-i2aryl. In embodiments, R20f is independently -CH2-Ci-nheteroaryl. In embodiments, R20f is independently Ci-nheteroaryl. In embodiments, R20f is independently -OR22. In embodiments, R20f is independently -SR22. In embodiments, R20f is independently -N(R22)(R23). In embodiments, R20f is independently - C(0)0R22. In embodiments, R20f is independently -0C(0)N(R22)(R23). In embodiments, R20f is independently - N(R24)C(0)N(R22)(R23). In embodiments, R20f is independently -N(R24)C(0)0R25. In embodiments, R20f is independently -N(R24)S(0)2R25. In embodiments, R20f is independently -C(0)R25. In embodiments, R20f is independently -S(0)R25. In embodiments, R20f is independently -0C(0)R25. In embodiments, R20f is independently -C(0)N(R22)(R23). In embodiments, R20f is independently -C(0)C(0)N(R22)(R23). In embodiments, R20f is independently -N(R24)C(0)R25. In embodiments, R20f is independently -S(0)2R25. In embodiments, R20f is independently -S(0)2N(R22)(R23)-. In embodiments, R20f is independently S(=0)(=NH)N(R22)(R23). In embodiments, R20f is independently -CH2C(0)N(R22)(R23). In embodiments, R20f is independently - CH2N(R24)C(0)R25. In embodiments, R20f is independently -CH2S(0)2R25. In embodiments, R20f is independently and -CH2S(0)2N(R22)(R23).
[00507] In embodiments, R20f is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Ci-6haloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C3-i2cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C3-i2cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Ci-nheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-Ci-nheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C6-i2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C6-i2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-Ci-nheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Ci-nheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00508] In embodiments, R20f is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C2alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C ialky l optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C lalky l optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Csalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cealkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C2alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cialkcnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cialkcnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Csalkcnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cealkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C2alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cialkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cialkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Csalkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cealkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cihaloalkyl. In embodiments, R20f is independently C2haloalkyl. In embodiments, R20f is independently Cihaloalkyl. In embodiments, R20f is independently Cihaloalkyl. In embodiments, R20f is independently Cshaloalkyl. In embodiments, R20f is independently Cehaloalkyl.
[00509] In embodiments, R20f is independently Cicycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cicycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cecycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cycycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Ciocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00510] In embodiments, R20f is independently C2heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, - SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cdictcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Ciheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cdictcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Ceheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cgheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cearyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)iR2S. -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C-arvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Csaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cyarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cnaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Ci2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cihctcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cihctcroaiy l optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cshctcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)iR2S. -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Ceheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently C-hctcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cioheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently Cnheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -OH. In embodiments, R20f is independently -SH. In embodiments, R20f is independently -NH2. In embodiments, R20f is independently -C(0)0H. In embodiments, R20f is independently -0C(0)NH2. In embodiments, R20f is independently -N(H)C(0)NH2. In embodiments, R20f is independently -N(H)C(0)0H. In embodiments, R20f is independently -N(H)S(0)2CH3. In embodiments, R20f is independently -C(0)H. In embodiments, R20f is independently -S(0)CH3. In embodiments, R20f is independently -0C(0)CH3. In embodiments, R20f is independently -C(0)NH2. In embodiments, R20f is independently -C(0)C(0)NH2. In embodiments, R20f is independently -N(H)C(0)H. In embodiments, R20f is independently -S(0)2CH3. In embodiments, R20f is independently -S(0)2NH2-. In embodiments, R20f is independently S(=0)(=NH)NH2. In embodiments, R20f is independently -CH2C(0)NH2. In embodiments, R20f is independently -CH2N(H)C(0)CH3. In embodiments, R20f is independently -CH2S(0)2CH3. In embodiments, R20f is independently and -CH2S(0)2NH2. In embodiments, R20f is independently -OCH3. In embodiments, R20f is independently -SCH3. In embodiments, R20f is independently -N(CH3)(H). In embodiments, R20f is independently - C(0)0CH3. In embodiments, R20f is independently -0C(0)N(CH3)(H). In embodiments, R20f is independently - N(H)C(0)N(CH3)(H). In embodiments, R20f is independently -N(H)C(0)0CH3. In embodiments, R20f is independently -N(H)S(0)2CH3. In embodiments, R20f is independently -C(0)CH3. In embodiments, R20f is independently -S(0)CH3. In embodiments, R20f is independently -0C(0)CH3. In embodiments, R20f is independently -C(0)N(CH3)(H). In embodiments, R20f is independently -C(0)C(0)N(CH3)(H). In embodiments, R20f is independently -N(H)C(0)CH3. In embodiments, R20f is independently -S(0)2CH3. In embodiments, R20f is independently -S(0)2N(CH3)(H)-. In embodiments, R20f is independently S(=0)(=NH)N(CH3)(H). In embodiments, R20f is independently -CH2C(0)N(CH3)(H). In embodiments, R20f is independently - CH2N(H)C(0)CH3. In embodiments, R20f is independently -CH2S(0)2CH3. In embodiments, R20f is independently and -CH2S(0)2N(CH3)(H). In embodiments, R20f is independently -0C(0)N(CH3)2. In embodiments, R20f is independently -N(H)C(0)N(CH3)2. In embodiments, R20f is independently -C(0)(CH3). In embodiments, R20f is independently -C(0)N(CH3)2. In embodiments, R20f is independently -C(0)C(0)N(CH3)2. In embodiments, R20f is independently -N(H)C(0)(CH3). In embodiments, R20f is independently -S(0)2N(CH3)2. In embodiments, R20f is independently S(=0)(=NH)N(CH3)2. In embodiments, R20f is independently -CH2C(0)N(CH3)2. In embodiments, R20f is independently and -CH2S(0)2N(CH3)2. In embodiments, R20f is independently -CH3. In embodiments, R20f is independently -CF3. In embodiments, R20f is independently -CHF2. In embodiments, R20f is independently -CFH2. In embodiments, R20f is independently ethyl. In embodiments, R20f is independently propyl. In embodiments, R20f is independently isopropyl. In embodiments, R20f is independently butyl. In embodiments, R20f is independently tert- butyl.
[00511] In embodiments, R20f is independently -CH2-C3cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, - SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CFF-Cicycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CFF-Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CFF-Cecycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CFF-Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CFF-Cgcycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)iR2S. -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-Ciocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00512] In embodiments, R20f is independently -CfH-Ciheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, - OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CfH-Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH 2-C i lictc rocy c loal ky 1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci- ehaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently - Cfb-Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-ealkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, - N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CEC-Ceheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently - CH 2 - Cs li c tc ro c > c 1 o a 1 k > 1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently - CH 2 - C<) h c tc ro c y c 1 o a 1 k y 1 optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00513] In embodiments, R20f is independently -CH2-C6aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C7aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C8aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CEC-Cgaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-Cioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-Cnaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-Ci2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C3heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C4heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CEC-Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C6heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C7heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CEC-Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-C9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-Cioheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20f is independently -CH2-Cnheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00514] In embodiments, R20g is independently halogen. In embodiments, R20g is independently oxo. In embodiments, R20g is independently -CN. In embodiments, R20g is independently Ci-6alkyl. In embodiments, R20g is independently C2-6alkenyl. In embodiments, R20g is independently C2-6alkynyl. In embodiments, R20g is independently C3-6cycloalkyl. In embodiments, R20g is independently -CH2-C3-6cycloalkyl. In embodiments, R20g is independently C2-9heterocycloalkyl. In embodiments, R20g is independently -CH2-C2-9heterocycloalkyl. In embodiments, R20g is independently C6-10aryl. In embodiments, R20g is independently -CH2-C6-10aryl. In embodiments, R20g is independently -CH2-Ci-9heteroaryl. In embodiments, R20g is independently Ci-gheteroaryl. In embodiments, R20g is independently -OR21. In embodiments, R20g is independently -SR21. In embodiments, R20g is independently -N(R22)(R23) . In embodiments, R20g is independently -C(0)0R22. In embodiments, R20g is independently -C(0)N(R22)(R23) . In embodiments, R20g is independently -C(0)C(0)N(R22)(R23) . In embodiments, R20g is independently -0C(0)N(R22)(R23) . In embodiments, R20g is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R20g is independently -N(R24)C(0)0R25. In embodiments, R20g is independently -N(R24)C(0)R25. In embodiments, R20g is independently -N(R24)S(0)2R25. In embodiments, R20g is independently -C(0)R25. In embodiments, R20g is independently -S(0)2R25. In embodiments, R20g is independently -S(0)2N(R22)(R23) . In embodiments, R20g is independently -0CH2C(0)0R22. In embodiments, R20g is independently -0C(0)R25. In embodiments, R20g is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently -CH2-C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20g is independently Ci-dictcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00515] In embodiments, R201 is independently halogen. In embodiments, R201 is independently oxo. In embodiments, R201 is independently -CN. In embodiments, R201 is independently Ci-6alkyl. In embodiments, R201 is independently C2-6alkenyl. In embodiments, R201 is independently C2-6alkynyl. In embodiments, R201 is independently C3-6cycloalkyl. In embodiments, R201 is independently -CH2-C3-6cycloalkyl. In embodiments, R201 is independently C2-9heterocycloalkyl. In embodiments, R201 is independently -CH2-C2-9heterocycloalkyl. In embodiments, R201 is independently C6-ioaryl. In embodiments, R201 is independently -CH2-C6-ioaryl. In embodiments, R201 is independently -CH2-Ci-9heteroaryl. In embodiments, R201 is independently Ci-gheteroaryl. In embodiments, R201 is independently -OR21. In embodiments, R201 is independently -SR21. In embodiments, R201 is independently -N(R22)(R23) . In embodiments, R201 is independently -C(0)0R22. In embodiments, R201 is independently -C(0)N(R22)(R23) . In embodiments, R201 is independently -C(0)C(0)N(R22)(R23) . In embodiments, R201 is independently -0C(0)N(R22)(R23) . In embodiments, R201 is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R201 is independently -N(R24)C(0)0R25. In embodiments, R201 is independently -N(R24)C(0)R25. In embodiments, R201 is independently -N(R24)S(0)2R25. In embodiments, R201 is independently -C(0)R25. In embodiments, R201 is independently -S(0)2R25. In embodiments, R201 is independently -S(0)2N(R22)(R23) . In embodiments, R201 is independently -0CH2C(0)0R22. In embodiments, R201 is independently -0C(0)R25. In embodiments, R201 is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Ci-gheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00516] In embodiments, R201 is independently halogen. In embodiments, R201 is independently oxo. In embodiments, R201 is independently -CN. In embodiments, R201 is independently Ci-6alkyl. In embodiments, R201 is independently C2-6alkenyl. In embodiments, R201 is independently C2-6alkynyl. In embodiments, R201 is independently C3-6cycloalkyl. In embodiments, R201 is independently -CH2-C3-6cycloalkyl. In embodiments, R201 is independently C2-9heterocycloalkyl. In embodiments, R201 is independently -CH2-C2-9heterocycloalkyl. In embodiments, R201 is independently C5-ioaryl. In embodiments, R201 is independently -CH2-C6-ioaryl. In embodiments, R201 is independently -CH2-Ci-9heteroaryl. In embodiments, R201 is independently Ci-gheteroaryl. In embodiments, R201 is independently -OR21. In embodiments, R201 is independently -SR21. In embodiments, R201 is independently -N(R22)(R23) . In embodiments, R201 is independently -C(0)0R22. In embodiments, R201 is independently -C(0)N(R22)(R23) . In embodiments, R201 is independently -C(0)C(0)N(R22)(R23) . In embodiments, R201 is independently -0C(0)N(R22)(R23) . In embodiments, R201 is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R201 is independently -N(R24)C(0)0R25. In embodiments, R201 is independently -N(R24)C(0)R25. In embodiments, R201 is independently -N(R24)S(0)2R25. In embodiments, R201 is independently -C(0)R25. In embodiments, R201 is independently -S(0)2R25. In embodiments, R201 is independently -S(0)2N(R22)(R23) . In embodiments, R201 is independently -0CH2C(0)0R22. In embodiments, R201 is independently -0C(0)R25. In embodiments, R201 is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C5-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Ci-gheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00517] In further embodiments of the subject compound, R201 is independently halogen. In some embodiments of the subject compound, R201 is independently oxo. In some embodiments of the subject compound, R201 is independently -CN. In additional embodiments of the subject compound, R201 is independently Ci-6alkyl. In embodiments of the subject compound, R201 is independently C2-6alkenyl. In some embodiments of the subject compound, R201 is independently C2-6alkynyl. In further embodiments of the subject compound, R201 is independently -OR22. In select embodiments of the subject compound, R201 is independently -N(R22)(R23). In additional embodiments of the subject compound, R201 is independently -C(0)0R22. In embodiments of the subject compound, R201 is independently -0C(0)N(R22)(R23). In some embodiments of the subject compound, R201 is independently -C(0)R25. In select embodiments of the subject compound, R201 is independently -NH2. In further embodiments of the subject compound, R201 is independently -C(0)0H. In additional embodiments of the subject compound, R201 is independently -0C(0)NH2. In embodiments of the subject compound, R201 is independently - C(0)CH3.
[00518] In embodiments, R201 is independently halogen. In embodiments, R201 is independently oxo. In embodiments, R201 is independently -CN. In embodiments, R201 is independently Ci-6alkyl. In embodiments, R201 is independently C2-6alkenyl. In embodiments, R201 is independently C2-6alkynyl. In embodiments, R201 is independently Ci-6haloalkyl. In embodiments, R201 is independently C3-i2cycloalkyl. In embodiments, R201 is independently -CH2-C3-i2cycloalkyl. In embodiments, R201 is independently Ci-nheterocycloalkyl. In embodiments, R201 is independently -CEC-Ci-nheterocycloalkyl. In embodiments, R201 is independently C6-i2aryl. In embodiments, R201 is independently -CH2-C6-i2aryl. In embodiments, R201 is independently -CEC-Ci-nheteroaryl. In embodiments, R201 is independently Ci-nheteroaryl. In embodiments, R201 is independently -OR22. In embodiments, R201 is independently -SR22. In embodiments, R201 is independently -N(R22)(R23). In embodiments, R201 is independently - C(0)0R22. In embodiments, R201 is independently -0C(0)N(R22)(R23). In embodiments, R201 is independently - N(R24)C(0)N(R22)(R23). In embodiments, R201 is independently -N(R24)C(0)0R25. In embodiments, R201 is independently -N(R24)S(0)2R25. In embodiments, R201 is independently -C(0)R25. In embodiments, R201 is independently -S(0)R25. In embodiments, R201 is independently -0C(0)R25. In embodiments, R201 is independently -C(0)N(R22)(R23). In embodiments, R201 is independently -C(0)C(0)N(R22)(R23). In embodiments, R201 is independently -N(R24)C(0)R25. In embodiments, R201 is independently -S(0)2R25. In embodiments, R201 is independently -S(0)2N(R22)(R23)-. In embodiments, R201 is independently S(=0)(=NH)N(R22)(R23). In embodiments, R201 is independently -CH2C(0)N(R22)(R23). In embodiments, R201 is independently - CH2N(R24)C(0)R25. In embodiments, R201 is independently -CH2S(0)2R25. In embodiments, R201 is independently and -CH2S(0)2N(R22)(R23).
[00519] In embodiments, R201 is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Ci-6haloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C3-i2cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C3-i2cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Ci-nheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-Ci-nheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C6-i2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C6-i2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-Ci-nheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Ci-nheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00520] In embodiments, R201 is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C2alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cialkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Csalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cealkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C2alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cialkcnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cialkcnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Csalkcnyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cealkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C2alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cialkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cialkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Csalkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cealkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cihaloalkyl. In embodiments, R201 is independently C2haloalkyl. In embodiments, R201 is independently Cihaloalkyl. In embodiments, R201 is independently Cihaloalkyl. In embodiments, R201 is independently Cshaloalkyl. In embodiments, R201 is independently Cehaloalkyl.
[00521] In embodiments, R201 is independently Cicycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C icycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cecycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Gjcycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Ciocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00522] In embodiments, R201 is independently C2heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, - SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cdictcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cihctcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cshctcrocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Ceheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)iR2S. -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Csdieterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Gsaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C-arvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Csaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Gjarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cnaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Ci2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cihctcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cihctcroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cshctcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Ceheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently C-hctcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cioheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently Cnheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -OH. In embodiments, R201 is independently -SH. In embodiments, R201 is independently -NH2. In embodiments, R201 is independently -C(0)0H. In embodiments, R201 is independently -0C(0)NH2. In embodiments, R201 is independently -N(H)C(0)NH2. In embodiments, R201 is independently -N(H)C(0)0H. In embodiments, R201 is independently -N(H)S(0)2CH3. In embodiments, R201 is independently -C(0)H. In embodiments, R201 is independently -S(0)CH3. In embodiments, R201 is independently -0C(0)CH3. In embodiments, R201 is independently -C(0)NH2. In embodiments, R201 is independently -C(0)C(0)NH2. In embodiments, R201 is independently -N(H)C(0)H. In embodiments, R201 is independently -S(0)2CH3. In embodiments, R201 is independently -S(0)2NH2-. In embodiments, R201 is independently S(=0)(=NH)NH2. In embodiments, R201 is independently -QHC/O/MH. In embodiments, R201 is independently -CH2N(H)C(0)CH3. In embodiments, R201 is independently -CH2S(0)2CH3. In embodiments, R201 is independently and -CH2S(0)2NH2. In embodiments, R201 is independently -OCH3. In embodiments, R201 is independently -SCH3. In embodiments, R201 is independently -N(CH3)(H). In embodiments, R201 is independently - C(0)0CH3. In embodiments, R201 is independently -0C(0)N(CH3)(H). In embodiments, R201 is independently - N(H)C(0)N(CH3)(H). In embodiments, R201 is independently -N(H)C(0)0CH3. In embodiments, R201 is independently -N(H)S(0)2CH3. In embodiments, R201 is independently -C(0)CH3. In embodiments, R201 is independently -S(0)CH3. In embodiments, R201 is independently -0C(0)CH3. In embodiments, R201 is independently -C(0)N(CH3)(H). In embodiments, R201 is independently -C(0)C(0)N(CH3)(H). In embodiments, R201 is independently -N(H)C(0)CH3. In embodiments, R201 is independently -S(0)2CH3. In embodiments, R201 is independently -S(0)2N(CH3)(H)-. In embodiments, R201 is independently S(=0)(=NH)N(CH3)(H). In embodiments, R201 is independently -CH2C(0)N(CH3)(H). In embodiments, R201 is independently - CH2N(H)C(0)CH3. In embodiments, R201 is independently -CH2S(0)2CH3. In embodiments, R201 is independently and -CH2S(0)2N(CH3)(H). In embodiments, R201 is independently -0C(0)N(CH3)2. In embodiments, R201 is independently -N(H)C(0)N(CH3)2. In embodiments, R201 is independently -C(0)(CH3). In embodiments, R201 is independently -C(0)N(CH3)2. In embodiments, R201 is independently -C(0)C(0)N(CH3)2. In embodiments, R201 is independently -N(H)C(0)(CH3). In embodiments, R201 is independently -S(0)2N(CH3)2. In embodiments, R201 is independently S(=0)(=NH)N(CH3)2. In embodiments, R201 is independently -CH2C(0)N(CH3)2. In embodiments, R201 is independently and -CH2S(0)2N(CH3)2. In embodiments, R201 is independently -CH3. In embodiments, R201 is independently -CF3. In embodiments, R201 is independently -CHF2. In embodiments, R201 is independently -CFH2.
In embodiments, R201 is independently ethyl. In embodiments, R201 is independently propyl. In embodiments, R201 is independently isopropyl. In embodiments, R201 is independently butyl. In embodiments, R201 is independently tert- butyl.
[00523] In embodiments, R201 is independently -CH2-C3cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, - SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CFF-Cicycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CFF-Cscycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C7cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-ehaloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)iR2S. -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-Cxcycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C9cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-Ciocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00524] In embodiments, R201 is independently -CH2-C2heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, - OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C3heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CEC-Ciheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci- ehaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently - CH2-C5heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-ealkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, - N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20i is independently -CH2-C6heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C7heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CEC-Csheterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00525] In embodiments, R201 is independently -CH2-C6aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C7aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CEC-Csaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CEC-Cgaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-Cioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-Cnaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-Ci2aryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C2heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C3heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C4heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CEC-Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C6heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-C7heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CEC-Csheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CEC-Cgheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-Cioheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R201 is independently -CH2-Cnheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. [00526] In embodiments, R20k is independently halogen. In embodiments, R20k is independently -CN. In embodiments, R20k is independently Ci-6alkyl. In embodiments, R20k is independently C2-6alkenyl. In embodiments, R20k is independently C2-6alkynyl. In embodiments, R20k is independently C3-6cycloalkyl. In embodiments, R20k is independently -CH2-C3-6cycloalkyl. In embodiments, R20k is independently C2-9heterocycloalkyl. In embodiments, R20k is independently -CH2-C2-9heterocycloalkyl. In embodiments, R20k is independently C6-ioaryl. In embodiments, R20k is independently -CH2-C6-ioaryl. In embodiments, R20k is independently -CH2-Ci-9heteroaryl. In embodiments, R20k is independently Ci-gheteroaryl. In embodiments, R20k is independently -OR21. In embodiments, R20k is independently -SR21. In embodiments, R20k is independently -N(R22)(R23) . In embodiments, R20k is independently - C(0)0R22. In embodiments, R20k is independently -C(0)N(R22)(R23) . In embodiments, R20k is independently - C(0)C(0)N(R22)(R23) . In embodiments, R20k is independently -0C(0)N(R22)(R23) . In embodiments, R20k is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R20k is independently -N(R24)C(0)0R25. In embodiments, R20k is independently -N(R24)C(0)R25. In embodiments, R20k is independently -N(R24)S(0)2R25. In embodiments, R20k is independently -C(0)R25. In embodiments, R20k is independently -S(0)2R25. In embodiments, R20k is independently -S(0)2N(R22)(R23) . In embodiments, R20k is independently -0CH2C(0)0R22. In embodiments, R20k is independently -0C(0)R25. In embodiments, R20k is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20k is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20k is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20k is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20k is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci- ehaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20k is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6 alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20k is independently - CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-ealkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, - N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20k is independently C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-ealkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, - N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20k is independently -CH2-C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, - N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20k is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, - N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R20k is independently Ci-dictcroarvl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, - N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25.
[00527] In embodiments, R12c is independently hydrogen. In embodiments, R12c is independently methyl. In embodiments, R12c is independently ethyl. In embodiments, R12c is independently halogen. In embodiments, R12c is independently -CN. In embodiments, R12c is independently Ci-6alkyl. In embodiments, R12c is independently C2. 6alkenyl. In embodiments, R12c is independently C2-6alkynyl. In embodiments, R12c is independently C3-6cycloalkyl. In embodiments, R12c is independently -CH2-C3-6cycloalkyl. In embodiments, R12c is independently C2. gheterocycloalkyl. In embodiments, R12c is independently -CH2-C2-9heterocycloalkyl. In embodiments, R12c is independently C6-ioaryl. In embodiments, R12c is independently -CH2-C6-ioaryl. In embodiments, R12c is independently -CH2-Ci-9heteroaryl. In embodiments, R12c is independently Ci-gheteroaryl. In embodiments, R12c is independently -OR21. In embodiments, R12c is independently -SR21. In embodiments, R12c is independently - N(R22)(R23) . In embodiments, R12c is independently -C(0)0R22. In embodiments, R12c is independently - C(0)N(R22)(R23) . In embodiments, R12c is independently -C(0)C(0)N(R22)(R23) . In embodiments, R12c is independently -0C(0)N(R22)(R23) . In embodiments, R12c is independently -N(R24)C(0)N(R22)(R23) . In embodiments, R12c is independently -N(R24)C(0)0R25. In embodiments, R12c is independently -N(R24)C(0)R25. In embodiments, R12c is independently -N(R24)S(0)2R25. In embodiments, R12c is independently -C(0)R25. In embodiments, R12c is independently -S(0)2R25. In embodiments, R12c is independently -S(0)2N(R22)(R23) . In embodiments, R12c is independently -0CH2C(0)0R22. In embodiments, R12c is independently -0C(0)R25. In embodiments, R12c is independently Ci-6alkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently C2-6alkenyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently C2-6alkynyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently -CH2-C3-6cycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently -CH2-C2-9heterocycloalkyl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently C5-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently -CH2-C6-ioaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently -CH2-Ci-9heteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. In embodiments, R12c is independently Ci-gheteroaryl optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, - N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25. WO 2022/266015 some embodiments, the compound is selected from atropisomer
In some embodiments, the compound is selected from
In embodiments, the compound is a compound described herein (e.g., one of compounds 101 to 372). In embodiments, the compound is a compound described herein (e.g., one of compounds 101 to 442). In embodiments, the compound is a compound described herein (e.g., one of compounds 101 to 454). In embodiments, the compound is a compound described herein.
[00529] In an aspect is provided a compound having the formula A-Lab-B wherein
A is a monovalent form of a compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X,
XI, XII, XIII, XIV, or XV;
LAB is a covalent linker bonded to A and B; and B is a monovalent form of a degradation enhancer.
[00530] In an aspect is provided a compound having the formula A-Lab-B wherein
A is a monovalent form of a compound of Formula I, G, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X,
XI, XII, XIII, XIV, or XV;
LAB is a covalent linker bonded to A and B; and B is a monovalent form of a degradation enhancer.
[00531] In an aspect is provided a compound having the formula A-Lab-B wherein
A is a monovalent form of a compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, F, IF, I”, II”, 1-1, 1-r, 1-1”, I-G”, 1-3, 1-4, II-l, XVI, XVII, XVIII, or XIX;
LAB is a covalent linker bonded to A and B; and B is a monovalent form of a degradation enhancer.
[00532] 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 ligase 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.
[00533] 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-RBX 1 -DDB 1 -CRBN (CRL4CRBN) ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBX04, FBX031, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885.
[00534] 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, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.
[00535] 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.
[00536] 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.
[00537] In embodiments LAB is -L 2 LAB3 LAB4 and am independently a bond. -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, - S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-6alkylene, (-0-Ci.6alkyl)z-, (-Ci- 6alkyl-0)z-, C2-6alkenylene, C2-6alkynylene, Ci-6haloalkylene, C3-i2cycloalkylene, Ci-nheterocycloalkylene, G,. i2arylene, or Ci-nheteroarylene, wherein Ci-6alkylene, C2-6alkenylene, C2-6alkynylene, Ci-6haloalkylene, G- i2cycloalkylcnc. Ci-nheterocycloalkylene, C6-i2arylene, or Ci-nheteroarylene, are optionally substituted with one, two, or three R20j; wherein each Ci-6alkyl of (-0-Ci-6alkyl)z- and (-Ci-6alkyl-0)z- is optionally substituted with one, two, or three R’(lj: z is independently an integer from 0 to 10; each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-G- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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
R20e; each R20d, R20e, R20f, and R2'1' are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, - CH2-Ci-9heteroaryl, Ci-9heteroaiyl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2. 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, G- ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, - SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), - N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, - S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; and each R25 is selected f7rom Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and G- gheteroaryl.
[00538] In embodiments, LAB is -(0-C2alkyl)z- and z is an integer from 1 to 10.
[00539] In embodiments, LAB is -(C2alkyl-0-)z- and z is an integer from 1 to 10. [00540] In embodiments, LAB is -(CH2)ZILAB2(CH20)Z2-, wherein LAli2 is a bond, a 5 or 6 membered heterocycloalkylene or heteroarylene, phenylene, -(C2-C4)alkynylene, -SO2- or -NH-; and zl and z2 are independently an integer from 0 to 10.
[00541] In embodiments, LAB is -(CH2)ZI(CH20)Z2-, wherein zl and z2 are each independently an integer from 0 to 10.
[00542] In embodiments, LAB is a PEG linker (e.g., divalent linker of 1 to 10 ethylene glycol subunits).
[00543] In embodiments, B is a monovalent form of a compound selected from
Table 1 Compound Formula Table 2. R10 Embodiments
Table 3. L1 Embodiments
Table 4. R19 Embodiments
Table 5. R2 Embodiments
Table 8 R4
Table 9 R8
[00544] In embodiment the subject compound is a compound of a Formula of Table 1 (e.g., one Formula selected from 1A-12B) combined with one R10 Embodiment of Table 2 (e.g., selected from 1A-9C, 10A) combined with one L1 Embodiment of Table 3 (e.g., selected from 1A-3C, 4A) combined with one R19 Embodiment of Table 4 (e.g., selected from lA-1 lE)(wherein L1 and R19 combine to form R17 of the formulae of Table 1) combined with one R2 Embodiment of Table 5 (e.g., selected from 1A-27D, 28A, 28B). R3, R8, and R16 are as described herein, including in any embodiment herein.
[00545] In embodiment the subject compound is a compound of a Formula of Table 1 (e.g., one Formula selected from 1A-12B) combined with one R10 Embodiment of Table 2 (e.g., selected from 1A-12C) combined with one L1 Embodiment of Table 3 (e.g., selected from 1A-3C, 4A) combined with one R19 Embodiment of Table 4 (e.g., selected from lA-16E)(wherein L1 and R19 combine to form R17 of the formulae of Table 1) combined with one R2 Embodiment of Table 5 (e.g., selected from 1A-36D). R3, R8, and R16 are as described herein, including in any embodiment herein.
[00546] In embodiment the subject compound is a compound of a Formula of Table 1 (e.g., one Formula selected from 1A-12B) combined with one R10 Embodiment of Table 2 (e.g., selected from 1A-20C) combined with one L1 Embodiment of Table 3 (e.g., selected from 1A-3C, 4A) combined with one R19 Embodiment of Table 4 (e.g., selected from lA-16E)(wherein L1 and R19 combine to form R17 of the formulae of Table 1) combined with one R2 Embodiment of Table 5 (e.g., selected from 1A-36D). R3, R8, and R16 are as described herein, including in any embodiment herein.
[00547] In embodiment the subject compound is a compound of a Formula of Table 1 (e.g., one Formula selected from 1A-12B) combined with one R10 Embodiment of Table 2 (e.g., selected from 1A-35D, 36A, 36B, 36C) combined with one L1 Embodiment of Table 3 (e.g., selected from 1 A-3C, 4A) combined with one R19 Embodiment of Table 4 (e.g., selected from lA-16E)(whereinL1 and R19 combine to form R17 of the formulae of Table 1) combined with one R2 Embodiment of Table 5 (e.g., selected from 1 A-36D, 37A, 37B), combined with one R4 Embodiment of Table 8 (e.g., selected from 1A-14D) combined with one R8 Embodiment of Table 9 (e.g., selected from 1 A-6D). R3 and R16 are as described herein, including in any embodiment herein. P is an integer from 0 to 12. In embodiments, p is 0. In embodiments, p is 1. In embodiments, p is 2. In embodiments, p is 3. In embodiments, p is 4. In embodiments, p is 5. In embodiments, p is 6.
[00548] Besides the inhibitory effect and high potency in reducing Kras signaling output by targeting Kras (including Kras mutants such as Kras G12D), compounds disclosed herein exhibit one or more advantageous DMPK properties. Exemplary superior DMPK properties associated with the subject compounds include but are not limited to improved metabolic stability, decreased serum protein binding (hence increasing the free and available compounds circulating in a subject’s blood upon administration of the compounds), and/or increased oral exposure. Fine-tuned pharmacological properties embodied in the subject compounds are of great significance for improving efficacy and/or safety of Kras inhibitors for therapeutic clinical applications.
[00549] In some embodiments, a compound of Formula I, F, I”, 1-1, 1-G, 1-1”, or I-G” exhibits an increase in unbound/free compound present in plasma as compared to a compound having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core) but with the similar or identical substituents R2, R10, R16, and R17. In an embodiment, a subject compound of Formula I, F, I”, 1-1, 1-G, I-G ’, or I-G ” exhibits an increase in unbound/free compound present in plasma by at least 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700 times or more in comparison to a corresponding compound having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core) but with the similar or identical substituents R2, R10, R16, and R17. In another embodiment, a subject compound of Formula I, F, I”, 1-1, 1-F, 1-1”, or I-G” exhibits an increase in unbound/free compound present in plasma by at least 10%, 20%, 30%, 40%, 50%, 100%, 200%, 300%, 400%, 500%, or even higher as compared to a corresponding compound having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core) but with the similar or identical substituents R2, R10, R16, and R17.
[00550] In an embodiment, a subject compound of Formula I, F, I”, 1-1, 1-G, 1-1”, or I-G” exhibits a decreased serum protein binding as compared to a compound having a different core scaffold but with similar or identical substituents R2, R10, R16, and R17.
[00551] In an embodiment, decreased serum protein binding is observed in compounds of Formula I, F, I”, 1-1, 1- G, 1-1”, or I-G”, as compared to a compound having the same substituents R2, R10, R16, and R17, but with a different 6-membered heteroaryl bicyclic core scaffold.
[00552] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, F, I”, 1-1, 1-G, 1-1”, or I-G” whereinR10 is -L7-R7; L7 is abond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-C6alkyl, C2- Cealkenyl, C2-C6alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cealkyl, C2-C6alkenyl, C2- Cealkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R20a; and R7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6.
[00553] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, G, I”, 1-1, 1- , 1-1”, or I- ” whereinR10 is -L7-R7; L7 is abond, -0-, or -N(R14)-; and R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more R4, and optionally substituted with one or more R6.
[00554] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, F, I”, 1-1, 1- , 1-1”, or I- ” whereinR10 is -L7-R7; L7 is abond; and R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more R4, and optionally substituted with one or more R6.
[00555] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, F, I”, 1-1, 1- , 1-1”, or I- ” whereinR10 is -L7-R7; L7 is abond; and R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more R4.
[00556] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, F, I”, 1-1, 1-G, 1-1”, or I-G” whereinR17 is -L'-R19: L1 is selected from abond, Ci-Cealkyl, C2- Cealkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, - S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg); R19 is selected from a C3-i2cycloalkyl, C2. liheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11.
[00557] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, F, I”, 1-1, 1-G, 1-1”, or I-G” whereinR17 is -L^R19; L1 is abond; R19 is selected from a C6-i2aryl and 9-10 membered heteroaryl, wherein the C6-i2aryl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11.
[00558] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, F, I”, 1-1, 1- , 1-1”, or I- ” whereinR17 is -L^R19; L1 is abond; R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11.
[00559] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula I, F, I”, 1-1, 1- , 1-1”, or I- ” whereinR17 is -L^R19; L1 is abond; R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-3alkyl, Ci- 3haloalkyl, C2-3alkenyl, C2-3alkynyl, -OH, -NH2, wherein Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, and C2-3alkynyl are optionally substituted with one, two, or three R201.
[00560] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula (1-1), (F-l), (la-1), (Ia’-l), (Ib-1), (Ib’-l), (Ic-1), or (Ic’-l), whereinR2 is -0-R12a; R12a is -C(R12c)2-(5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d. [00561] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds of Formula (1-1), (G-1), (la-1), (Ia’-l), (Ib-1), (Ib’-l), (Ic-1), or (Ic’-l), wherein R2 is -0-R12a; R12a is -C(R12c)2-(5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d; R12c is independently selected from hydrogen and methyl.
[00562] In an embodiment, an increase in unbound/free compound present in plasma is associated with compounds having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core).
[00563] In some embodiments, a compound of Formula I, F, I”, 1-1, 1- , 1-1”, or I-G” exhibits superior metabolic stability as compared to a compound having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core) but with the similar or identical substituents R2, R10, R16, and R17. For example, a subject compound exhibit significantly longer metabolic stability as ascertained by the Tl/2 of liver microsomal metabolism (see Example 12 for experimental procedures). In an embodiment, improved microsomal metabolic stability is observed as compared to such a corresponding compound by at least, 10%, 20%, 30%, 40%, 50%, 100%, 200%, 300%, 400%, 500%, or even higher. In an embodiment, improved microsomal metabolic stability is observed as compared to such a corresponding compound by at least, 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700, or more times higher.
[00564] In an embodiment, a subject compound of Formula I, F, I”, 1-1, 1-G, 1-1”, or I-G” exhibits superior metabolic stability as compared to a compound having a different core scaffold but with similar or identical substituents R2, R10, R16, and R17.
[00565] In an embodiment, superior metabolic stability is observed in compounds of Formula I, F, I”, 1-1, 1-G, I- 1 ”, or I-G ”, as compared to a compound having the same substituents R2, R10, R16, and R17, but with a different 6- membered heteroaryl bicyclic core scaffold.
[00566] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I, F, I”, 1-1, 1-r, 1-1”, or I-G” whereinR10 is -L7-R7; L7 is abond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, - C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-C6alkyl, C2- Cealkenyl, C2-C6alkynyl, or 2 to 4 membered heteroalkylene linker, wherein Ci-Cealkyl, C2-C6alkenyl, C2- Cealkynyl, and 2 to 4 membered heteroalkylene linker are optionally substituted with one, two, or three R20a; and R7 is a 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl, wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, and 5-12 membered heteroaryl each comprises one or more ring nitrogen atoms or one or more ring oxygen atoms and wherein the 4-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 7-12 membered aryl, or 5-12 membered heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6.
[00567] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I, F, I”, 1-1, 1-G, 1-1”, or I-G” whereinR10 is -L7-R7; L7 is abond, -0-, or -N(R14)-; and R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more R4, and optionally substituted with one or more R6.
[00568] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I, G, I”, 1-1, 1-G, 1-1”, or I-G” whereinR10 is -L7-R7; L7 is abond; andR7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more R4, and optionally substituted with one or more R6.
[00569] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I, F, I”, 1-1, 1-G, 1-1”, or I-G” whereinR10 is -L7-R7; L7 is abond; andR7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl comprises one or more ring nitrogen atoms and wherein the 3-12 membered heterocycloalkyl, is optionally substituted with one or more R4.
[00570] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I, F, I”, 1-1, 1-G, 1-1”, or I-G” whereinR17 is -I^-R19; L1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2- Cealkynyl, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, - N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, -N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg); R19 is selected from a C3-i2cycloalkyl, C2-iiheterocycloalkyl, G,. naryl, and C2-i2heteroaryl, wherein the C3-i2cycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11.
[00571] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I, F, I”, 1-1, 1-G, 1-1”, or I-G” whereinR17 is -G-R19; L1 is abond; R19 is selected from a G-naryl and 9-10 membered heteroaryl, wherein the C6-i2aryl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11.
[00572] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I, F, I”, 1-1, 1-G, 1-1”, or I-G” whereinR17 is -G-R19; L1 is abond; R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11.
[00573] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula I, F, I”, 1-1, 1-G, 1-1”, or I-G” whereinR17 is -G-R19; L1 is abond; R19 is selected from a naphthyl and 9-10 membered heteroaryl, wherein the naphthyl and 9-10 membered heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-3alkyl, Ci-3haloalkyl, C2- 3alkenyl, C2-3alkynyl, -OH, -NH2, wherein Ci-3alkyl, Ci-3haloalkyl, C2-3alkenyl, and C2-3alkynyl are optionally substituted with one, two, or three R201.
[00574] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula (1-1), (F-l), (la-1), (Ia’-l), (Ib-1), (Ib’-l), (Ic-1), or (Ic’-l), whereinR2 is -0-R12a; R12a is -C(R12c)2-(5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d.
[00575] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula (1-1), (F-l), (la-1), (Ia’-l), (Ib-1), (Ib’-l), (Ic-1), or (Ic’-l), whereinR2 is -0-R12a; R12a is -C(R12c)2-(5-8 membered heterocycloalkyl), wherein -C(R12c)2-(5-8 membered heterocycloalkyl) is optionally substituted with one, two, or three R20d; R12c is independently selected from hydrogen and methyl. [00576] In an embodiment, an improved microsomal metabolic stability is associated with compounds of Formula corresponding compound having a different 6-membered heteroaryl bicyclic core (e.g., quinazoline core).
[00577] 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.
[00578] Further Embodiments
1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Wherein
W is C(O), S(O), or S(0)2;
V is C(R17) and J is C(R16), or V is C(R17) and J is N, or J is C(R17) and V is C(R16), or J is C(R17) and V is N;
R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, - N(R14)S(0)-, -N(R14)S(0)2-, Ci-Cealkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein Ci-Cealkyl, C2-C6alkenyl, and C2- Cealkynyl, are optionally substituted with one, two, or three R20a;
R7 is a 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl, wherein the 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl are optionally substituted with one or more R1, one or more R4, or one or more R6; wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-iiheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a; 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-dictcroaiyl are optionally substitirted with one, two, or three R20a;
R6 is -L2-R5; each L2 is independently selected from a bond, Ci-Cealkyl, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, - S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, -N(R14)C(0)0-, and - N(R14)C(0)N(R14)-; each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, Ce-ioaryl, Ci-9heteroaiyl, -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), - N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), - CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20c;
R17 is -lA-R19;
L1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -
C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, - N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg);
Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2. 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R201
R19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3- i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, Gs- ioaryl, and Ci-dictcroaiyl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, C’l-dictcroaiyl. -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20g;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R12)(R13), - (Ci-C6alkyl)-R12b, -(C2.6alkenyl)-R12b, -(C2.6alkynyl)-R12b, -0-R12a, -N(R14)-R12b, -S-R12b, -(C3. iocycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-ioaryl)-R12b, or -(Ci-9heteroaryl)-R12b, wherein said G- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and G-gheteroaryl are optionally substituted with one, two, or three R20d;
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, Ce-ioaiyl, Ci-9heteroaiyl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), - N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), - CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three j^20b. each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-
6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R201 are each independently selected from halogen, -CN, Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, G,. ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, Ci-gheteroaryl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, - N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CEh-Ci-gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, G- ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25; eachR21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- gheteroaryl; and
. indicates a single or double bond such that all valences are satisfied.
2. The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R3).
3. The compound of Embodiment 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.
4. The compound of any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein V is C(R16) and J is C(R17).
5. The compound of any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein V is N and J is C(R17).
6. The compound of any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein J is N and V is C(R17).
7. The compound of any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R16) and V is C(R17).
8. The compound of any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein W is C(O). The compound of any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein W is S(O). The compound of any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein W is S(0)2. The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure: The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure: , ). The compound of any one of Embodiments 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein L7 is a bond. The compound of any one of Embodiments 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein L7 is -NH-. The compound of any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R1, one or more R4, or one or more R6; and wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3- i2cycloalkyl. Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a.
16. The compound of any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, wherein p is an integer from 0 to 12;
X1 is selected from CH2, C(R4)(R6), C=N-OR4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), O, S, S(O), S(=0)(=NR4), S(0)2N(R4), N(R4)S(0)N(R4), N(R4)S(0)2N(R4), S(0)N(R4), 0C(0)N(R4), N(R4)C(0)N(R4), S(0)2, CH2C(R4)(R6), CH2C(R4)(R6)CH2, C(R4)(R6)C(R4)(R6)C(R4)(R6), C(R4)(R6)C=N-OR4, CH2C=NN(R4)(R6), C(R4)(R6)C(0)N(R4), C(R4)(R6)N(R4), C(R4)(R6)N(R6), C(R4)(R6)0, C(R4)(R6)OC(R4)(R6), C(R4)(R6)S, C(R4)(R6)SC(R4)(R6), C(R4)(R6)S(0), C(R4)(R6)S(0)C(R4)(R6), C(R4)(R6)S(0)2C(R4)(R6), C(R4)(R6)S(=0)(=NR4), C(R4)(R6)S(0)2N(R4), C(R4)(R6)N(R4)S(0)N(R4), C(R4)(R6)N(R4)S(0)2N(R4), C(R4)(R6)S(0)N(R4), C(R4)(R6)0C(0)N(R4), C(R4)(R6)N(R4)C(0)N(R4), C(R4)(R6)S(0)2, C=NN(R4)(R6)C(R4)(R6), C(0)N(R4)C(R4)(R6), S(0)2N(R4)C(R4)(R6), S(0)N(R4)C(R4)(R6), 0C(0)N(R4)C(R4)(R6), C(R4)(R4), C=N-OR4, C=NN(R4)(R4), CH2C(R4)(R4), CH2C(R4)(R4)CH2, C(R4)(R4)C(R4)(R6)C(R4)(R4), C(R4)(R4)C(R4)(R4)C(R4)(R4), C(R4)(R4)C=N-OR4, CH2C=NN(R4)(R4), C(R4)(R4)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0, C(R4)(R4)OC(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(R4), C(R4)(R4)S(0), C(R4)(R4)S(0)C(R4)(R4), C(R4)(R4)S(0)2C(R4)(R4), C(R4)(R4)S(=0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(R4)(R4)N(R4)C(0)N(R4), C(R4)(R4)S(0)2, C=NN(R4)(R4)C(R4)(R4), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R4)(R4), S(0)N(R4)C(R4)(R4), and 0C(0)N(R4)C(R4)(R4);
X2 is selected from N, C, C(R6), C(R4), CH, N(R'). N(R4), N(R6), O, S, S(O), C(H)(R6), C(R4)2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2; and X3 is selected from N, C, C(R6), and C(R4).
17. The compound of Embodiment 16, or a pharmaceutically acceptable salt or solvate thereof, wherein
he compound of any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, he compound of Embodiment 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is The compound of Embodiment 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is The compound of any one of Embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl are optionally substituted with one, two, or three R20g. The compound of any one of Embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from hydrogen and halogen. The compound of any one of Embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from hydrogen and fluoro. The compound of any one of Embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, Ci-dictcroarvl. -OR12, -SR12, -N(H)(R12), -C(0)OR12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -OC(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-s>heterocycloalkyl, G,. ioaryl, and Ci-yhctcroan l are optionally substituted with one, two, or three R20c. The compound of any one of Embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from Ci-6alkyl, C3-iocycloalkyl, and C2-s>heterocycloalkyl, wherein Ci-6alkyl, C3- locycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c independently selected from halogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl. The compound of any one of Embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. The compound of any one of Embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl. The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen or CN. The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. The compound of any one of Embodiments 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is a bond. The compound of any one of Embodiments 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is selected from a Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -C(O)-, -NHC(O)-, -C(0)NH-, CH20, CH2NH, and CH2. The compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a monocyclic ring. The compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a bicyclic ring system. The compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a polycyclic ring system. The compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is:
Q1, Q3, and Q5 are independently N or C(Rld);
Q4 and Q6 are independently O, S, C(Rla)(Rlb), orN(Rlc);
X4, X5, X6, X9, X10, X11, and X12 are independently selected from C(Rla) or N;
X7 and X8 are independently selected from C(Rla), C(Rla)(Rlb), N, or N(Rlc); each Rla, Rlb, Rld, and Rlh are each independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. - OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), - CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201; or Rla and Rlb bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6-ioaryl ring, 5-12 membered heteroaryl ring, or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlh and one of Rla, Rlb, Rlc, and Rld bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3- locycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, and C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; and each Rlc is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, Ci-dictcroaiyl. wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-dictcroaiyl are optionally substituted with one, two, or three R201. The compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is:
37. The compound of any one of Embodiments 1-36, or a pharmaceutically acceptable salt or solvate thereof, The compound of any one of Embodiments 1 to 7 and 10 to 37, or a pharmaceutically acceptable salt or solvate thereof, wherein each R5 is independently selected from: A compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof: Wherein
W is C(O), S(O), or S(0)2;
V is C(R16) or N;
R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, -
N(R14)S(0)-, -N(R14)S(0)2-, Ci-Cealkyl, C2-C6alkenyl, or C2-Cealkynyl, wherein Ci-Cealkyl, C2-C6alkenyl, and C2-
Cealkynyl, are optionally substituted with one, two, or three R20a;
R7 is a 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl, wherein the 3-12 membered heterocycloalkyl or 5-12 membered heteroaryl are optionally substituted with one or more R1, one or more R4, or one or more R6; two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci- liheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a; wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20a;
R6 is -L2-R5; each L2 is independently selected from a bond, Ci-Cealkyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, - S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, -N(R14)C(0)0-, and - N(R14)C(0)N(R14)-; each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein;
R8 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, Ce-ioaryl, Ci-9heteroaiyl, -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), - N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), - CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20c;
R17 is -LkR19;
L1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -
C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, - N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg);
Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2. 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R201
R19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3- i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, CV,. ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20g;
R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R12)(R13), - (Ci-C6alkyl)-R12b, -(C2.6alkenyl)-R12b, -(C2-6alkynyl)-R12b, -0-R12a, -N(R14)-R12b, -S-R12b, -(C3. iocycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-ioaryl)-R12b, or -(Ci-9heteroaryl)-R12b, wherein said Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d;
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-G5-ioaryl, -CH2-Ci-9heteroaryl, and Ci-dictcroan l are optionally substituted with one, two, or three R20d;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, Ce-ioaryl, Ci-9heteroaiyl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), - N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), - CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three
£20b. each R12 is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-
6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R201 are each independently selected from halogen, -CN, Ci-6alkyl, C2. 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, Ce- ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, Ci-gheteroaryl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, - N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2. gheterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci- ealkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), - 0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, - S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- siheterocycloalkyl, C6-ioaryl, and Ci-dictcroaryl: each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- dictcroaryl: and
. indicates a single or double bond such that all valences are satisfied.
40. The compound of Embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R3).
41. The compound of Embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.
42. The compound of any one of Embodiments 39 to 41, or a pharmaceutically acceptable salt or solvate thereof, wherein V is C(R16).
43. The compound of any one of Embodiments 39 to 41, or a pharmaceutically acceptable salt or solvate thereof, wherein V is N.
44. The compound of any one of Embodiments 39 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein W is C(O).
45. The compound of any one of Embodiments 39 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein W is S(O).
46. The compound of any one of Embodiments 39 to 43, or a pharmaceutically acceptable salt or solvate thereof, wherein W is S(0)2.
47. The compound of Embodiment 39, or a pharmaceutically acceptable salt or solvate thereof, having the structure:
).
48. The compound of any one of Embodiments 39 to 47, or a pharmaceutically acceptable salt or solvate thereof, wherein L7 is a bond.
49. The compound of any one of Embodiments 39 to 47, or a pharmaceutically acceptable salt or solvate thereof, wherein L7 is -NH-.
50. The compound of any one of Embodiments 39 to 49, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally substituted with one or more R1, one or more R4, or one or more R6; and wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-iiheterocycloalkyl, C6-i2aryl, or Ci-iiheteroaryl, wherein the C3- ncycloalkyl, Ci-iiheterocycloalkyl, C6-i2aryl, or Ci-iiheteroaryl are optionally substituted with one, two, or three R20a.
51. The compound of any one of Embodiments 39 to 49, or a pharmaceutically acceptable salt or solvate thereof, wherein p is an integer from 0 to 12; X1 is selected from CH2, C(R4)(R6), C=N-OR4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), O, S, S(O), S(=0)(=NR4), S(0)2N(R4), N(R4)S(0)N(R4), N(R4)S(0)2N(R4), S(0)N(R4), 0C(0)N(R4), N(R4)C(0)N(R4), S(0)2, CH2C(R4)(R6), CH2C(R4)(R6)CH2, C(R4)(R6)C(R4)(R6)C(R4)(R6), C(R4)(R6)C=N-OR4, CH2C=NN(R4)(R6), C(R4)(R6)C(0)N(R4), C(R4)(R6)N(R4), C(R4)(R6)N(R6), C(R4)(R6)0, C(R4)(R6)OC(R4)(R6), C(R4)(R6)S, C(R4)(R6)SC(R4)(R6), C(R4)(R6)S(0), C(R4)(R6)S(0)C(R4)(R6), C(R4)(R6)S(0)2C(R4)(R6), C(R4)(R6)S(=0)(=NR4), C(R4)(R6)S(0)2N(R4), C(R4)(R6)N(R4)S(0)N(R4), C(R4)(R6)N(R4)S(0)2N(R4), C(R4)(R6)S(0)N(R4), C(R4)(R6)0C(0)N(R4), C(R4)(R6)N(R4)C(0)N(R4), C(R4)(R6)S(0)2, C=NN(R4)(R6)C(R4)(R6), C(0)N(R4)C(R4)(R6), S(0)2N(R4)C(R4)(R6), S(0)N(R4)C(R4)(R6), 0C(0)N(R4)C(R4)(R6), C(R4)(R4), C=N-OR4, C=NN(R4)(R4), CH2C(R4)(R4), CH2C(R4)(R4)CH2, C(R4)(R4)C(R4)(R6)C(R4)(R4), C(R4)(R4)C(R4)(R4)C(R4)(R4), C(R4)(R4)C=N-OR4, CH2C=NN(R4)(R4), C(R4)(R4)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0, C(R4)(R4)OC(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(R4), C(R4)(R4)S(0), C(R4)(R4)S(0)C(R4)(R4), C(R4)(R4)S(0)2C(R4)(R4), C(R4)(R4)S(=0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(R4)(R4)N(R4)C(0)N(R4), C(R4)(R4)S(0)2, C=NN(R4)(R4)C(R4)(R4), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R4)(R4), S(0)N(R4)C(R4)(R4), and 0C(0)N(R4)C(R4)(R4);
X2 is selected from N, C, C(R6), C(R4), CH, N(R'). N(R4), N(R6), O, S, S(O), C(H)(R6), C(R4)2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2; and X3 is selected from N, C, C(R6), and C(R4).
52. The compound of Embodiment 51, or a pharmaceutically acceptable salt or solvate thereof, wherein
53. The compound of any one of Embodiments 39 to 49, or a pharmaceutically acceptable salt or solvate thereof, wherein The compound of Embodiment 51, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is The compound of Embodiment 51, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is r—NH r— NH vo
' or The compound of any one of Embodiments 39 to 55, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl are optionally substituted with one, two, or three R20g. The compound of any one of Embodiments 39 to 55, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from hydrogen and halogen. The compound of any one of Embodiments 39 to 55, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from hydrogen and fluoro. The compound of any one of Embodiments 39 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-s>heterocycloalkyl, Ce-ioaiyl, Ci-gheteroaiyl, -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), - C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), - CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2. 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-yhctcroan l are optionally substituted with one, two, or three R20c. The compound of any one of Embodiments 39 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from Ci-6alkyl, C3-iocycloalkyl, and C2-9heterocycloalkyl, wherein Ci-6alkyl, C3- locycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c independently selected from halogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl. The compound of any one of Embodiments 39 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl. The compound of any one of Embodiments 39 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl. The compound of any one of Embodiments 39 to 62, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen or CN. The compound of any one of Embodiments 39 to 62, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. The compound of any one of Embodiments 39 to 64, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is a bond. The compound of any one of Embodiments 39 to 64, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is selected from a Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -C(O)-, -NHC(O)-, -C(0)NH-, CH20, CH2NH, and CH2. The compound of any one of Embodiments 39 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a monocyclic ring. The compound of any one of Embodiments 39 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a bicyclic ring system. The compound of any one of Embodiments 39 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a polycyclic ring system. The compound of any one of Embodiments 39 to 66, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is:
Q1, Q3, and Q5 are independently N or C(Rld);
Q4 and Q6 are independently O, S, C(Rla)(Rlb), orN(Rlc);
X4, X5, X6, X9, X10, X11, and X12 are independently selected from C(Rla) or N;
X7 and X8 are independently selected from C(Rla), C(Rla)(Rlb), N, or N(Rlc); each Rla, Rlb, Rld, and Rlh are each independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. - OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), - CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C^alkenyl, C2- 6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201; or Rla and Rlb bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6-ioaryl ring, 5-12 membered heteroaryl ring, or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlh and one of Rla, Rlb, Rlc, and Rld bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3- locycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, and C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; and each Rlc is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201. The compound of any one of Embodiments 39 to 70, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is: The compound of any one of Embodiments 39 to 50and 56 to 72, or a pharmaceutically acceptable salt or solvate thereof, wherein each R5 is independently selected from: , -CN,
A compound having the formula A-L AB-E> wherein
A is a monovalent form of a compound of one of Embodiments 1 to 73;
LAB is a covalent linker bonded to A and B; and
B is a monovalent form of a degradation enhancer. The compound of Embodiment 74 wherein 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, SMURF 1, SMURF2, STUB1, TOPORS, TRIP 12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHF (von-Hippel-Findau 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), CUF4-RBX1-DDB1-CRBN (CRP4CRBN) ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KFHF12, UBR2, SPOP, KFHF3, KFHF20, KFHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBX04, FBX031, BTRC, FBW7, CDC20, PMF, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885. The compound of Embodiment 74 wherein 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, UBE2F3, UBE2F6, UBE2F1, UBE2F2, UBE2F4, UBE2M, UBE2N, UBE20, UBE2Q1,
UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1. The compound of any one of Embodiments 74 to 76, wherein nheteroarylene,are optionally substituted with one, two, or three R20j; wherein each Ci-6alkyl of (-O-Ci- 6alkyl)z- and (-Ci-6alkyl-0)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, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2- C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-CI- gheteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-C1- gheteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20f; each R20d, R20e, R20f, and R20j are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, - CH2-C6-ioaryl, -OE-Ci-sheteroaryl, C^heteroaiyl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and - 0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-ealkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; and each R25 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl. The compound of any one of Embodiments 74 to 76, wherein LAli is -(0-C2alkyl)z- and z is an integer from 1 to 10. The compound of any one of Embodiments 74 to 76, wherein LAli is -(C2alkyl-0-)z- and z is an integer from 1 to 10. The compound of any one of Embodiments 74 to 76, wherein LAli is -(CH2)ZILAB2(CH20)Z2-, wherein L Ali2 is a bond, a 5 or 6 membered heterocycloalkylene or heteroarylene, phenylene, -(C2- C4)alkynylene, -SO2- or -NH-; and zl and z2 are independently an integer from 0 to 10. The compound of any one of Embodiments 74 to 76, wherein LAli is -(CH2)ZI(CH20)Z2-, wherein zl and z2 are each independently an integer from 0 to 10. The compound of any one of Embodiments 74 to 76, wherein LAli is a PEG linker. The compound of any one of Embodiments 74 to 82, wherein B is a monovalent form of a compound A pharmaceutical composition comprising a compound of any one of Embodiments 1 to 6583 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 Embodiments 1 to 83, or a pharmaceutically acceptable salt or solvate thereof. 86. A method of modulating activity of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound of any one of Embodiments 1 to 83, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.
87. The method of Embodiment 85 or Embodiment 86 comprising administering an additional agent or therapy.
88. A method of inhibiting cell growth, comprising administering an effective amount of a compound of one of Embodiments 1 to 83, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells.
89. The method of one of Embodiments 85 to 88 comprising administering an additional agent to said cell.
90. A Ras protein bound by a compound of one of Embodiments 1 to 83 , or a pharmaceutically acceptable salt or solvate thereof, wherein activity of said Ras protein is reduced as compared to a Ras protein unbound to said compound.
Further Forms of Compounds Disclosed Herein
Isomers
[00579] 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, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.
Labeled compounds
[00580] 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, 170, 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 drag 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, 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.
[00581] 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
[00582] 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.
[00583] 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
[00584] 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.
[00585] 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.
Synthesis of Compounds
[00586] 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. [00587] 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.
[00588] 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 Supplementals (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 method may be utilized.
[00589] In some embodiments, the compounds of the present invention exhibit one or more functional characteristics disclosed herein. For example, a subject compound binds to a Ras protein, Kras protein or a mutant form thereof. In some embodiments, a subject compound binds specifically and also inhibits a Ras protein, Kras protein or a mutant form thereof. In some embodiments, a subject compound selectively inhibits a Kras mutant relative to a wildtype Kras. In some embodiments, a subject compound selectively inhibits KrasG12D and/or KrasG12V relative to wildtype Kras. In some embodiments, the IC50 of a subject compound for a Kras mutant (e.g., including G12D) is less than about 5 mM, less than about 1 mM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5 nM, less than about 100 pM, or less than about 50 pM, as measured in an in vitro assay known in the art or exemplified herein.
[00590] In some embodiments, a subject compound of the present disclosure is capable of reducing Ras signaling output. Such reduction 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, and (v) reduction (e.g., inhibition) of cell growth of Ras-driven tumor cells (e.g., those derived from a tumor cell line disclosed herein). In some cases, the reduction in Ras signaling output can be evidenced by two, three, four or all of (i)-(v) above.
Methods
[00591] In an aspect is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, 1 A3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, II A 11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-F, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject method comprises administering an additional agent or therapy.
[00592] In an aspect is provided a method of modulating activity of a Ras (e.g., K-Ras) protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, 1 A3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-r, I-l”, I-l’”, 1-3, 1-4, II-l, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras (e.g., K-Ras) protein.
[00593] In some embodiments, the subject method comprises administering an additional agent or therapy.
[00594] In an aspect is provided a method of inhibiting cell growth, comprising administering an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, I-l, I-l’, I-l”, I-l”’, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras (e.g., K- Ras) protein, thereby inhibiting growth of said cells. In embodiments, the subject method comprises administering an additional agent to said cell.
[00595] In an aspect is provided a Ras (e.g., K-Ras) protein bound by a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5,
IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, I-l, I-l’, I-l”, I-l”’, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein activity of said Ras (e.g., K-Ras) protein is reduced as compared to a Ras (e.g., K-Ras) protein unbound to said compound.
[00596] 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 described herein (e.g., compound of Formula I, IA1, IA2, 1 A3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, II A 11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, I-l, I-F, I-l”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), 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 described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10,
IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, I-l, I-l’, I-l”, I-F”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), 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 described herein (e.g., compound of Formula I, IA1, IA2,
I A3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, II A 11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, I-l, I-F, I-l”, I-F”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), 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 described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, II A3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-G, 1-1”, I-G”, 1-3, 1-4, II-l, XVI, XVII, XVIII, or XIX), 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 described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-G, I- 1 ”, I-G ”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), 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, Burkitf 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 pre-leukemia. 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 described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-F, 1-1”, I- ”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), 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).
[00597] 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.
[00598] In some embodiments, 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.
[00599] In one embodiment, a subject treatment method is combined with a chemotherapeutic agent. [00600] 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® orNeosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), daunorubicin hydrochloride (Cembidine®), daunombicin citrate liposome injection (DaunoXome®), dexamethasone, doxombicin 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 (Admcil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), ifosfamide (IFEX®), 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®).
[00601] Anti-cancer agents of particular interest for combinations with a compound of the present invention include: anthracy clines; alkylating agents; antimetabolites; drags 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.
[00602] Exemplary antimetabolites include, without limitation, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors): methotrexate (Rheumatrex®, Trexall®), 5-fluorouracil (Admcil®, 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. [00603] 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 (Hemel®, 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 TSPA, Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and Bendamustine HC1 (Treanda®).
[00604] 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.
[00605] 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-L PD-L1, CTLA-4, IDO, TΪM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs and CDS 9), 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 immunostimulatory 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., oxeiatnab, PF-G5082566), an anti-OX40 antibody (poga! umab. tavolixizumah, PF-04518600), an anti-ICOS antibody (BMS986226, MEDI-570, GSK3359609, JTX- 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 (atezotiziunab. avelntnab. durvahsmab, BMS-936559), anti-CTLA-4 antibodies (e.g., tiemdimumab. ipilirtusmab), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab), anti-LAG3 antibodies (e.g., C9B7W, 4 Ϊ 0C9), 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. Immunostimulants can be vaccines, colony stimulating agents, interferons, interleukins, viruses, antigens, costimulatory 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 IU/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 IU/kg, 200,000 IU/kg, 300,000 IU/kg, 400,000 IU/kg, 500,000 IU/kg, 600,000 IU/kg, 700,000 IU/kg, 800,000 IU/kg, 900,000 IU/kg, or up to about 1,000,000 IU/kg. In some cases, aldesleukin can be administered at a dose from about 100,000 IU/kg to 300,000 IU/kg, from 300,000 IU/kg to 500,000 IU/kg, from 500,000 IU/kg to 700,000 IU/kg, from 700,000 IU/kg to about 1,000,000 IU/kg.
[00606] In some embodiments, any of the compounds herein that is capable of binding a Ras protein (e.g., KRAS) to modulate activity of such Ras protein may be administered in combination or in conjunction with one or more pharmacologically active agents comprising (1) an inhibitor of MEK (e.g., MEK1, MEK2) or of mutants thereof (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib); (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 drag (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 and/or B-Raf 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) anMDM2 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, as well as SHIP1 inhibitors; (27) an inhibitor of SRC (e.g., dasatinib); (28) an inhibitor of JAK (e.g., tofacitinib); (29) a PARP inhibitor (e.g. Olaparib, Rucaparib, Niraparib, Talazoparib), (30) a BTK inhibitor (e.g. Ibrutinib, Acalabrutinib, Zanubmtinib), (31) a ROS1 inhibitor (e.g., entrectinib), (32) an inhibitor of SHP pathway including SHP2 inhibitor (e.g., 6-(4-amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazin-2- amine, as well as SHP1 inhibitors, (33) an inhibitor of Src, FLT3, HD AC, VEGFR, PDGFR, LCK, Bcr-Abl or AKT or (34) an inhibitor of KrasG12C 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 publically known) (e.g., an inhibitor of Ras G12C as described inUS20180334454, 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, WO2018112240, WO2019204442, WO2019204449, W02019104505, WO2016179558,
WO2016176338, or related patents and applications, each of which is incorporated by reference in its entirety), (35) a SHC inhibitor (e.g., PP2, AID371185), (36) a GAB inhibitor (e.g., GAB-0001), (37) a GRB inhibitor, (38) a PI-3 kinase inhibitor (e.g., Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, NVP-BEZ235-AN), (39) aMARPK inhibitor, (40) CDK4/6 (e.g., palbociclib, ribociclib, abemaciclib), or (41) 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 (42) an inhibitor of SHP pathway including SHP2 inhibitor (e.g., 6-(4-amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazin-2-ainine, RMC-4630, TN0155 ( -398 (
), as well as SHP1 inhibitors. In some embodiments, any of the compounds herein that is capable of binding a Ras protein (e.g., Kras) to modulate activity of such Ras protein 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). In some embodiments, any of the compounds herein that is capable of binding a Ras protein (e.g., KRAS) to modulate activity of such Ras protein may be administered in combination or in conjunction with one or more pharmacologically active agents comprising an inhibitor against one or more targets selected from the group of: MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, 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, SHIP1, SHIP2, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, KrasG12C mutant, and ROS1. Where desired, the additional agent can be an inhibitor against one or more targets selected from the group of: MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, mitotic kinase, topoisomerase, ALK, c-MET, ErbB2, AXL, NTRK1, RET, A- Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF 1/2, IGF1-R, CDK9, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, KrasG12C mutant, and ROS1. In some embodiments, any of the compounds herein that is capable of binding a Ras protein (e.g., KRAS, mutant Ras protein) to modulate activity of such Ras mutant (e.g., G12C, G12D, G12S, G12V, G13C, or G13D) may be administered in combination or in conjunction with one or more additional pharmacologically active agents comprising an inhibitor of SOS (e.g.,
SOS1, SOS2) or of mutants thereof. In embodiments, the additional pharmacologically active agent administered in combination or in conjunction with a compound described herein (e.g., compound capable of binding a Ras protein) is an inhibitor of SOS (e.g., SOS1, SOS2). In embodiments, the additional pharmacologically active agent administered in combination or in conjunction with a compound (e.g., compound capable of binding a Ras protein) described herein is an inhibitor of SOS (e.g., SOS1, SOS2). In embodiments, the additional pharmacologically active agent administered in combination or in conjunction with a compound (e.g., compound capable of binding a Ras protein) described herein is an inhibitor of SOS (e.g., SOS1, SOS2) selected from RMC-5845, BI-3406 ( ). n em o ments, t e a ona p armaco og ca y actve agent administered in combination or in conjunction with a compound described herein (e.g., compound capable of binding a Ras protein) is an inhibitor of SOS (e.g., SOS1, SOS2) described in W02021092115, WO2018172250, WO2019201848, WO2019122129, WO2018115380, WO2021127429, W02020180768, or W02020180770, all of which are herein incorporated by reference in their entirety for all purposes.
[00607] In some embodiments, any of the compounds herein that is capable of binding a Ras protein (e.g., Kras) to modulate activity of such Ras protein 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).
[00608] In some embodiments, any of the compounds described herein that is capable of binding a Ras protein (e.g., KRAS) may be administered in combination or in conjunction with one or more pharmacologically active agents comprising an inhibitor of: (1) SOS1 or a mutant thereof (e.g., RMC-5845, BI-3406, BAY-293, MRTX0902, BI- 1701963); (2) SHP2 or a mutant thereof (e.g., 6-(4-amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazin-2- amine, TN0155, RMC-4630, ERAS-601, JAB-3068, IACS-13909/BBP-398, SHP099, RMC-4550); (3) SHC or a mutant thereof (e.g., PP2, AID371185); (4) GAB or a mutant thereof (e.g., GAB-0001); (5) GRB or a mutant thereof; (6) JAK or a mutant thereof (e.g., tofacitinib); (7) A-RAF, B-RAF, C-RAF, or a mutant thereof (e.g., RAF- 709, LY-3009120); (8) BRAF or a mutant thereof (e.g., Sorafenib, Vemurafenib, Dabrafenib, Encorafenib, regorafenib, GDC-879); (9) MEK or a mutant thereof (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib, AZD6244); (10) ERK or a mutant thereof (e.g., ulixertinib, MK-8353, LTT462, AZD0364,
SCH772984, BIX02189, LY3214996, ravoxertinib); (11) PI3K or a mutant thereof (e.g., Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, NVP-BEZ235-AN); (12) MAPK or a mutant thereof (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); (13) EGFR or a mutant thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab panitumumab, osimertinib, olmutinib, EGF-816); (14) c-MET or a mutant thereof (e.g., K252a, SU11274, PHA665752, PF2341066); (15) ALK or a mutant thereof (e.g. crizotinib, alectinib, entrectinib, brigatinib); (16) FGFR1, FGFR-2, FGFR-3, FGFR-4 or a mutant thereof (e.g., nintedanib); (17) BCR- ABL or a mutant thereof (e.g., imatinib, dasatinib, nilotinib); (18) ErbB2 (Her2) or a mutant thereof (e.g., afatinib, lapatinib, trastuzumab, pertuzumab); (19) AXL or a mutant thereof (e.g., R428, amuvatinib, XL-880); (20) NTRKl or a mutant thereof (e.g., merestinib); (21) ROS1 or a mutant thereof (e.g., entrectinib); (22) RET or a mutant thereof (e.g., BLU-667, Lenvatinib); (23) MDM2 or a mutant thereof (e.g., HDM-201 , NVP-CGM097, RG-71 12, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115); (24) mTOR or a mutant thereof (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus); (25) BET or a mutant thereof (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); (26) IGF1, IGF2, IGF1R, or a mutant thereof (e.g., xentuzumab, MEDI-573); (27) CDK9 or a mutant thereof (e.g., DRB, flavopiridol, CR8, AZD 5438, purvalanol B, AT7519, dinaciclib, SNS-032); or (28) CDK4/6 (e.g., palbociclib, ribociclib, abemaciclib).
[00609] 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.
[00610] In some embodiments, the 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 drags, and tolerance of the individual drags, 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 drag more often than the other during the treatment cycle and at different doses per administration of the drag.
[00611] 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 rd 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 a bacterial 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 cyclic lipopeptide such as daptomycin, glycylcyclines such as tigecycline, oxazolidiones 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.
[00612] In some cases, an anti-viral agent may be administered as part of a treatment regime. In some cases, a herpes virus 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.
[00613] 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.
[00614] 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.
[00615] In some embodiments, the subject method comprises administering an additional agent or therapy.
[00616] In some embodiments is a method of modulating activity of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-G, I- 1 ”, I-G ”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein said modulating comprises inhibiting the Ras (e.g., K-Ras) protein activity. In some embodiments is a method of modulating activity of a Ras (e.g., K-Ras) protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8,
IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V,
VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-G, 1-1”, 1-1”’, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein the Ras protein is a K-Ras protein. In some embodiments is a method of modulating activity of a Ras (e.g., K-Ras) protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-G, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein the Ras protein is a G12D or G12V mutant K-Ras. In some embodiments is a method of modulating activity of a Ras (e.g., K-Ras) protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-F, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein the Ras protein is a G12D mutant K-Ras. In some embodiments is a method of modulating activity of a Ras (e.g., K-Ras) protein, comprising contacting a Ras protein with an effective amount of a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-G, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), ora pharmaceutically acceptable salt or solvate thereof, wherein the Ras protein is a G12V mutant K-Ras.
[00617] In some embodiments, provided is a method of reducing Ras signaling output in a cell by contacting the cell with a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula G, IF, I”, II”, 1-1, 1-G, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX). A reduction in Ras signalling 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, and (v) reduction (e.g., inhibition) of cell growth of Ras-driven tumor cells (e.g., those derived from a tumor cell line).
In some cases, the reduction in Ras signaling output can be evidenced by two, three, four or all of (i)-(v) above. In some embodiments, the reduction any one or more of (i)-(v) can be 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), C0L0678 (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 GOD), HP AC (e.g., K-Ras G12D), HPAFII (e.g., K-Ras G12D), HUCCT1 (e.g., K-Ras G12D), KARPAS620 (e.g., K-Ras GOD), KOPN8 (e.g., K-Ras GOD), KP-3 (e.g., K-Ras GOV), KP-4 (e.g., K-Ras GOD), L3.3 (e.g., K-Ras GOD), LoVo (e.g., K-Ras GOD), LS180 (e.g., K-Ras GOD), LS513 (e.g., K-Ras GOD), MCAS (e.g., K-Ras GOD), NB4 (e.g., K-Ras A18D), NCI-H1355 (e.g., K-Ras G13C), NCI-H1573 (e.g., K-Ras GOA), NCI-H1944 (e.g., K-Ras GOD), NCI-H2009 (e.g., K-Ras GOA), NCI-H441 (e.g., K-Ras GOV), NCI-H747 (e.g., K-Ras GOD), NOMO-1 (e.g., K-Ras GOD), OV7 (e.g., K-Ras GOD), PANC0203 (e.g., K-Ras GOD), PANC0403 (e.g., K-Ras GOD), PANC0504 (e.g., K-Ras GOD), PANC0813 (e.g., K-Ras GOD), PANC1 (e.g., K-Ras GOD), Panc-10.05 (e.g., K-Ras GOD), PaTu-8902 (e.g., K-Ras GOV), PK1 (e.g., K-Ras GOD), PK45H (e.g., K-Ras GOD), PK59 (e.g., K-Ras GOD), SK-CO-1 (e.g., K-Ras GOV), SKLU1 (e.g., K-Ras GOD), SKM-1 (e.g., K-Ras K117N), SNU1 (e.g., K-Ras GOD), SNU1033 (e.g., K-Ras GOD), SNU1197 (e.g., K-Ras GOD), SNU407 (e.g., K-Ras GOD), SNU410 (e.g., K-Ras GOD), SNU601 (e.g., K-Ras GOD), SNU61 (e.g., K- Ras GOD), SNU8 (e.g., K-Ras GOD), SNU869 (e.g., K-Ras GOD), SNU-C2A (e.g., K-Ras GOD), SU.86.86 (e.g., K-Ras GOD), SUIT2 (e.g., K-Ras GOD), SW1990 (e.g., K-Ras GOD), SW403 (e.g., K-Ras GOV), SW480 (e.g., K-Ras GOV), SW620 (e.g., K-Ras GOV), SW948 (e.g., K-Ras Q61L), T3M10 (e.g., K-Ras GOD), TCC- PAN2 (e.g., K-Ras G12R), TGBC1 lTKB (e.g., K-Ras GOD), and MIA Pa-Ca (e.g., MIA Pa-Ca 2 (e.g., K-Ras G12Q).
[00618] In some embodiments is a method of inhibiting activity of a KrasGOD mutant protein, comprising contacting the KrasGOD mutant protein with a compound described herein (e.g., compound of Formula I, IA1, IA2, I A3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, II A 11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-F, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof. [00619] In some embodiments is a method of inhibiting activity of a KrasG12D mutant protein, comprising contacting the KrasG12D mutant protein with a compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V,
VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of inhibiting activity of a KrasG12D mutant protein, comprising contacting the KrasG12D mutant protein with a compound of Formula I, F, IF, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of inhibiting activity of a KrasG12D mutant protein, comprising contacting the KrasG12D mutant protein with a compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2,
II A3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV; F, IF, I”, II”, 1-1, 1-G, 1-1”, I-G”, 1-3, 1-4, II-l, XVI, XVII, XVIII, or XIX.
Pharmaceutical compositions and methods of administration
[00620] In an aspect is provided a pharmaceutical composition comprising a compound described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-G, 1-1”, 1-1”’, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), ora pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
[00621] The compounds described herein (e.g., compounds of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V,
VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-G, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, 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 described herein (e.g., compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV; compound of Formula F, IF, I”, II”, 1-1, 1-G, I- 1 ”, I-G ”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX), or a pharmaceutically acceptable salt or solvate thereof, alone or in combination with a pharmaceutically acceptable carrier.
[00622] 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)).
[00623] 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.
[00624] In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV, 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, G, IF, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11,
IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV, 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, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IA9, IA10, IA11, IA12, II, IIA1, IIA2, IIA3, IIA4, IIA5, IIA6, IIA7, IIA8, IIA9, IIA10, IIA11, IIA12, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV;
F, IF, I”, II”, 1-1, 1-r, 1-1”, I-G”, 1-3, 1-4, II- 1, XVI, XVII, XVIII, or XIX, 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 IA1, 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 IA2, 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 IA3, 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 IA4, 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 IA5, 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 IA6, 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 IA7, 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 IA8, 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 IA9, 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 IA10, 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 IA11, 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 IA12, 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 IIA1, 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 IIA2, 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 IIA3, 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 IIA4, 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 IIA5, 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 IIA6, 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 IIA7, 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 IIA8, 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 IIA9, 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 IIA10, 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 IIA11, 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 IIA12, 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 F, 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 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 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 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 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 XVI, 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 XVII, 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 XVIII, 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 XIX, or a pharmaceutically acceptable salt or solvate thereof.
[00625] 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.
[00626] 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 non- aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.
[00627] 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.
[00628] 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.
[00629] 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 fatty 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 carboxymethyl 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.
[00630] 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
[00631] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
[00632] 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,T-binaphthalene
Bn benzyl
BOC or Boc tert- butyl carbamate i-Bu /50-butyl t-Bu tert-butyl
DCM dichloromethane (CH2CI2)
DIBAL-H diisobutylaluminum hydride
DIPEA or DIEA diisopropylethylamine
DMAP 4-( Y, Y-di mcthy lam ino)pyridinc
DME 1 ,2-dimethoxy ethane
DMF Y, Y-di mcthy 1 fo rma m idc
DMA Y, Y-di mcthy lacctamidc
DMSO dimethylsulfoxide
Dppf or dppf 1 , 1 '-bis(dipheny lphosphino)ferrocene
EDC or ED Cl Y-(3-di mcthy lam inopropyl)-Y'-cthy lea rbodiim idc hydrochloride eq equivalent(s)
Et ethyl
Et20 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 iso- propyl
RP-HPLC reverse-phase high-pressure liquid chromatography
RT room temperature
TBS fcrt-biityldimcthylsilyl
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl
TsOH//?-TsOH p-toluenesulfonic acid.
EXAMPLE 1: Synthesis of 4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fhiorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-l-yl)pyrido[4,3-d]pyrimidin-5(6H)-one (Compound 103) [00633] To a stirred solution of ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (1-1) (988 mg, 4 mmol) in dichloromethane (15 mL) at ice-water bath was added triethylamine (835 pL. 6 mmol) followed by tert- butyl (lR,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (934 mg, 4.4 mmol). The reaction mixture was stirred for 1 h, diluted with water, extracted with dichloromethane. The combined organic layers were combined, dried over anhydrous Na>SOi. filtered then concentrated. The residue was purified by silica gel column chromatography eluting with 0-50% ethyl acetate/hexane to afford compound 1-2 (1.65 g). ESI-MS m z: 423.2 [M+H]+.
[00634] To a stirred solution of compound 1-2 (730 mg, 1.73 mmol) in anhydrous THF (10 mL) was added a 2 M solution of lithium diisopropylamide in THF (3.03 mL, 6.06 mmol) under nitrogen at -78 °C. The reaction mixture was stirred for 30 min, then dimethyl carbonate (262 pL 3.1 mmol). The reaction mixture was stirred at that temperature for 30 min, then slowly warmed up for 3 h. The resulting mixture was quenched with saturated aqueous NH4CI solution, extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na SOi. filtered, then concentrated. The residue was purified by silica gel column chromatography eluting with 0-70% ethyl acetate/hexane to afford compound 1-3 (606 mg). ESI-MS in z: 481.2 [M+H]+.
[00635] The reaction mixture of compound 1-3 (606 mg, 1.26 mmol) and 2,4-dimethoxybenzylamine (1.14 mL,
7.58 mmol) in dioxane (5 mL) was heated at 140 °C for 4 h under microwave irradiation. The mixture was concentrated, the residue was purified by silica gel column chromatography eluting with 0-70% ethyl acetate/hexane to afford compound 1-4 (428 mg). ESI-MS m/z: 616.3 [M+H]+.
[00636] To a stirred solution of compound 1-4 (200 mg, 0.33 mmol) in methanol (8 mL) was added a solution of 25% sodium methoxide in methanol (150 pL, 0.65 mmol) at room temperature. The reaction mixture was stirred for 1 h, concentrate. The residue was dissolved in water, acidified with 10% aqueous citric acid to pH 3-4. The solid was collected, washed with water and dried in vacuo to afford compound 1-5 (180 mg). ESI-MS m/z: 570.2 [M+H]+. [00637] To a stirred solution of compound 1-5 (180 mg, 0.31 mmol) in dichloromethane (4 mL) at ice-water bath was added triethylamine (86 pL, 0.62 mmol) under nitrogen followed by a 1 M solution of trifluoromethanesulfonic anhydride in dichloromethane (450 pL, 0.45 mmol). The reaction mixture was stirred for 30 min, concentrated. The residue was purified by silica gel column chromatography eluting with 0-40% ethyl acetate/hexane to afford compound 1-6 (197 mg). ESI-MS m/z: 702.1 [M+H]+.
[00638] The reaction mixture of compound 1-6 (197 mg, 0.28 mmol), 3-hydroxynaphthalene-l-boronic acid (80 mg, 0.42 mmol), K3PO4 (107 mg, 0.5 mmol) and dichloro[l,l’-bis(di-tert-butylphosphino)ferrocene]palladium (II) (34 mg, 0.056 mmol) in a mixed solvent of dioxane-water (6 mL, 3:1) was heated at 90 °C for 2 h. Filtered through Celite, the filtrate was concentrated, the residue was purified by silica gel column chromatography with 0-80% ethyl acetate/hexane to afford compound 1-7 (40 mg). ESI-MS m/z: 696.2 [M+H]+.
[00639] To s stirred solution of compound 1-7 (40 mg, 0.057 mmol) in dichloromethane (2 mL) was added 3- choroperbenzoic acid (< 77%) (38 mg, 0.17 mmol) at ice-water bath. The reaction mixture was stirred for 1 h. Saturated aqueous NaHCCh was added, extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous NaiSCti, filtered then concentrated. The residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane to afford compound 1-8 (20 mg). ESI-MS m/z: 728.2 [M+H]+. [00640] To a stirred suspension of sodium hydride (60% dispersion in mineral oil) (4 mg, 0.11 mmol) in DMF (0.5 mL) was added ((2R,7aS)-2-fluorohexahydro-lH-pyrrolizin-7a-yl)methanol (17 mg, 0.11 mmol) in DMF (0.5 mL) at room temperature under nitrogen. The reaction mixture was stirred for 15 min, then compound 1-8 (20 mg, 0.027 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 50 °C for 40 min. Cooled down, saturated aqueous NH C1 was added, the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na>SOi. filtered, then concentrated. The residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane then 0-10% ethyl acetate/MeOH to afford compound 1-9 (9 mg). ESI-MS m/ 807.3 [M+H]+.
[00641] The reaction mixture of compound 1-9 (9 mg) in 50% trifluoroacetic acid in dichloromethane (2 mL) was stirred at room temperature overnight, concentrated. The residue was purified by semi preparative HPLC (5-60% CH3CN/H2O with 0.1% formic acid) to afford compound 103 as formic acid salt (2 mg). ESI-MS m/r. 557.3 [M+H]+; ¾NMR (400 MHz, d6-DMSO): <5 11.50 (s, 1H), 8.29 (s, 1H x 2) (1 formic acid), 7.78 (dd, J= 14.4 and 8.3 Hz, 2H), 7.46 (t, J = 7.3 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H) 7.27 (d, J = 2.2 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.20 (s, 1H), 5.33-5.20 (m, 1H), 4.10-3.95 (m, 3H), 4.06 (d , J = 10.3 Hz, 1H), 3.95 (d , J = 10.3 Hz, 1H), 3.60-3.50 (m, 2H), 3.35-3.25 (m, 2H), 3.14-3.06 (m, 2H), 3.05-2.98 (m, 1H), 2.85-2.78 (m, 1H), 2.14-1.95 (m, 3H), 1.88-1.60 (m, 7H).
EXAMPLE 2: Synthesis of 7-(2-amino-7-fhiorobenzo[d]thiazol-4-yl)-4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan- 3-yl)-6-cyclopropyl-2-(((2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-5(6H)-one (Compound 104)
[00642] The reaction mixture of compound 1-3 (480 mg, 1 mmol) and cyclopropylamine (700 L. 10 mmol) in xylene (6 mL) was heated at 120 °C overnight. The mixture was concentrated, the residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate/hexane) to afford compound 2-1 (204 mg). ESI-MS m/z\ 506.2 [M+H]+.
[00643] To a stirred solution of compound 2-1 (204 mg, 0.40 mmol) in methanol (8 mL) was added a solution of 25% sodium methoxide in methanol (183 pL, 0.81 mmol). The reaction mixture was stirred at 50 °C for 30 min, concentrate. The residue was dissolved in water, acidified with 10% aqueous citric acid to pH 3-4. The solid was collected, washed with water then dried in vacuo to afford compound 2-2 (177 mg). ESI-MS m/z: 460.2 [M+H]+. [00644] To a stirred solution of compound 2-2 (177 mg, 0.38 mmol) in dichloromethane (5 mL) at ice-water bath was added triethylamine (107 pL. 0.77 mmol) under nitrogen followed by a 1 M solution of trifluoromethanesulfonic anhydride in dichloromethane (570 pL, 0.57 mmol). The reaction mixture was stirred for 30 min, concentrated. The residue was purified by silica gel column chromatography eluting with 0-50% ethyl acetate/hexane to afford compound 2-3 (150 mg). ESI-MS m/z: 592.2 [M+H]+.
[00645] The reaction mixture of compound 2-3 (150 mg, 0.25 mmol), (2-((tert-butoxycarbonyl)amino)-7- fluorobenzo[d]thiazol-4-yl)boronic acid (120 mg, 0.38 mmol), K3PO4 (80 mg, 0.38 mmol) and dichloro[l,l’-bis(di- tert-butylphosphino)ferrocene]palladium (II) (30 mg, 0.05 mmol) in a mixed solvent of dioxane-water (6 mL, 3:1) was heated at 90 °C for 2 h. Filtered through Celite, the filtrate was concentrated, the residue was purified by silica gel column chromatography with 0-50% ethyl acetate/hexane to afford compound 2-4 (70 mg). ESI-MS m/z: 710.2 [M+H]+.
[00646] To s stirred solution of compound 2-4 (70 mg, 0.099 mmol) in dichloromethane (2 mL) was added 3- chloroperbenzic acid (< 77%) (45 mg, 0.2 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature, saturated aqueous NaHCCh was added, extracted with dichloromethane. The combined organic layers were concentrated, the residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane to afford compound 2-5 (20 mg) and compound 2-6 (45 mg). Compound 2-5 ESI-MS m/z: 742.2 [M+H]+. Compound 2-6 ESI-MS m/z: 726.2 [M+H]+.
[00647] To a stirred suspension of sodium hydride (60% in mineral oil) (10 mg, 0.26 mmol) in DMF (0.5 mL) was added ((2R,7aS)-2-fluorohexahydro-lH-pyrrolizin-7a-yl)methanol (43 mg, 0.26 mmol) in DMF (1 mL) at room temperature under nitrogen. The reaction mixture was stirred for 15 min, then compound 2-5 (20 mg, 0.027 mmol) and compound 2-6 (45 mg, 0.062 mmol) in DMF (1.5 mL) was added. The reaction mixture was stirred at 50 °C for 40 min. Cooled down, saturated aqueous NH C1 was added, the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous NaiSCb, filtered, then concentrated. The residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane then 0-10% ethyl acetate/MeOH to afford compound 2-7 (13 mg). ESI-MS m/z: 821.3 [M+H]+.
[00648] The reaction mixture of compound 2-7 (13 mg) in 20% trifluoroacetic acid in dichloromethane (2 mL) was stirred at room temperature for 4 h, concentrated. The residue was purified by semi preparative HPLC (5-60% CH3CN/H2O with 0.1% formic acid) to afford compound 104 as formic acid salt (3 mg). ESI-MS m/z: 621.2 [M+H]+; !HNMR (400 MHz, d6-DMSO): <58.31 (s, 1H) (1 formic acid), 8.00 (s, 2H), 7.35 (dd, J= 8.4 and 5.7 Hz, 1H), 7.03 (t, J= 8.7 Hz, 1H), 6.08 (s, 1H), 5.30-5.20 (m, 1H), 4.25-4.10 (m, 1H), 4.04 (d ,J = 10.3 Hz, 1H), 3.93 (d, J= 10.3 Hz, 1H), 3.56-3.30 (m, 6H), 3.10-3.04 (m, 2H), 3.01-2.98 (m, 1H), 2.95-2.88 (m,lH), 2.85-2.78 (m, 1H), 2.15-1.92 (m, 3H), 1.90-1.55 (m, 7H), 0.80-0.70 (m, 1H), 0.44-0.24 (m, 3H).
Example 2a: Synthesis of 5-(7-(2-amino-7-fhiorobenzo[d]thiazol-4-yl)-6-cyclopropyl-8-fluoro-2-(((2R,7aS)-2- fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-4-yl)-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrazine-3-carbonitrile (Compound 453)
3-11 453
[00649] To a solution of t-BuOK (27.2 g, 243 mmol) in THF (250 mL) at 0 °C, BnOH (26.2 g, 243 mmol) was added, and the resulting mixture was stirred at 60 °C under argon atmosphere for 1.5 h. The mixture was cooled to 0 °C and the solution was added to the solution of compound 1-1 (50 g, 202 mmol) in THF (100 mL) at -20 °C under argon atmosphere. The mixture was stirred at -20 °C under argon atmosphere for 1 h. The mixture was diluted with aqueous NH C1 (200 mL) at -20 °C, extracted with EtOAc (3 c 200 mL). The organic layers were washed with brine (200 mL), dried with Na>SOi. filtered, and the filtrate was concentrated by vacuum to give compound 3-2 (67 g, crude) which was used directly in the next step. ESI-MS m/z 319.1 [M+H]+.
[00650] To a solution of compound 3-2 (81.7 g, 257 mmol) in THF (817 mL) at -78 °C under argon atmosphere, LiHMDS (643 mL, 643 mmol, 1 M) was added, and the resulting mixture was stirred at this temperature for 1 h. Dimethyl carbonate (23.1 g, 257 mmol) was added at -78 °C, then the reaction mixture was warmed naturally to room temperature and stirred for 2 h. The mixture was diluted with aqueous NH4C1 (1 L) at 0 °C, extracted with EtOAc (3 x 1 L), the organic layers were washed with brine (1 L), dried withNa2S04, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column (15 % EtOAc in PE) to give compound 3-3 (84 g). ESI-MS m/z\ 377.1 [M+H]+.
[00651] Under N2, to a suspension of compound 3-3 (1.1 g, 2.86 mmol) in THF (15 mL) at -70 °C, LiHMDS (1 M) (2.86 mL, 2.86 mmol) was added. The mixture was warmed to 0 °C and was stirred at 0 °C for 1 h. The mixture was cooled to -70 °C and NFSI (924 mg, 2.86 mmol) in THF (5 mL) was added. The mixture was warmed to 0 °C and was stirred at 0 °C for 1 h. NH C1 aqueous (5 mL) was added to quench the mixture and extracted with EA (15 mL x 3). The organic layers were concentrated, and the residue was purified by Flash Column Chromatography on silica gel (eluting with 0~15% of EA in PE) to give compound 3-4 (850 mg). ESI-MS in z: 395.1 [M+H]+.
[00652] To a suspension of compound 3-4 (700 mg, 1.776mmol) in EtOH (10 mL) was added DBU (1 mL). Cyclopropylamine (2 mL) was then added and stirred at room temperature until the mixture became clear. The mixture was stirred at room temperature for 1 h. KOH powder (100 mg, 1.776 mmol) was added, and the mixture was stirred for 0.5 h. The mixture was poured into ice water and adjusted pH=4~5 with HC1. The resulted precipitate was filtered to give compound 3-5 (470 mg). ESI-MS m/z: 374.0 [M+H]+.
[00653] A suspension of compound 3-5 (9.0 g, 24.13 mmol) in dry DCM (450 mL), 4 M solution of HC1 in dioxane (200 mL) was added. The reaction mixture was stirred at 50 °C for 3 h. The mixture was concentrated, and diluted with tert-butyl methyl ether. The solid was collected, rinsed with tert-Butyl methyl ether and dried to afford compound 3-6 (5.6 g). ESI-MS m/z : 284.2 [M+H]+.
[00654] Compound 3-6 (5.6 g) was dissolved in POCL (230 mL) and heated to 105 °C, and the mixture was stirred at 105 °C for 3 h. The mixture was concentrated in vacuo, the residue was diluted with ice-water, and extracted with ethyl acetate. The combined organic layers were washed with water, brine and then concentrated. The residue was purified by silica gel column chromatography eluting with 0-70% ethyl acetate/hexane to afford compound 3-7 (2.2 g). ESI-MS m/z 320.1 [M+H]+.
[00655] To a solution of compound 3-7 (170 mg, 0.53 mmol) in DCM (10 mL), TEA (108 mg, 1.07 mmol) and 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-3-carbonitrile (110 mg, 0.75 mmol) were added. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue was purified by Flash Column Chromatography on silica gel (eluting with 0-60% of EA in PE) to give compound 3-8 (260 mg). ESI-MS m/z:
402.0 [M+H]+.
[00656] To a solution of compound 3-8 (240 mg, 0.56 mmol) in DCM (10 ml), m-CPBA (241 mg, 1.39 mmol) was added at room temperature and the mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was purified by Flash Column Chromatography on silica gel (eluting with 0-60% of EA in PE) to give compound 3-9 (240 mg). ESI-MS m/z: 464.2 [M+H]+.
[00657] Under N2, to a suspension of ((2R,7aS)-2-fluorotetrahydro-lH-pynx)lizin-7a(5H)-yl)methanol (106 mg,
0.66 mmol) in THF (5 mL), NaH (27 mg, 0.66 mmol) was added, and the mixture was stirred at 0 °C for 1 h. Compound 3-9 (120 mg, 0.22 mmol) was added under N2 and the reaction mixture was stirred at 0 °C for 1 h. Water ( 5 mL) was added and the residue was extracted with EA (15 mL x 3). The organic layers were concentrated, and the residue was purified by Flash Column Chromatography on silica gel (eluting with 0-10% of MeOH in DCM) to give compound 3-10 (70 mg). ESI-MS m/z: 543.3 [M+H]+.
[00658] To a solution of compound 3-10 (50 mg, 0.09 mmol) in DMF (2 mL), (2-((tert-butoxycarbonyl)amino)-7- fluorobenzo[d]thiazol-4-yl)boronic acid (72 mg, 0.23 mmol) was added under argon atmosphere, and the resulting mixture was bubbled with argon for 1 h. Cs2CC>3 (90 mg, 0.28 mmol) and DPEPhosPdCL (20 mg) were added. Then the reaction mixture was stirred at 110 °C under argon atmosphere for 3 h. The mixture was filtered through celite, rinsed with ethyl acetate. The combined organic layer was concentrated, and the residue was purified by silica gel column chromatography with 0-100% ethyl acetate/PE followed by 0-20% MeOH/DCM. The combined fractions were concentrated and the residue was further purified by prep-TLC plate (MeOH : DCM = 15: 1) to give compound 3-11 (15 mg). ESI-MS m/z: 775.2 [M+H]+. [00659] To a solution of compound 3-11 (15 mg, 0.02 mmol) in DCM (3 mL), TFA (1 mL) was added. The mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to afford compound 453 (6.66 mg). ESI-MS m/z: 675.2 [M+H]+. Ή NMR (400 MHz, CD3OD): d 7.92 (s, 1H), 7.44 - 7.35 (m, 1H), 7.03 (t, J = 8.9 Hz, 1H), 5.49 (d, J= 52.2 Hz, 1H), 5.02 (s, 2H), 4.56 (dd, J = 30.8, 11.0 Hz, 4H), 4.27 (s, 2H), 3.67 (t, J= 67.9 Hz, 4H), 2.98 (s, 1H), 2.67 - 2.43 (m, 2H), 2.26 (dd, J = 66.7, 33.7 Hz, 4H), 0.63 (t, J= 65.1 Hz, 4H).
Example 2b: Synthesis of 4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-cyclopropyl-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-oxo-5,6-dihy(lropyrido[4,3-(l]pyrimi(lin-7-yl)-2- amino-7-fluorobenzo[b]thiophene-3-carbonitrile (Compound 447)
[00660] To a stirred solution of compound 3-7 (50 mg, 0.16 mmol) in DCM (3 mL) was added Et N (43 pL. 0.31 mmol) followed by 3-oxa-7,9-diazabicyclo[3.3.1]nonane (53 mg, 0.23 mmol) at room temperature. The reaction mixture was stirred for 30 min and then concentrated. The residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate/hexane to afford compound 4-1 (70 mg). ESI-MS m/z: 512.3 [M+H]+.
[00661] To a stirred solution of compound 4-1 (70 mg, 0.14 mmol) in DCM (3 mL) was added m-CPBA (77%) (80 mg, 0.34 mmol) at room temperature. The reaction mixture was stirred for 2.5 h and then partially concentrated. The residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate/hexane to afford compound 4-2 (60 mg). ESI-MS m/z : 544.3 [M+H]+.
[00662] The reaction mixture of compound 4-2 (60 mg, 0.11 mmol), ((2A,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5//)-yl)mcthanol (53 mg, 0.33 mmol) and 4Ά molecular sieves (over-dried and cooled) in anhydrous toluene (3 mL) was stirred in ice-water bath for 40 min, then NaO/Bu (32 mg, 0.33 mmol) was added. The reaction mixture was stirred at that temperature for 30 min. The mixture as diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with brine and concentrated. The residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane with 0.5% Et N then 0-20% MeOH/ethyl acetate to afford compound 4-3 (58 mg). ESI-MS m/z: 623.4 [M+H]+.
[00663] The reaction mixture of compound 4-3 (58 mg, 0.093 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl-l,3,2- dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (75 mg, 0.19 mmol), DPEphosPdCL (14 mg, 0.019 mmol) in toluene (2.5 mL) was added cesium carbonate (76 mg, 0.23 mmol). The reaction mixture was degassed and charged with nitrogen then heated at 105 °C overnight. Filtered through Celite, washed with ethyl acetate. The filtrate was concentrated, the residue was purified by silica gel column chromatography with 0-20% MeOH/ethyl acetate with 0.5% Et3N then HPLC (10-95% CH CN/H20 with 0.1% formic acid). The combined fractions were lyophilized to afford compound 4-4. ESI-MS in z: 879.5 [M+H]+.
[00664] The reaction solution of compound 4-4 in 20% TFA/DCM (2 mL) was stirred at room temperature for 2 h, and then concentrated. The residue was purified by prep.-HPLC (5-65% CH3CN/H2O with 0.1% formic acid) to afford compound 447 as formic acid salt (1.5 mg). ESI-MS in z: 679.4 [M+H]+.
Example 2c: Synthesis of 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-4-(azepan-l-yl)-6-cyclopropyl-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5(6H)-one
[00665] To a stirred solution of compound 3-7 (34 mg, 0.11 mmol) in DCM (2 mL) was added Eb,N (29 pL. 0.21 mmol) followed by hexamethyleneimine (16 mg, 0.16 mmol) at room temperature. The reaction mixture was stirred for 30 min and then concentrated. The residue was purified by silica gel column chromatography eluting with 0-60% ethyl acetate/hexane to afford compound 5-1 (35 mg). ESI-MS in z: 383.2 [M+H]+.
[00666] To a stirred solution of compound 5-1 (35 mg, 0.16 mmol) in DCM (2 mL) was added m-CPBA (77%) (51 mg, 0.23 mmol) at room temperature. The reaction mixture was stirred for 2.5 h and then purified by silica gel column chromatography eluting with 0-100% ethyl acetate/hexane to afford compound 5-2 (47 mg). ESI-MS in z: 415.2 [M+H]+.
[00667] The reaction mixture of compound 5-2 (47 mg, 0.11 mmol), ((2A,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5//)-yl)mcthanol (54 mg, 0.34 mmol) and 4Ά molecular sieves (over-dried and cooled) in anhydrous toluene (3 mL) was stirred in ice-water bath for 40 min, and then NaO/Bu (33 mg, 0.34 mmol) was added. The reaction mixture was stirred at that temperature for 30 min. The mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with brine then concentrated. The residue was purified by silica gel column chromatography with 0-100% ethyl acetate/hexane with 0.5% EhN to afford compound 5-3 (43 mg). ESI- MS m/z: 494.3 [M+H]+.
[00668] The reaction mixture of compound 5-3 (43 mg, 0.09 mmol), (2-((tert-butoxycarbonyl)amino)-7- fluorobenzo[d]thiazol-4-yl)boronic acid (56 mg, 0.18 mmol), Pd(PPli3)4 (23 mg, 0.02 mmol) in 1,4-dioxane (2 mL) was added a 2 M solution ofNa CO, in water (112 pL, 0.23 mmol). The reaction mixture was degassed and charged with nitrogen and then heated at 95 °C overnight. The mixture was filtered through Celite, washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography with 0- 100% ethyl acetate/hexane with 0.5% EhN to afford compound 5-4. ESI-MS in z: 726.5 [M+H]+. [00669] The reaction solution of compound 5-4 in 20% TFA/DCM (2 mL) was stirred at room temperature for 3 h, and then concentrated. The residue was purified by prep-HPLC (5-60% CH3CN/H2O with 0.1% formic acid) to afford compound 449 as formic acid salt (11 mg). ESI-MS in z: 626.4 [M+H]+; 'HNMR (400 MHz, DMSO-d6): d 8.05 (s, 2H), 7.41 (dd, J= 8.5 and 5.6 Hz, 1H), 7.07 (t , J = 8.8 Hz, 1H), 5.35-5.20 (m, 1H), 4.10-3.95 (m, 2H), 3.75- 3.45 (m, 7H), 3.10-2.98 (m, 3H), 2.85-2.75 (m, 2H), 2.10-2.08 (m, 1H), 2.06-2.02 (m, 1H), 2.00-1.92 (m,lH), 1.88-
1.72 (m, 4H), 1.54-1.38 (m, 4H), 0.65-0.60 (m, 1H), 0.52-0.48 (m, 1H), 0.38-0.32 (m, 2H).
Example 2d: Synthesis of 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-cyclopropyl-4-((lR,5S)-8-(2,2- difluorocyclopropane-l-carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5(6H)-one (Compound 452)
[00670] To a solution of compound 3-7 (315 mg, 0.99 mmol) in DCM (4 mL), tert-butyl (lR,5S)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 1.08 mmol) in DCM (3 mL) and EtiN (300 mg, 2.96 mmol) were added, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and the residue was purified by flash silica column chromatography (eluting with 0~40 % of EA in PE to give compound 6-1 (350 mg). ESI-MS m/z 496.1 [M+H]+.
[00671] To a solution of compound 6-1 (350 mg, 0.71 mmol) in DCM (5 mL), m-CPBA (308 mg, 1.77 mmol) was added at 0 °C, Then the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with aqueous HNaO.S (10 mL) and extracted with DCM (3 c 20 mL). The organic layer was washed with aqueous NaHCCh (3 c 10 mL) and brine (10 mL), dried over Na>SOi. filtered, and the filtrate was concentrated in vacuo to give compound 6-2 (300 mg) which was used directly in the next step. ESI-MS m/z\ 528.3 [M+H]+.
[00672] To a solution of ((7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (136 mg, 0.85 mmol) in THF (3 mL) at -20 °C under argon atmosphere, t-BuOK (1.13 mL, 1.13 mmol, 1 M) was added and the resulting mixture was stirred at this temperature for 1 h. Compound 6-2 (300 mg, 0.57 mmol) in THF (5 mL) was added at -20 °C, and then the mixture was stirred at this temperature for 2 h. The mixture was diluted with aqueous NH C1 (10 mL) at -20 °C and extracted with DCM (3 c 20 mL). The organic layer was washed with brine (10 mL), dried with Na>SOi. filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica column chromatography (eluting with 0~15 of MeOH in DCM to give compound 6-3 (230 mg). ESI-MS m z: 607.3 [M+H]+.
[00673] To a solution of 6-3 (50 mg, 0.08 mmol) in DMF (2 mL) under argon atmosphere, (2-((tert- butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (66 mg, 0.21 mmol) was added, and the resulting mixture was bubbled with argon for 1 h. CS2CO3 (81 mg, 0.25 mmol) and DPEPhosPdCL (20 mg) were added. Then the reaction mixture was stirred at 110 °C under argon atmosphere for 4 h. The mixture was filtered through celite and rinsed with ethyl acetate. The combined organic layer was concentrated, and the residue was purified by silica gel column chromatography with 0-100% ethyl acetate/PE then 0-20% MeOH/DCM. The combined fractions were concentrated and the residue was further purified by prep-TLC plate (MeOH : DCM = 15: 1) to give compound 6-4 (50 mg). ESI-MS m/z: 839.4 [M+H]+.
[00674] To a solution of compound 6-4 (50 mg, crude) in DCM (3 mL) was added TFA (1 mL), then the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by prep-HPLC (FA) to give compound 6-5 (8 mg). ESI-MS m/z : 639.3 [M+H]+.
[00675] To a solution of 6-5 (8 mg, 0.013 mmol) in DMF (0.1 mL), 2,2-difluorocyclopropane-l -carboxylic acid (1.5mg, 0.013 mmol), HATU (4.7 mg, 0.013 mmol) and DIEA (5 mg, 0.038 mmol) were added, and the resulting mixture was stirred at room temperature under argon atmosphere for 2 h. The reaction mixture was concentrated, and the residue was purified by prep-HPLC (FA) to give compound 452 (3 mg). ESI-MS m/z : 743.3 [M+H]+; Ή NMR (400 MHz, CD3OD): d 8.45 (s, 2H), 7.38 (dd, J = 8.4, 5.4 Hz, 1H), 7.02 (t, J = 8.8 Hz, 1H), 5.47 (d, J = 52.7 Hz, 2H), 4.48 (dd, J = 30.4, 11.5 Hz, 3H), 3.66 (s, 4H), 3.01 (dd, J = 33.1, 22.2 Hz, 3H), 2.46 (d, J = 22.3 Hz, 2H), 2.30 (d, J = 8.8 Hz, 1H), 2.21 (t, J = 12.1 Hz, 3H), 2.03 (d, J = 25.4 Hz, 4H), 1.90 (d, J = 16.4 Hz, 4H), 0.79 (s, 1H), 0.50 (d, J = 37.9 Hz, 4H).
Example 2e: Synthesis of 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-8- yl)-6-cyclopropyl-8-fhioro-2-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrido[4,3-d]pyrimidin-5(6H)-one (Compound 448) [00676] To s stirred solution of compound 3-4 (220 mg, 1.0 eq) in dichloromethane (2 mL) at 0 °C, mCPBA (143 mg, 1.5) was added and the resulting mixture was stirred at 0 °C for 30 min. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with ethyl acetate/hexane to afford compound 7-1 (222.8 mg). ESI-MS m/r 411.2 [M+H]+.
[00677] To a solution of compound 7-1 (222.8 mg, 1.0 eq) in 1,4-dioxane (1.0 mL), DIEA (141 ul, 1.5 eq) and (1S)- l-[(2S)-l-methylpyrrolidin-2-yl] ethanol (77.2 mg, 1.1 eq) were added, and the resulting mixture was stirred at 100 °C for 2 h. The mixture was concentrated, and the residue was purified by reverse phase chromatography eluting with water/QLCN to afford compound 7-2 (88.1 mg). ESI-MS m/r. 476.3 [M+H]+.
[00678] To a solution of compound 7-2 (88.1 mg, 1.0 eq) in MeOH (2.0 mL), cyclopropylamine (257 ul, 20.0 eq) and NaOMe (25%) ( 60 ul, 1.5 eq) were added, and the resulting mixture was stirred at 50 °C for 1 h. The mixture was concentrated, and the residue was purified by reverse phase chromatography eluting with water/QLCN to afford compound 7-3 (40.8 mg). ESI-MS m/ . 379.3 [M+H]+.
[00679] The compound 7-3 (40.8 mg, 1.0 eq) was dissolved in POCL (2.0 mL) and stirred at 105 °C for 24 h. The mixture was concentrated to remove the volatiles to give compound 7-4 which was used directly in the next step. ESI-MS m/r 401.2 [M+H]+.
[00680] To a solution of above obtained crude compound 7-4 in DCM (5 mL) at 0 °C, DIEA (177 ul, 10.0 eq) and tert-butyl (lR,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (65 mg, 3.0 eq) were added, and the resulting mixture was stirred at 0 °C for 10 min. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluting with ethyl acetate/hexane to afford compound 7-5 (20.5 mg). ESI-MS m/r. 577.4 [M+H]+.
[00681] The reaction mixture of compound 7-5 (20.5 mg, 1.0 eq), 2-((tert-butoxycarbonyl)amino)-7- fluorobenzo[d]thiazol-4-yl)boronic acid (22 mg, 2.0 eq), K2C03(14.3 mg, 3.0 eq) and dichloro[l,r-bis(di-tert- butylphosphino)ferrocene]palladium (II) (8.2 mg, cat.) in a mixed solvent of dioxane-water (3 mL, 3:1) was stirred at 90 °C for 2 h. The mixture was concentrated, and the residue was purified by reverse phase chromatography eluting with water/CELCN to afford compound 7-6 (9.2 mg). ESI-MS m/r. 809.5 [M+H]+.
[00682] The reaction mixture of compound 7-6 (9.2 mg) in 20% trifluoroacetic acid in dichloromethane (2 mL) was stirred at room temperature for 4 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (5-60% CH3CN/H2O with 0.1% formic acid) to afford compound 448 as formic acid salt (1.96 mg). ESI-MS m/ . 609.4 [M+H]+.
Example 2f: Synthesis of 7-(2-amino-7-fhiorobenzo[d]thiazol-4-yl)-6-cyclopropyl-8-fhioro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)pyrido[4,3- d]pyrimidin-5(6H)-one (Compound 451)
[00683] To a solution of compound 3-7 (100 mg, 0.157 mmol) inDCM (5 mL), tert-butyl hexahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxylate (80 mg, 0.376 mmol) and Et3N (40 mg, 0.314 mmol) were added, and the resulting mixture was stirred at room temperature for 30 min. The mixture was concentrated in vacuo, and the residue was purified by flash silica column chromatography (eluting with 0~60 % of EA in PE to give compound 8-1 (170 mg). ESI-MS m/z\ 496.3 [M+H]+.
[00684] To a solution of compound 8-1 (170 mg, 0.34 mmol) in DCM (5 mL) at 0 °C, m-CPBA (120 mg, 0.68 mmol) was added, and the resulting mixture was stirred at room temperature for 2.5 h. The mixture was diluted with aqueous NaiSCh (10 mL) and extracted with DCM (3 c 10 mL). The organic layer was washed with aqueous NaHCCh (3 c 10 mL) and brine (10 mL), dried with Na>SOi. filtered, and the filtrate was concentrated in vacuo to give compound 8-2 (150 mg, crude) which was used in the next step. ESI-MS m/z: 528.1 [M+H]+.
[00685] To a solution of compound ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (120 mg, 0.75 mmol) in THF (5 mL) at -20 °C under argon atmosphere, t-BuOK (0.75 mL, 0.75 mmol, 1 M) was added, and the resulting mixture was stirred at this temperature for 30 min. Compound 8-2 (200 mg, 0.37 mmol) in THF (5 mL) was added at -20 °C, and the mixture was stirred at this temperature for 1 h. The mixture was diluted with aqueous NH4CI (20 mL) at this temperature, extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine (10 mL), dried with Na>SOi. filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash silica column chromatography (eluting with 0~15 of MeOH in DCM to give compound 8-3 (150 mg). ESI-MS m/z: 607.3 [M+H]+.
[00686] To a solution of 8-3 (100 mg, 0.16 mmol) in DMF (3 mL) under argon atmosphere, (2-((tert- butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (132 mg, 0.16 mmol) was added, and the resulting mixture was bubbled with argon for 1 h. CS2CO3 (162mg, 0.48 mmol) and DPEPhosPdCL (20 mg) were added, and the mixture was stirred at 110 °C under argon atmosphere for 4 h. The mixture was filtered through celite and rinsed with ethyl acetate. The combined organic layer was concentrated, and the residue was purified by silica gel column chromatography with 0-100% ethyl acetate/PE then 0-20% MeOH/DCM. The combined fractions were concentrated and the residue was purified by prep-TLC plate (MeOH : DCM = 15: 1) to give compound 8-4 (35 mg). ESI-MS m/z: 839.3 [M+H]+. [00687] To a solution of compound 8-4 (30 mg) in DCM (3 mL), TFA (1 mL) was added, and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by prep-HPLC (FA) to give compound 451 (6.10 mg). ESI-MS m/z: 639.2 [M+H]+;
[00688] ¾ NMR (400 MHz, DMSO-d6): d 10.89 (s, 1H), 9.00 (s, 2H), 8.05 (s, 2H), 7.50 - 7.29 (m, 1H), 7.09 (t, J = 8.8 Hz, 1H), 5.51 (d , J = 55.1 Hz, 1H), 4.49 (s, 2H), 3.95 - 3.67 (m, 7H), 3.57 (s, 3H), 3.08 (s, 5H), 2.83 (s, 1H), 2.12 (s, 3H), 1.99 (s, 1H), 1.24 (s, 2H), 0.59 (d, J= 30.4 Hz, 2H), 0.40 (s, 2H).
[00689] The compounds in Table 6 were prepared, or can be prepared, in a similar manner as described in
Examples 1 ,2, and 2a-2f. Table 6
EXAMPLE 3: Ras sequence
[00690] Human K-Ras4b (SEQ ID NO. 1):
1 MTEYKLVWG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET 51 CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI 101 KRVKDSEDVP MVL V GNKCDL PSRTVDTKQA QDLARSYGIP FIETSAKTRQ 151 GVDDAFYTLV REIRKHKEKM SKDGKKKKKK SKTKCVIM EXAMPLE 4: Protein expression
[00691] 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. coli 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
[00692] 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 ventors. 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 centrilugation 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 lurther purification.
EXAMPLE 5: Ras protein purification [00693] A Ras (e.g., K-Ras wildtype or a mutant such as K-Ras G12S, K-Ras G12D, K-Ras G12V or K-RasG12C) constmct 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, 500mMNaCI,l mM 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 (f6 h, f 0Ό). 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) are 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 constmct can be performed to assess its homogeneous load with GDP.
EXAMPLE 6: HTRF (homogenous time-resolved fluorescence resonance energy transfer assay [00694] The ability of a compound of the present disclosure to reduce a Ras signaling output can be demonstrated by an HTRF assay. This assay can be also used to assess a selective inhibition or reduction of signaling output of a mutant Ras protein (e.g., G12D, G12S, G12C, G12V, G13D, G13S, G13C, or G13V) relative to a wildtype, or relative to a different mutant Ras protein. For example, the equilibrium interaction of wildtype Kras or K-Ras mutant (e.g., wildtype or a mutant thereof) with SOS1 (e.g., hSOSl) can be assessed as a proxy or an indication for a subject compound’s ability to bind and inhibit Ras protein. HTRF assay detects from (i) a fluorescence resonance energy transfer (FRET) donor (e.g., antiGST-Europium) that is bound to GST-tagged K-Ras mutant to (ii) a FRET acceptor (e.g., anti-6His-XL665) bound to a His-tagged hSOSl.
[00695] The assay buffer can contain -5 mM HEPES pH 7.4, -150 mM NaCI, - 1 mM DTT, 0.05% BSA and 0.0025% (v/v) Igepal. A Ras working solution is prepared in an assay buffer containing typically a suitable amount of the protein constmct (e.g., GST-tagged K-Ras mutant) and the FRET donor (e.g., antiGST-Eu(K) from Cisbio, France). A SOS1 working solution is prepared in an assay buffer containing suitable amount of the protein constmct (e.g., His-hSOSl) and the FRET acceptor (e.g., anti-6His-XL665 from Cisbio, France). A suitable amount of the protein constmct will depend on the range of activity or range of IC50 values being detected or under investigation. For detecting IC50 within a range of 500 nM, the protein constmcts of the same range of molarity can be utilized. An inhibitor control solution is prepared in an assay buffer containing comparable amount of the FRET acceptor without the SOS1 protein.
[00696] 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. SOS1 working solution is added to all wells except for those that are subsequently filled the inhibitor control solution. Upon incubation for about 10 minutes or longer, 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 mM, 2.5 mM, 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 Ras using GraphPad Prism (GraphPad software). Following this general procedure, samples were tested with or without a subject compound disclosed herein including compounds exemplified in Table 6 to assess their abilities to inhibit a K-Ras mutant relative to another mutant or WT. Signaling output measured in terms of IC50 values can be obtained, a ratio of IC50 against one mutant relative to another mutant can be calculated. For instance, a selective reduction of K-Ras G12D signaling output can be evidenced by a ratio greater than one. In particular, a selective reduction of K-Ras G12D signaling relative to K-Ras WT signaling is evidenced as the ratio of IC50 (against K-Ras WT) to IC50 (against K-Ras G12D) is greater than 1. In embodiments, one or more subject compounds disclosed herein are expected to exhibit selective inhibition of a Ras mutant (e.g., G12C, G12D, G12S, G1V, G13C, or G13D) over WT by at least 1-fold, and in some instances greater than 2-, 3-, 4- or 5-fold. In embodiments, the compounds listed below in Table 7 exhibit the indicated IC50 values against KRas mutant G12D. In embodiments, subject compounds are expected to exhibit an IC50 against KRas mutants (e.g., G12C, G12D, G12S, G1V, G13C, or G13D) less than 500 nM, less than 100 nM, 50 nM, 10 nM or even less. Table 7
‘+++’ means IC50 at or less than about 1.5 mM, ‘++’ means IC50 greater than about 1.5 mM.
EXAMPLE 7: GTPase activity assay
[00697] The ability of any compound of the present disclosure to inhibit a Ras protein signalling can be demonstrated by a reduced GTPase activity. This assay can be also used to assess a selective inhibition of a mutant Ras protein relative to a wildtype, or relative to a different mutant Ras protein. For instance, the assay can be used to establish a subject compound’s ability to selectively inhibit Kras G12D relative to wildtype, G12S relative to wildtype, Kras G12V relative to wildtype, KrasG12S relative KrasG12V, KrasG12S relative KrasG12D, KrasG12D relative KrasG12S, or KrasG12D relative KrasG12V. In particular, intrinsic and GTPase -activating protein (GAP)- stimulated GTPase activity for K-Ras construct or a mutant thereof can be measured using EnzCheck phosphate assay system (Life Technologies). For example, K-Ras WT, K-Ras D154Q mutant, K-Ras G12D mutant, K-Ras G12S mutant, and K-Ras G12D/D154Q mutant proteins (2.5 mg/ml) in buffer (20 mmol/L Tris, pH 8.0, 50 mM NaCl) is loaded with GTP at room temperature for 2 hours by exposing to exchange buffer containing EDTA. Proteins are buffer exchanged to assay buffer (30 mM Tris, pH 7.5, 1 mM DTT) and the concentration is adjusted to 2 mg/ml. GTP loading is verified by back extraction of nucleotide using 6M urea and evaluation of nucleotide peaks by HPLC using an ion-exchange column. The assay is performed in a clear 384-well plate (Costar) by combining GTP-loaded K-Ras proteins (50 mM final) with 2-amino-6-mercapto-7-methylpurine ribonucleoside (MESG) (200 mM final), and purine nucleotide phosphorylase (5 U/ml final). GTP hydrolysis is initiated by the addition of MgCb at a working concentration of 40 mM. For GAP stimulation, Ras p21 protein activator 1 (P120GAP) can be included at 50 mM. Absorbance at 360 nm canbe measured every 8 to 15 s for 1,000 s at 20 °C. Samples are tested with or without a subject compound disclosed herein to assess each compound’s ability to inhibit signaling of a given Ras protein (e.g., a given mutant Kras) of interest.
EXAMPLE 8: Nucleotide exchange assay
[00698] The ability of a compound of the present disclosure to inhibit a Ras protein signaling can be demonstrated by a reduced nucleotide exchange activity. This assay can be also used to assess a selective inhibition of a mutant Ras protein relative to a wildtype, or relative to a different mutant Ras protein. For example, 250 nM or 500 nM GDP-loaded K-Ras proteins (e.g., wildtype or a mutant thereof including those mentioned in Example 7), each is incubated with different concentrations of compounds (for example -60 mM, ~20 mM, -6.7 pM, ~2.2 pM, -0.7 pM, -0.2 pM subject compound). A control reaction without subject compound is also included. SOS1 (catalytic domain) protein is added to the K-Ras protein solution. The nucleotide exchange reaction is initiated by adding fluorescent labelled GDP (Guanosine 5 ’-Diphosphate, BODIPY™ FL 2’-(or-3’)-0-(N-(2-Aminoethyl) Urethane) to a final concentration of 0.36 pM. Fluorescence is measured every 30 s for 70 minutes at 490nm/515nm (excitation/emission) in a MIOOOPro plate reader (Tecan). Data is exported and analyzed to calculate an IC50 using GraphPad Prism (GraphPad Software). Sample(s) can be tested with or without a subject compound disclosed herein including compound(s) exemplified in Table 1 to assess compound’s ability to inhibit K-Ras signaling or its IC50 against a given Ras protein (e.g., a given mutant K-Ras) of interest.
EXAMPLE 9: Testing for modification of Ras protein
[00699] Test compounds are prepared as 10 mM stock solutions in DMSO (Fisher cat#BP231-100). KRAS protein (e.g., His-tagged GDP-loaded wildtype 1-169, His-tagged GDP-loaded G12C 1-169, His-tagged GDP-loaded G12D 1-169, or His-tagged GDP-loaded G12S 1-169) is diluted to -2 pM in appropriate buffer (e.g., a Hepes buffer at physiological conditions). For testing KRAS modification, compounds are diluted to 50X final test concentration in DMSO in 96- well storage plates. 1 pi of the diluted 50X compounds are added to appropriate wells in the PCR plate (Fisher cat#AB-0800). -49 pi of the stock protein solution is added to each well of the 96-well PCR plate. Reactions are mixed carelully. The plate is sealed well with aluminum plate seal, and stored in drawer at room temperature for 24hrs. 5 pi of 2% formic acid (Fisher cat#Al 17-50) in MilliQ H20 is then added to each well followed by mixing with a pipette. The plate is then resealed with aluminum seal and stored until mass spectrometry analysis.
The extent of covalent modification of KRAS proteins can be determined by liquid chromatography electrospray mass spectrometry analysis of the intact proteins on a Thermo Q-Exactive Plus mass spectrometer. 20 pi of sample is injected onto a bioZen 3.6 pm Intact C4 column (Phenomenex cat#00B-4767-AN) placed in a column oven set to 40°C and separated using a suitable LC gradient from -20% to -60% solvent B. Solvent A isis 0.1% formic acid and solvent B is 0.1% formic acid in acetonitrile. HESI source settings are set to 40, 5 and 1 for the sheath, auxiliary and sweep gas flow, respectively. The spray voltage is 4 kV, and the capillary temperature is 320°C. S-lens RF level is 50 and auxiliary gas heater temperature is set to 200°C. The mass spectrometry is acquired using a scan range from 650 to 1750 m/z using positive polarity at a mass resolution of 70,000, AGC target of le6 ions and maximum injection time of 250ms. The recorded protein mass spectrum is deconvoluted from the raw data file using Protein Deconvolution v4.0 (Thermo). The protein mass and adduct masses are exported with their peak intensities. The peak intensities for the unmodified and modified protein are used to calculate the percent covalent modification of the KRAS protein based on the following equation: %KRAS protein modification = ((KRAS-compound) / (KRAS) + (KRAS-Compound)) *100. EXAMPLE 10: Ras cellular assay
[00700] 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. For example, this assay can be also used to assess a selective growth inhibition of a mutant Ras protein relative to a wildtype, or relative to a different mutant Ras protein. a. Growth of cells with K-Ras G12C mutation
[00701] 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.
[00702] On a first day (e.g., Day 1), Softagar (Select Agar, Invitrogen, 3% in ddH20 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% C02.
[00703] 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% C02. 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%). [00704] On a tenth 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. b. Growth of cells with K-Ras G12D mutation
[00705] ASPC-1 (ATCC CRL-1682), Panc-10.05 (ATCC CRL-2547), A427, GP2d cell lines or any other cell lines comprising a G12D mutation and can be used to assess Ras cellular signaling in vitro, e.g., in response to the compounds herein. For example, ASPC-1 culture medium is prepared with RPMI-1640 and 10% heat-inactivated FBS. Panc-10.05 culture medium is prepared with RPMI-1640, 10 Units/ml human recombinant insulin, and 10% FBS. A427 cell culture is prepared with RPMI-1640 and 10% heat-inactivated FBS. A CellTiter-Glo (CTG) luminescent based assay (Promega) is used to assess growth of the cells, as a measurement of the ability of the compounds herein to inhibit Ras signaling in the cells. The cells (e.g., 800 per well) are seeded in their respective culture medium in standard tissue culture-treated 384-well format plates (Falcon #08-772-116) or ultra-low attachment surface 384-well format plates (S-Bio # MS-9384UZ ). The day after plating, cells are treated with a dilution series (e.g., a 9 point 3-fold dilution series) of the compounds herein (e.g., approximately 40 mΐ final volume per well). Cell viability can be monitored (e.g., approximately 5 days later) according to the manufacturer’s recommended instructions, where the CellTiter-Glo reagent is added (e.g., approximately 10 mΐ), vigorously mixed, covered, and placed on a plate shaker (e.g., approximately for 20 min) to ensure sufficient cell lysis prior to assessment of luminescent signal. 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. 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. The ability of one or more compounds exemplified in Table 6 to inhibit growth of one or more cell lines comprising a given Kras mutation is demonstrated utilizing the procedures described above. Corresponding assays for other mutants (e.g., G12S, G12C, G12V, G13D, G13S, G13C, or G13V) are conducted in a similar manner with appropriate cell lines.
EXAMPLE 11: In vivo Ras inhibition
[00706] The in vivo reduction in Ras signaling output by a compound of the present disclosure is determined in a mouse tumor xenograft model, (e.g., in a K-Ras mutant (G12D, G12S, G12C, G12V, G13D, G13S, G13C, or G13V) model utilizing cells including a KRas G12D mutant (e.g., G12D, G12S, G12C, G12V, G13D, G13S, G13C, or G13 V) to generate a xenograft model comparable to the xenograft model exemplified below.
Xenograft with K-Ras G12C mutation
[0001] 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.
[0002] 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 lxlOE7 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 a subject compound disclosed herein 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.
[0003] 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 identity 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 = (p * 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.
Xenograft with K-Ras G12D mutation
[0004] In another example, tumor xenografts are established by administration of tumor cells with K-Ras mutation (e.g. G12D, G12S, G12C, G12V, G13D, G13S, G13C, or G13V) (e.g., ASPC-1 cells) into mice. Female 6- to 8-week-old athymic BALB/c nude (NCr) nu/nu mice are used for xenografts. The tumor cells (e.g., approximately 5xl06) are harvested on the day of use and injected in growth-factor-reduced Matrigel/PBS (e.g.,
50% final concentration in 100 mΐ). One flank is inoculated subcutaneously per mouse. Mice are monitored daily, weighed twice weekly, and caliper measurements begin when tumors become visible. For efficacy studies, animals are randomly assigned to treatment groups by an algorithm that assigns animals to groups to achieve best case distributions of mean tumor size with lowest possible standard deviation. Tumor volume can be calculated by measuring two perpendicular diameters using the following formula: (L x w2) / 2 in which L and w refer to the length and width tumor diameter, respectively. Percent tumor volume change can be calculated using the following formula: (Vfinai -VinitiaD/Vmitiai x 100. Percent of tumor growth inhibition (%TGI) can be calculated using the following formula: %TGI = 100 x (1 - (average Vfinai -Vinitiai of treatment group) / (average Vfmai -VmMai of control group). When tumors reach a threshold average size (e.g., approximately 200-400 mm3), mice are randomized into 3-10 mice per group and are treated with vehicle (e.g., 100% Labrasol®) or a subject compound disclosed herein using, for example, a daily schedule by oral gavage. Results can be expressed as mean and standard deviation of the mean.
Example 12: Metabolic (Microsomal) Stability Assay
[0005] The metabolic stability of the test compound is assayed at 37 °C using pooled liver microsomes (mouse or human liver microsomes). An aliquot of 10 pL of 50 mM test compound is mixed with 490 pL of 0.611 mg/mL liver microsomes, and then, 50 pL of the mixtures are dispensed to the 96 well tubes and warmed at 37°C for 10 minutes. The reactions are initiated by adding 50 pL of the pre-warmed NADPH regeneration system solution (add 1.2 pL solution, 240 mΐ solution B, mix with 10.56 ml KPBS) and then incubated at 37°C. The final incubation solution contains 100 mM potassium phosphate (pH 7.4), 1.3 mM NADP+, 3.3 mM glucose 6-phosphate, 0.4 Unit/mL of glucose 6-phosphate dehydrogenase, 3.3 mM magnesium chloride, 0.3 mg/mL liver microsomes and 0.5 pM test article. After 0, 15, 30 and 60 minutes in a shaking incubator, the reactions are terminated by adding 100 pL of acetonitrile containing 200 nM buspirone as an internal standard. All incubations are conducted in duplicate. Plates are vortexed vigorously by using Fisher Scientific microplate vortex mixer (Henry Troemner, US). Samples are then centrifuged at 3500 rpm for 10 minutes (4 °C) using Sorvall Legend XRT Centrifuge (Thermo Scientific, GE). Supernatants (40 pL) are transferred into clean 96-deep well plates. Each well is added with 160 pL of ultrapure water (Milli-Q, Millipore Corporation) with 0.1% (v/v) formic acid (Fisher Chemical), mixed thoroughly and subjected to LC/MS/MS analysis in MRM positive ionization mode.
[0006] All the samples are measured using a mass spectrometer (QTrap 5500 quadrupole/ion trap) coupled with a Shimadzu HPLC system. The HPLC system consisted of a Shimadzu series degasser, binary quaternary gradient pumps, column heater coupled to an autosampler, and a Phenomenex Gemini-NX, C18, 3.0 pm or Phenomenex Lunar, C8, 5.0 mM HPLC column (Phenomenex, Torrance, CA), and eluted with a mobile phase gradient consisting of Solution A (0.1% formic acid water) and Solution B (0.1% formic acid acetonitrile). The column temperature is maintained at 40 °C. All the analytes are detected with positive-mode electrospray ionization (ES+).
[0007] The half-life for the metabolic degradation of the test compound is calculated by plotting the time-course disappearance of the test compound during the incubation with liver microsomes. Each plot is fitted to a first-order equation for the elimination of the test compound (% remaining compound) versus time using non-linear regression (Equation 1).
Equation 1 : where Ct is the mean relative substrate concentration at time t and Co is the initial concentration (0.5 pM) at time 0. Note that the area ratio of the substrate peak to an internal standard peak is proportional to the analyte concentration and are used for regression analysis to derive a value of k.
[0008] The half-life tm for metabolic (microsome) stability is derived from the test compound elimination constant k using Equation 2 below.
Equation 2:
_ 0.693 tl/2 ~k~
Example 13: Mouse and Human Protein Binding Assay to Assess Free Drug Concentration [0009] The assay is to determine the plasma protein binding of the test compound in the plasma of human and animal species using a Rapid Equilibrium Dialysis (RED) device for equilibrium dialysis and LC-MS/MS for sample analysis. Test compound is spiked in. The stock solution of the test compound is prepared at 5 mM concentration. One pL of 5 mM working solution into 1000 mΐ plasma. The final concentration is 5 mM. The spiked plasma is placed on a rocker, and gently agitated for approximately 20 minutes. A volume of 300 pL of the plasma sample containing 5 pM test compound from each species is added to designate RED device donor chambers followed by addition of 500 pL of potassium phosphate buffer to the corresponding receiver chambers in duplicate. The RED device is then sealed with sealing tape and shaken at 150 RPM for 4 hours at 37 °C. Post-dialysis donor and receiver compartment samples are prepared for LC-MS/MS analysis, including spiking samples with an internal standard for the bioanalytical analysis. Warfarin and propranolol are purchased from Sigma-Aldrich (St. Louis,
MO), and used as positive controls for low and high plasma protein binding, respectively.
[0010] All the samples are analyzed using an Agilent Technologies 6430 Triple Quad LC/MS system. The HPLC system consisted of Agilent 1290 Infinity Liquid Chromatograph coupled to an autosampler (Agilent 1290 Infinity LC Injector HTC), and a Phenomenex Gemini-NX, C18, 3.0 pm or Phenomenex Lunar, C8, 5.0 pM HPLC column (Phenomenex, Torrance, CA), and eluted with a mobile phase gradient consisting of Solution A (0.1% formic acid water) and Solution B (0.1% formic acid acetonitrile). The column temperature is maintained at 40 °C. All the analytes are detected with positive-mode electrospray ionization (ES+). The percentage of the test compound bound to plasma is calculated following Equation 3 and 4.
Equation 3 100
Equation 4
% Plasma protein bound test compound = 100 — % Free test compound
[0011]

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Wherein
W is C(O), S(O), or S(0)2;
V is C(R17) and J is C(R16), or V is C(R17) and J is N, or J is C(R17) and V is C(R16), or J is C(R17) and V is N;
R10 is -L7-R7;
L7 is a bond, -0-, -N(R14)-, -C(0)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -
N(R14)S(0)-, -N(R14)S(0)2-, Ci-Cealkyl, C2-C6alkenyl, or C2-Cealkynyl, wherein Ci-Cealkyl, C2-C6alkenyl, and C2-
Cealkynyl, are optionally substituted with one, two, or three R20a;
R7 is a 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl, wherein the 3-12 membered nitrogen containing heterocycloalkyl or 5-12 membered nitrogen containing heteroaryl are optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6; wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, Gs-naryl, or Ci-nheteroaryl, wherein the C3-i2cycloalkyl, Ci-iiheterocycloalkyl, Gs-naryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a; wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-s>heterocycloalkyl, C6-ioaryl, and Ci-dictcroaryl are optionally substituted with one, two, or three R20a;
R6 is -L2-R5; each L2 is independently selected from a bond, Ci-Cealkyl, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -C(0)N(R14)-, -S-, - S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, -N(R14)C(0)0-, and - N(R14)C(0)N(R14)-; each R5 is independently hydrogen, or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS protein; R8 is selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaiyl, -OR12, -SR12, -N(H)(R12), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), - N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), - CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C^alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20c;
R17 is -L3-R19;
L1 is selected from a bond, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, -
C(0)N(R14)-, -S-, -S(0)2-, -S(0)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, -OCON(R14)-, - N(R14)C(0)0-, N(Rle), C(0)N(Rlc), S(0)2N(Rlc), S(0)N(Rlc), C(Rlf)(Rlg)0, C(Rlf)(Rlg)N(Rlc), and C(Rlf)(Rlg);
Rle, Rlf, and Rlg are independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201;
Rlc is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R201
R19 is selected from a C3-i2cycloalkyl, C2-nheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl, wherein the C3- ncycloalkyl, C2-iiheterocycloalkyl, C6-i2aryl, and C2-i2heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R11; each R11 is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, - 0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R201;
R16 is selected from hydrogen, halogen, -CN, Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci-gheteroaryl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), - N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, - C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, and - CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,- loaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20g; R2 is -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, - S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, -CH2S(0)2R15, -CH2S(0)2N(R12)(R13), - (Ci-C6alkyl)-R12b, -(C2.6alkenyl)-R12b, -(C2.6alkynyl)-R12b, -0-R12a, -N(R14)-R12b, -S-R12b, -(C3. iocycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-ioaryl)-R12b, or -(Ci-9heteroaryl)-R12b, wherein said Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d;
R12a is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d;
R12b is selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, -CH2-C3-iocycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d;
X is C(R3) or N;
R3 is selected from hydrogen, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, Ce-ioaiyl, Ci-9heteroaiyl, -OR12, -SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), - N(R14)C(0)0R15, -N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), - CH2N(R14)C(0)R15, -CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three j^20b. each R12 is independently selected from hydrogen, Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-
6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci^alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci^alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R20f; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, and R201 are each independently selected from halogen, oxo, -CN, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2. gheterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, Ci-gheteroaryl, -OR21, -SR21, -N(R22)(R23), - C(0)0R22, -C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), - N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and -0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2. gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci-ghaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, -C(0)N(R22)(R23), - C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, - N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; each R25 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, G,. ioaryl, and Ci-gheteroaryl; and indicates a single or double bond such that all valences are satisfied.
2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R3).
3. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.
4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R16) and V is C(R17).
5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein W is C(O).
6. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure: , IA12).
7. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the structure : ,
8. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure: Formula (IA1).
9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein L7 is a bond.
10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein L7 is -NH-.
11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is a 3-12 membered nitrogen containing heterocycloalkyl, wherein the 3-12 membered nitrogen containing heterocycloalkyl is optionally substituted with one or more R1, optionally substituted with one or more R4, and optionally substituted with one or more R6; and wherein two substituents selected from R1, R4, and R6 that are bonded to the same or adjacent atoms are optionally joined to form a C3-i2cycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl, wherein the C3- ncycloalkyl, Ci-nheterocycloalkyl, C6-i2aryl, or Ci-nheteroaryl are optionally substituted with one, two, or three R20a.
12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein p is an integer from 0 to 12;
X1 is selected from CH2, C(R4)(R6), C=N-OR4, C=NN(R4)(R6), C(0)N(R4), N(R4), N(R6), O, S, S(O), S(=0)(=NR4), S(0)2N(R4), N(R4)S(0)N(R4), N(R4)S(0)2N(R4), S(0)N(R4), 0C(0)N(R4), N(R4)C(0)N(R4), S(0)2, CH2C(R4)(R6), CH2C(R4)(R6)CH2, C(R4)(R6)C(R4)(R6)C(R4)(R6), C(R4)(R6)C=N-OR4, CH2C=NN(R4)(R6), C(R4)(R6)C(0)N(R4), C(R4)(R6)N(R4), C(R4)(R6)N(R6), C(R4)(R6)0, C(R4)(R6)OC(R4)(R6), C(R4)(R6)S, C(R4)(R6)SC(R4)(R6), C(R4)(R6)S(0), C(R4)(R6)S(0)C(R4)(R6), C(R4)(R6)S(0)2C(R4)(R6), C(R4)(R6)S(=0)(=NR4), C(R4)(R6)S(0)2N(R4), C(R4)(R6)N(R4)S(0)N(R4), C(R4)(R6)N(R4)S(0)2N(R4), C(R4)(R6)S(0)N(R4), C(R4)(R6)0C(0)N(R4), C(R4)(R6)N(R4)C(0)N(R4), C(R4)(R6)S(0)2, C=NN(R4)(R6)C(R4)(R6), C(0)N(R4)C(R4)(R6), S(0)2N(R4)C(R4)(R6), S(0)N(R4)C(R4)(R6), 0C(0)N(R4)C(R4)(R6), C(R4)(R4), C=N-OR4, C=NN(R4)(R4), CH2C(R4)(R4), CH2C(R4)(R4)CH2, C(R4)(R4)C(R4)(R6)C(R4)(R4), C(R4)(R4)C(R4)(R4)C(R4)(R4), C(R4)(R4)C=N-OR4, CH2C=NN(R4)(R4), C(R4)(R4)C(0)N(R4), C(R4)(R4)N(R4), C(R4)(R4)N(R6), C(R4)(R4)0, C(R4)(R4)OC(R4)(R4), C(R4)(R4)S, C(R4)(R4)SC(R4)(R4), C(R4)(R4)S(0), C(R4)(R4)S(0)C(R4)(R4), C(R4)(R4)S(0)2C(R4)(R4), C(R4)(R4)S(=0)(=NR4), C(R4)(R4)S(0)2N(R4), C(R4)(R4)N(R4)S(0)N(R4), C(R4)(R4)N(R4)S(0)2N(R4), C(R4)(R4)S(0)N(R4), C(R4)(R4)0C(0)N(R4), C(R4)(R4)N(R4)C(0)N(R4), C(R4)(R4)S(0)2, C=NN(R4)(R4)C(R4)(R4), C(0)N(R4)C(R4)(R4), S(0)2N(R4)C(R4)(R4), S(0)N(R4)C(R4)(R4), and 0C(0)N(R4)C(R4)(R4);
X2 is selected from N, C, C(R6), C(R4), CH, N(R'). N(R4), N(R6), O, S, S(O), C(H)(R6), C(R4)2, CH2, C(R4)(R6), S(=0)(=NR4), S(0)2; and X3 is selected from N, C, C(R6), and C(R4).
13. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein
14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from hydrogen and halogen.
15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from hydrogen and fluoro.
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from Ci-6alkyl, C3-iocycloalkyl, and C2-s>heterocycloalkyl, wherein Ci-6alkyl, C3-iocycloalkyl, and C2-s>heterocycloalkyl are optionally substituted with one, two, or three R20c independently selected from halogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, and C2-9heterocycloalkyl.
17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl, wherein said methyl, cyclopropyl, cyclobutyl, and oxetanyl are optionally substituted with one, two, or three R20c independently selected from fluoro, methyl, cyclopropyl, cyclobutyl, and oxetanyl.
18. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from methyl, cyclopropyl, cyclobutyl, and oxetanyl.
19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen or CN.
20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is a bond.
21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is selected from a Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -C(O)-, -NHC(O)-, -C(0)NH-, CH20, CH2NH, and CH2.
22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a monocyclic ring.
23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a bicyclic ring system.
24. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is a polycyclic ring system.
25. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is:
Q1, Q3, and Q5 are independently N or C(Rld);
Q4 and Q6 are independently O, S, C(Rla)(Rlb), or N(Rlc);
X4, X5, X6, X9, X10, X11, X12, and X16 are independently selected from C(Rla) or N;
X7 and X8 are independently selected from C(Rla), C(Rla)(Rlb), N, or N(Rlc);
X13 is selected from a bond, C(O), C(Rla)(Rlb), C(0)C(Rla)(Rlb), C(Rla)(Rlb)C(Rla)(Rlb), C(Rla)(Rlb)N(Rlc), and N(Rlc);
X14 and X15 are independently selected from a bond, C(O), C(Rla)(Rlb), and N(Rlc); each Rla, Rlb, Rld, Rlf, Rlg, and Rlh are each independently selected from hydrogen, halogen, -CN, Ci-6alkyl, Ci- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-dictcroarvl. -OR12, - SR12, -N(R12)(R13), -C(0)0R12, -0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)R15, -0C(0)R15, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), -N(R14)C(0)R15, - S(0)2R15, -S(0)2N(R12)(R13)-, S(=0)(=NH)N(R12)(R13), -CH2C(0)N(R12)(R13), -CH2N(R14)C(0)R15, - CH2S(0)2R15, and -CH2S(0)2N(R12)(R13), wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, and Cj-dictcroaryl are optionally substituted with one, two, or three R201; or Rla and Rlb bonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or two Rla bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6-ioaryl ring, 5-12 membered heteroaryl ring, or C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlh and one of Rla, Rlb, Rlc, and Rld bonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, or a C3-iocycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6-ioaryl ring, a 5-12 membered heteroaryl ring, and C3-iocycloalkyl ring are optionally substituted with one, two, or three R201; or Rlf and Rlg are joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R201; and each Rlc is independently selected from hydrogen, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, Ci-dictcroarvl. wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C2- dictcrocycloalkyl. C6-ioaryl, and Cj-dictcroaryl are optionally substituted with one, two, or three R201.
6. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein
27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or solvate thereof, wherein R2
28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein each L2 is independently a bond.
29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein each R5 is independently selected from:
30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is independently -C(0)R15.
31. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein said R15 is independently selected from C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, and Ciohctcroaiy l. wherein C2- 6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20f.
32. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein said R15 is independently C2-6alkenyl, wherein C2-6alkenyl is optionally substituted with one, two, or three R20f.
33. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein said R15 is independently C2-9heterocycloalkyl, wherein C2-9heterocycloalkyl is optionally substituted with one, two, or three R20f.
34. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein said R15 is independently Ci-gheteroaryl, wherein Ci-gheteroaryl is optionally substituted with one, two, or three R20f.
35. The compound of one of claims 30-34, or a pharmaceutically acceptable salt or solvate thereof, wherein said R4 is an electrophilic moiety capable of forming a covalent bond with a cysteine, serine, or aspartate residue at an amino acid position corresponding to 12 or 13 of a human KRAS protein.
36. A compound having the formula A-LAB-E> wherein
A is a monovalent form of a compound of one of claims 1 to 35; LAB is a covalent linker bonded to A and B; and B is a monovalent form of a degradation enhancer.
37. The compound of claim 36 wherein 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, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBX04, FBX031, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885.
38. The compound of claim 36 wherein 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, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.
39. The compound of any one of claims 36 to 38, wherein LAli is -LAm-LAli2-LAli3-LAli4-LAli3-: independently a bond, -0-, -N(R14)-, -C(O)-, -N(R14)C(0)-, - C(0)N(R14)-, -S-, -S(0)2-, -S(O)-, -S(0)2N(R14)-, -S(0)N(R14)-, -N(R14)S(0)-, -N(R14)S(0)2-, Ci-6alkylene, (-0-Ci-6alkyl)z-, (-Ci-6alkyl-0)z-, C2-6alkenylene, C2-6alkynylene, Ci-6haloalkylene, C3-i2cycloalkylene, Ci- liheterocycloalkylene, C6-i2arylene, or Ci-nheteroarylene, wherein Ci-6alkylene, C2-6alkenylene, C2. 6alkynylene, Ci-6haloalkylene, C3-i2cycloalkylene, Ci-iiheterocycloalkylene, C6-i2arylene, or Ci- nheteroarylene,are optionally substituted with one, two, or three R20j; wherein each Ci-6alkyl of (-O-Ci- 6alkyl)z- and (-Ci-6alkyl-0)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, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2- C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-CI- gheteroaryl, and CiHictcroarvl. wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-CI- gheteroaryl, and C’lHictcroarvl are optionally substituted with one, two, or three R20d; each R13 is independently selected from hydrogen, Ci-6alkyl, and Ci-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 R20e; each R14 is independently selected from hydrogen, Ci-6alkyl, and Ci-6haloalkyl; each R15 is independently selected Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl are optionally substituted with one, two, or three R20f; each R20d, R20e, R20f, and R20j are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-
6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, - CH2-C6-ioaryl, -CH2-Ci-9heteroaiyl, Ci-9heteroaiyl, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), -0CH2C(0)0R22, and - 0C(0)R25, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-ioaryl, -CH2-C6-ioaryl, -CH2-Ci-9heteroaryl, and Ci- gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-ealkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(0)0R22, - C(0)N(R22)(R23), -C(0)C(0)N(R22)(R23), -0C(0)N(R22)(R23), -N(R24)C(0)N(R22)(R23), -N(R24)C(0)0R25, -N(R24)C(0)R25, -N(R24)S(0)2R25, -C(0)R25, -S(0)2R25, -S(0)2N(R22)(R23), and -0C(0)R25; each R21 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R22 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-gheteroaryl; each R23 is independently selected from H and Ci-6alkyl; each R24 is independently selected from H and Ci-6alkyl; and each R25 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl.
40. The compound of any one of claims 36 to 38, wherein LAB is -(0-C2alkyl)z- and z is an integer from 1 to 10.
41. The compound of any one of claims 36 to 38, wherein LAB is -(C2alkyl-0-)z- and z is an integer from 1 to 10.
42. The compound of any one of claims 36 to 38, wherein LAB is -(CH2)ZILAB2(CH20)Z2-, wherein LAB2 is a bond, a 5 or 6 membered heterocycloalkylene or heteroarylene, phenylene, -(C2-C4)alkynylene, -SO2- or -NH-; and zl and z2 are independently an integer from 0 to 10.
43. The compound of any one of claims 36 to 38, wherein LAB is -(CH2)ZI(CH20)Z2-, wherein zl and z2 are each independently an integer from 0 to 10.
44. The compound of any one of claims 36 to 38, wherein LAB is a PEG linker.
45. The compound of any one of claims 36 to 44, wherein B is a monovalent form of a compound selected from
HVYV JV HY oV-"V a
46. A pharmaceutical composition comprising a compound of any one of claims 1 to 45 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
47. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof.
48. A method of modulating activity of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.
49. The method of one of claims 47-48 comprising administering an additional agent or therapy.
50. A method of inhibiting cell growth, comprising administering an effective amount of a compound of one of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells.
51. The method of claim 50 comprising administering an additional agent to said cell.
52. A Ras protein bound by a compound of one of claims 1 to 45, or a pharmaceutically acceptable salt or solvate thereof, wherein activity of said Ras protein is reduced as compared to a Ras protein unbound to said compound.
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