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WO2024173234A1 - Inhibitors of parg - Google Patents

Inhibitors of parg Download PDF

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Publication number
WO2024173234A1
WO2024173234A1 PCT/US2024/015371 US2024015371W WO2024173234A1 WO 2024173234 A1 WO2024173234 A1 WO 2024173234A1 US 2024015371 W US2024015371 W US 2024015371W WO 2024173234 A1 WO2024173234 A1 WO 2024173234A1
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WO
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Prior art keywords
alkyl
alkenyl
independently selected
cycloalkyl
membered heteroaryl
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Application number
PCT/US2024/015371
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French (fr)
Inventor
Katherine Widdowson
Paul Chang
Xijun QIAN
Yanli Wang
Enwang TAN
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ARase Therapeutics Inc
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ARase Therapeutics Inc
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Publication of WO2024173234A1 publication Critical patent/WO2024173234A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to sulfonamides and related compounds which are inhibitors of PARG and are useful in the treatment of cancer.
  • BACKGROUND OF THE INVENTION Cancer is a disease caused by abnormal and unregulated cell division.
  • One of the hallmarks of cancer is the up or downregulation of cellular stress pathways which the cancer cells or tumor use for a proliferative advantage. These cellular stress pathways often include, but are not limited to, oxidative stress, DNA damage stress, DNA replicative stress, transcriptional stress, hypoxia, and others.
  • ADP-ribose as well as the enzymes that generate ADP-ribose (Poly(ADP-ribose) polymerases or PARPs) and hydrolyze ADP-ribose (Poly(ADP-ribose) glycohydrolases or PARGs), play critical roles in regulating cellular stress responses.
  • ADP-ribose There are two forms of ADP-ribose in the cell, mono(ADP-ribose) (MAR) and Poly(ADP-ribose) (PAR). Both forms of ADP-ribose are generated by a family of 17 PARP proteins, whose key roles in the cell are to regulate cellular stress responses (Cohen MS, Chang P. Nat Chem Biol. 2018).
  • PARG exists as a single gene with 3 splicing isoforms. These isoforms function in and are localized to the nucleus, cytoplasm, and mitochondria. The best understood function for PARG is in DNA damage repair. However, PARG also regulates gene splicing, transcriptional and epigenetic pathways (Bock FJ, Todorova TT, Chang P. Mol Cell 2015) (Le May, Litis et al. Mol Cell. 2012) (Dahl, Maturi et al. Plos One, 2014) (Guastafierro, Catizone et al. Biochem J 2013) (Caiafa, Guastafierro et al.
  • MAR and PAR levels have been shown to be effective treatments for multiple cancers.
  • Inhibiting ADP-ribose synthesis through the use of PARP inhibitors can be used for the treatment of multiple cancer types.
  • PARG inhibitors work by modulating cellular stress responses such as the DNA damage response (DDR) and the replicative stress response. DDR and replicative stress are very important cellular stress responses for cancers because they are a consequence of all cellular stress responses, thus many cancers have them.
  • DDR DNA damage response
  • replicative stress are very important cellular stress responses for cancers because they are a consequence of all cellular stress responses, thus many cancers have them.
  • SSBs single-strand breaks
  • PARP1 single strand break repair
  • BER base excision repair
  • PARP1 recognizes the break, binds to it, and rapidly synthesizes PAR onto itself (automodification) and histone proteins.
  • Multiple DNA repair proteins including a master regulator XRCC1, bind to and are recruited to the newly synthesized PAR and then repair the break (Mortusewicz, Fouquerel et al. Nucleic Acid Res. 2011).
  • RNA interference RNA interference
  • This invention seeks to provide cell permeable inhibitors of PARG.
  • the present invention is directed to a compound of Formula I: I or a pharmaceutically acceptable salt thereof, wherein constituent members are defined below.
  • Attorney Docket No.: 53238-0003WO1 The present invention is further directed to a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention is further directed to a method of inhibiting the activity of PARG comprising contacting a compound of Formula I, or a pharmaceutically acceptable salt thereof, with PARG.
  • the present invention is further directed to a method of treating a disease or disorder in a patient in need of treatment, where the disease or disorder is characterized by overexpression or increased activity of PARG, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention is further directed to a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits PARG activity, such as a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides uses of the compounds described herein in the manufacture of a medicament for use in therapy.
  • the present disclosure also provides the compounds described herein for use in therapy.
  • the present invention is directed to a compound of Formula I: I or a pharmaceutically acceptable salt thereof, wherein: Q is NH or CH 2 ; A is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy 1 , Cy 1 -C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl- C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10
  • Q is NH. In some embodiments, Q is CH 2 .
  • A is C 1-6 alkyl. In some embodiments, A is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a ,
  • A is C 2-6 alkenyl. In some embodiments, A is C 2-6 alkenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a , embodiments, A is C 2-6 alkynyl.
  • A is C 2-6 alkynyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 Attorney Docket No.: 53238-0003WO1 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a , embodiments, A is Cy 1 .
  • A is Cy 1 -C 1-4 alkyl-. In some embodiments, integer selected from 0, 1, 2, 3, 4, and 5.
  • B is a group of formula (a): In some embodiments, B is a group of formula (b): Attorney Docket No.: 53238-0003WO1 (b). In some embodiments, B is a group of formula (c): (c).
  • B is a group of formula (d): In some embodiments, B is a group of formula (e): In some embodiments, B is a group of formula (f): In some embodiments, B is a group of formula (a), formula (c), or formula (f): Attorney Docket No.: 53238-0003WO1 integer selected from 0, 1, 2, 3, 4, and 5; and B is a group of formula (a), formula (c), or formula (f): integer selected from 0, 1, 2, 3, 4, and 5; and B is a group of formula (a): In some embodiments, 3, 4, and 5; and B is a group of formula (c): Attorney Docket No.: 53238-0003WO1 In some embodiments, integer selected from 0, 1,, 3, 4, and 5; and B is a group of formula (f): In some embodiments, X 1 is N.
  • X 1 is CR 1 .
  • X 2 is N.
  • X 2 is CR 2 .
  • X 3 is N.
  • X 3 is CR 3 .
  • X 4 is N.
  • X 4 is CR 4 .
  • X 5 is N.
  • X 5 is CR 5 .
  • X 6 is N.
  • X 6 is CR 6 .
  • X 7 is N.
  • X 7 is CR 7 .
  • X 8 is N.
  • X 8 is CR 8 .
  • X 9 is N. In some embodiments, X 9 is CR 9 . In some embodiments, X 10 is N. In some embodiments, X 10 is CR 10 . In some embodiments, X 11 is N. In some embodiments, X 11 is CR 11 . In some embodiments, X 12 is N. In some embodiments, X 12 is CR 12 . In some embodiments, X 13 is N. In some embodiments, X 13 is CR 13 . In some embodiments, X 14 is N. In some embodiments, X 14 is CR 14 . In some embodiments, X 15 is N. In some embodiments, X 15 is CR 15 . In some embodiments, X 16 is N.
  • X 16 is CR 16 .
  • X 17 is N.
  • X 17 is CR 17 .
  • X 18 is N.
  • X 18 is CR 18 .
  • X 1 is CR 1
  • X 2 is CR 2
  • X 3 is CR 3 .
  • X 4 is CR 4
  • X 5 is CR 5
  • X 6 is CR 6 .
  • X 7 is CR 7
  • X 8 is CR 8
  • X 9 is CR 9 .
  • X 10 is CR 10
  • X 11 is CR 11
  • X 12 is CR 12
  • X 13 is CR 13
  • X 14 is CR 14
  • X 15 is CR 15
  • X 16 is CR 16
  • X 17 is CR 17
  • X 18 is CR 18 .
  • Z 1 is N.
  • Z 1 is C.
  • Z 2 is N.
  • Z 2 is C.
  • at least one Cy 1 is C 6-10 aryl.
  • At least one Cy 1 is C 6-10 aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy . In some embodiments, at least one Cy 1 is C 3-7 cycloalkyl. In some embodiments, at least one Cy 1 is C 3-7 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy . In some embodiments, at least one Cy 1 is 5-10 membered heteroaryl. In some embodiments, at least one Cy 1 is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy . In some embodiments, at least one Cy 1 is 4-10 membered heterocycloalkyl.
  • At least one Cy 1 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy . In some embodiments, at least one Cy 1 is C 3-7 cycloalkyl or 4-10 membered heterocycloalkyl. In some embodiments, at least one Cy 1 is C 3-7 cycloalkyl or 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy . In some embodiments, at least one Cy 1 is cyclopropyl. In some embodiments, at least one Cy 1 is cyclopropyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • At least one Cy 1 is cyclopropyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and CN.
  • at least one Cy 1 is 4-membered heterocycloalkyl.
  • at least one Cy 1 is 4-membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • at least one Cy 1 is oxetanyl.
  • at least one Cy 1 is oxetanyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • At least one Cy 1 is oxetanyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and CN.
  • R 1 is H.
  • R 1 is halo.
  • R 1 is C 1-4 alkyl.
  • R 2 is H.
  • R 2 is halo.
  • R 2 is C 1-4 alkyl.
  • R 4 is H.
  • R 4 is halo.
  • R 4 is C 1-4 alkyl.
  • R 5 is H.
  • R 5 is halo. In some embodiments, R 5 is C 1-4 alkyl.
  • R 7 is H. In some embodiments, R 7 is halo. In some embodiments, R 7 is C 1-4 alkyl.
  • R 8 is H. In some embodiments, R 8 is halo. In some embodiments, R 8 is C 1-4 alkyl.
  • R 10 is H. In some embodiments, R 10 is halo. In some embodiments, R 10 is C 1-4 alkyl.
  • R 11 is H. In some embodiments, R 11 is halo. In some embodiments, R 11 is C 1-4 alkyl. In some embodiments, R 13 is H.
  • R 13 is halo. In some embodiments, R 13 is C 1-4 alkyl. In some embodiments, R 14 is H. In some embodiments, R 14 is halo. In some embodiments, R 14 is C 1-4 alkyl. In some embodiments, R 16 is H. In some embodiments, R 16 is halo. In some embodiments, R 16 is C 1-4 alkyl. In some embodiments, R 17 is H. In some embodiments, R 17 is halo. In some embodiments, R 17 is C 1-4 alkyl. In some embodiments, R 3 is H. In some embodiments, R 3 is halo. In some embodiments, R 3 is OR a2 .
  • R 3 is NR c2 R d2 . In some embodiments, R 3 is C 6-10 aryl. In some embodiments, R 3 is C 3-7 cycloalkyl. In some embodiments, R 3 is C 3-7 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl- C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 ,
  • R 3 is H or 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C(O)R b2 .
  • R 3 is piperazinyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl
  • R 6 is H.
  • R 6 is halo.
  • R 6 is OR a2 .
  • R 6 is NR c2 R d2 .
  • R 6 is C 6-10 aryl.
  • R 9 is H. In some embodiments, R 9 is halo. In some embodiments, R 9 is OR a2 . In some embodiments, R 9 is NR c2 R d2 . In some embodiments, R 9 is C 6-10 aryl. In some embodiments, R 9 is C 3-7 cycloalkyl.
  • R 12 is H. In some embodiments, R 12 is halo. In some embodiments, R 12 is OR a2 . In some embodiments, R 12 is NR c2 R d2 . In some embodiments, R 12 is C 6-10 aryl. In some embodiments, R 12 is C 3-7 cycloalkyl.
  • R 15 is H. In some embodiments, R 15 is halo. In some embodiments, R 15 is OR a2 . In some embodiments, R 15 is NR c2 R d2 . In some embodiments, R 15 is C 6-10 aryl. In some embodiments, R 15 is C 3-7 cycloalkyl.
  • R 18 is H. In some embodiments, R 18 is halo. In some embodiments, R 18 is OR a2 . In some embodiments, R 18 is NR c2 R d2 . In some embodiments, R 18 is C 6-10 aryl. In some embodiments, R 18 is C 3-7 cycloalkyl.
  • R 1 is H and R 2 is H. In some embodiments, R 1 is H, R 2 is H, and R 3 is H. In some embodiments, R 1 is H, R 2 is H, and R 3 is H or 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C(O)R b2 . In some embodiments, R 1 is H, R 2 is H, and R 3 is piperazinyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C(O)R b2 .
  • R 1 is In some embodiments, R 4 is H and R 5 is H. In some embodiments, R 4 is H, R 5 is H, and R 6 is H. Attorney Docket No.: 53238-0003WO1
  • R 7 is H and R 8 is H. In some embodiments, R 7 is H, R 8 is H, and R 9 is H.
  • R 10 is H and R 12 is H. In some embodiments, R 11 is H, R 12 is H, and R 13 is H. In some embodiments, R 13 is H and R 14 is H. In some embodiments, R 13 is H, R 14 is H, and R 15 is H. In some embodiments, R 16 is H and R 17 is H.
  • R 16 is H
  • R 17 is H
  • R 18 is H.
  • R B1 is H.
  • R B1 is C 1-4 alkyl.
  • R B1 is C 1-4 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , halo, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, S(O) 2 R b3 , and S(O) 2 NR c3 R d3 .
  • R B1 is C 2-6 alkenyl.
  • R B1 is C 2-6 alkenyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , halo, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, In some embodiments, R C1 is C 1-6 alkyl. In some embodiments, R C1 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, R C1 is C 2-6 alkenyl. In some embodiments, R C1 is C 2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, R C1 is 5-membered heteroaryl.
  • R C1 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’.
  • R C1 is C 1-6 alkyl or C 2-6 alkenyl, wherein the C 1-6 alkyl or C 2-6 alkenyl is optionally substituted with 1, 2, 3, or 4 R’ C(O)NR c4 R d4 , C(O)OR a4 , and NR c4 R d4 .
  • R C1 is 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, and NR c4 C(O)R b4 .
  • R C1 is thiazolyl or 1,3,4-thiadiazolyl, optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-7 Attorney Docket No.: 53238-0003WO1 cycloalkyl, and NR c4 C(O)R b4 .
  • m is an integer selected from 0, 1, and 2.
  • R C2 is C 1-6 alkyl.
  • R C2 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’.
  • R C2 is C 2-6 alkenyl.
  • R C2 is C 2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’.
  • R C2 is 5-membered heteroaryl.
  • R C2 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’.
  • R C3 is C 1-6 alkyl.
  • R C3 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’.
  • R C3 is C 2-6 alkenyl.
  • R C3 is C 2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’.
  • R C3 is 5-membered heteroaryl.
  • R C3 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’.
  • R C3 is C 1-6 alkyl or C 2-6 alkenyl, wherein the C 1-6 alkyl or C 2-6 alkenyl is optionally substituted with 1, 2, 3, or 4 R’ C(O)NR c4 R d4 , C(O)OR a4 , and NR c4 R d4 .
  • R C3 is 5-membered heteroaryl, wherein the 5-membered heteroaryl is Attorney Docket No.: 53238-0003WO1 optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, and NR c4 C(O)R b4 .
  • R C3 is thiazolyl or 1,3,4-thiadiazolyl, optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, and NR c4 C(O)R b4 .
  • m is an integer selected from 0, 1, and 2.
  • R C4 is C 1-6 alkyl.
  • R C4 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’.
  • R C4 is C2-6 alkenyl.
  • R C4 is C 2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, R C4 is 5-membered heteroaryl. In some embodiments, R C4 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, R C5 is C 1-6 alkyl. In some embodiments, R C5 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, R C5 is C 2-6 alkenyl. In some embodiments, R C5 is C 2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, R C5 is 5-membered heteroaryl.
  • R C5 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’.
  • R C6 is H.
  • R C6 is C 1-6 alkyl.
  • R C6 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’.
  • R C6 is C 2-6 alkenyl.
  • R C6 is C 2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’.
  • R C6 is 5-membered heteroaryl.
  • R C6 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’.
  • R D1 is H. In some embodiments, R D1 is halo. In some embodiments, R D1 is C 1-4 alkyl. In some embodiments, R E1 is H. In some embodiments, R E1 is C 1-4 alkyl. In some embodiments, R E1 is C 1-4 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , halo, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, S(O) 2 R b3 , and S(O) 2 NR c3 R d3 . In some embodiments, R E1 is C 2-6 alkenyl.
  • R E1 is C 2-6 alkenyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy 2 , halo, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, In some embodiments, R E2 is H. In some embodiments, R E2 is C 1-6 alkyl.
  • R E2 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl- C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(O)OR
  • R E2 is C 2-6 alkenyl. In some embodiments, R E2 is C 2-6 alkenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , Attorney Docket No.: 53238-0003WO1 SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR
  • R E2 is 5-membered heteroaryl. In some embodiments, R E2 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl- C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2
  • R F1 is H. In some embodiments, R F1 is C 1-6 alkyl. In some embodiments, R F1 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl- C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,
  • R F1 is C 2-6 alkenyl. In some embodiments, R F1 is C 2-6 alkenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2
  • R F1 is 5-membered heteroaryl.
  • R F1 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl- C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered Attorney Docket No.: 53238-0003WO1 heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR
  • At least one R’ is CN. In some embodiments, at least one R’ is NO 2 . In some embodiments, at least one R’ is OR a4 . In some embodiments, at least one R’ is SR a4 . In some embodiments, at least one R’ is C(O)R b4 . In some embodiments, at least one R’ is C(O)NR c4 R d4 . In some embodiments, at least one R’ is C(O)OR a4 . In some embodiments, at least one R’ is OC(O)R b4 . In some embodiments, at least one R’ is OC(O)NR c4 R d4 .
  • At least one R’ is NR c4 S(O)R b4 . In some embodiments, at least one R’ is NR c4 S(O) 2 R b4 . In some embodiments, at least one R’ is NR c4 S(O) 2 NR c4 R d4 . In some embodiments, at least one R’ is S(O)R b4 . In some embodiments, at least one R’ is S(O)NR c4 R d4 . In some embodiments, at least one R’ is S(O) 2 R b4 . In some embodiments, at least one R’ is S(O) 2 NR c4 R d4 .
  • At least one Cy 2 is 5-10 membered heteroaryl. In some embodiments, at least one Cy 2 is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl- C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, S(O) 2 R b3 , and S(O) 2 NR c3 R d3 .
  • At least one Cy 2 is 4-10 membered heterocycloalkyl. In some embodiments, at least one Cy 2 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , In some embodiments, R c and R d , together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, CN, OR
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula II-B: II-B or a pharmaceutically acceptable salt thereof.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula III-C: III-C or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula III-B-2: or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula III-C-2: Attorney Docket No.: 53238-0003WO1 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-C: or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-F: or a pharmaceutically acceptable salt thereof, wherein p is an integer selected from 0, 1, 2, 3, and 4; and each R 3’ is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C( NR
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-A-1: IV-A-1 or a pharmaceutically acceptable salt thereof.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-D-1: Attorney Docket No.: 53238-0003WO1 IV-D-1 or a pharmaceutically acceptable salt thereof.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-A-2: or a pharmaceutically acceptable salt thereof.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-A: or a pharmaceutically acceptable salt thereof.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-E: V-E or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-A-2: Attorney Docket No.: 53238-0003WO1 or a pharmaceutically acceptable salt thereof.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-D-2: or a pharmaceutically acceptable salt thereof.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-C: Attorney Docket No.: 53238-0003WO1 VI-C or a pharmaceutically acceptable salt thereof.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-B-1: VI-B-1 or a pharmaceutically acceptable salt thereof.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-A-2: or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-B-2: VI-B-2 or a pharmaceutically acceptable salt thereof having Formula VI-B-2 or a pharmaceutically acceptable salt thereof.
  • Attorney Docket No.: 53238-0003WO1 provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-C-2: VI-C-2 or a pharmaceutically acceptable salt thereof.
  • Q is NH or CH 2 ;
  • A is C 1-6 alkyl, C 2-6 alkenyl, Cy 1 , Cy 1 -C 1-4 alkyl-, wherein said C 1-6 alkyl, and C 2-6 alkenyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered and S(O) 2 NR c R d
  • B is a group of formula (a), formula (b), formula (c), formula (d), formula (e), or formula (f): Attorney Docket
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein: Q is NH or CH 2 ; A is C 1-6 alkyl, C 2-6 alkenyl, Cy 1 , Cy 1 -C 1-4 alkyl-, wherein said C 1-6 alkyl, and C 2-6 alkenyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , B is a group of formula (a), formula (c), or formula (f): X 2 is N or CR 2 ; X 3 is N or CR 3 ; X 7 is N or
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein: Q is NH or CH 2 ; A is Cy 1 or Cy 1 -C 1-4 alkyl-; Attorney Docket No.: 53238-0003WO1 B is a group of formula (a), formula (c), or formula (f): X 2 is N or CR 2 ; X 3 is N or CR 3 ; X 7 is N or CR 7 ; X 8 is N or CR 8 ; X 9 is N or CR 9 ; X 16 is N or CR 16 ; X 17 is N or CR 17 ; X 18 is N or CR 18 ; wherein no more than two of X 1 , X 2 , and X 3 are simultaneously N; wherein no more than two of X 7 , X 8 , and X 9 are simultaneously N; wherein no more than two of X 16 , X 17 , and X 18 are simultaneously N; Z 1
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof selected from: 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((1S,2R)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide; 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((1R,2S)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide; 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((1R,2R)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide; 2-(5-
  • aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached Attorney Docket No.: 53238-0003WO1 to the rest of the molecule at any ring member as permitted by valency.
  • pyridinyl “pyridyl,” or “a pyridine ring” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.
  • n-membered where “n” is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is “n”.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazolyl is an example of a 5-membered heteroaryl ring
  • pyridyl is an example of a 6-membered heteroaryl ring
  • 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • each variable can be a different moiety independently selected from the group defining the variable.
  • the two R groups can represent different moieties independently selected from the group defined for R.
  • the phrase “optionally substituted” means unsubstituted or substituted.
  • substituted means that a hydrogen atom is replaced by a non-hydrogen group. It is to be understood that substitution at a given atom is limited by valency.
  • C 1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • alkyl refers to a saturated hydrocarbon group that may be straight-chain or branched. In some embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3- pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, and the like.
  • the alkyl group is methyl, ethyl, or propyl.
  • alkenyl employed alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms.
  • Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.
  • alkynyl employed alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds.
  • Example alkynyl groups Attorney Docket No.: 53238-0003WO1 include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms. As used herein, “halo” or “halogen”, employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl.
  • haloalkyl employed alone or in combination with other terms, refers to an alkyl group having up to the full valency of halogen atom substituents, which may either be the same or different.
  • the halogen atoms are fluoro atoms.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.
  • alkoxy employed alone or in combination with other terms, refers to a group of formula -O-alkyl.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • haloalkoxy employed alone or in combination with other terms, refers to a group of formula -O-(haloalkyl).
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • An example haloalkoxy group is -OCF 3 .
  • amino employed alone or in combination with other terms, refers to NH 2 .
  • cycloalkyl employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon including cyclized alkyl and alkenyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems.
  • cycloalkyl moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclohexene, cyclohexane, and the like, or pyrido derivatives of cyclopentane or cyclohexane. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo. Cycloalkyl groups also include cycloalkylidenes.
  • cycloalkyl also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as admantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused at a single carbon atom, such as spiro[2.5]octane and the like).
  • the cycloalkyl group has 3 to 10 ring members, or 3 to 7 ring members.
  • the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic.
  • the cycloalkyl group is a C 3-7 monocyclic cycloalkyl Attorney Docket No.: 53238-0003WO1 group.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • heterocycloalkyl employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) ring systems.
  • the heterocycloalkyl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen.
  • moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) to the non-aromatic heterocycloalkyl ring, for example, 1,2,3,4-tetrahydro-quinoline and the like.
  • Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least one bridgehead atom, such as azaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least two rings fused at a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like).
  • the heterocycloalkyl group has 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring forming atoms.
  • the heterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms.
  • the carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized.
  • the heterocycloalkyl portion is a C 2-7 monocyclic heterocycloalkyl group.
  • the heterocycloalkyl group is a morpholine ring, pyrrolidine ring, piperazine ring, piperidine ring, tetrahydropyran ring, tetrahyropyridine, azetidine ring, or tetrahydrofuran ring.
  • aryl refers to a monocyclic or polycyclic (e.g., a fused ring system) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms or 6 carbon atoms. In some Attorney Docket No.: 53238-0003WO1 embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl.
  • heteroaryl refers to a monocyclic or polycyclic (e.g., a fused ring system) aromatic hydrocarbon moiety, having one or more heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl group is a monocyclic or a bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen.
  • Example heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl or the like.
  • the carbon atoms or heteroatoms in the ring(s) of the heteroaryl group can be oxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized, provided the aromatic nature of the ring is preserved.
  • the heteroaryl group has from 3 to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to 5 carbon atoms, from 1 to 5 carbon atoms, or from 5 to 10 carbon atoms.
  • the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring- forming atoms.
  • the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
  • Cis and trans geometric isomers of the compounds of the present invention may be isolated as a mixture of isomers or as separated isomeric forms.
  • Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example Attorney Docket No.: 53238-0003WO1 prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the invention include at least one deuterium atom.
  • the term, “compound,” as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted, unless otherwise specified.
  • All compounds, and pharmaceutically acceptable salts thereof can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates) or can be isolated.
  • the compounds of the invention, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compounds of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., Attorney Docket No.: 53238-0003WO1 temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W.
  • reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry
  • HPLC high performance liquid chromatography
  • ambient temperature e.g. a reaction temperature
  • room temperature e.g. a temperature from about 20 oC to about 30 oC.
  • reaction temperature e.g. a temperature from about 20 oC to about 30 oC.
  • an appropriately substituted, aldehyde fluoride- containing compound of Formula (1-1) is substituted with amine compound (1-2) in the presence of a base to form the aldehyde compound of Formula (1-3).
  • the compound of Formula (1-3) is reacted with a hydrazine compound of Formula (1-4) to form the indazole compound of Formula (1-5).
  • the indazole compound of Formula (1-5) is substituted with thiadiazole-bromide compound of Formula (1-6) in the presence of a base to form a 1- indazole compound of Formula (1-7) and a 2-indazole compound of Formula (1-8).
  • an appropriately substituted, sulfonic acid chloride containing compound of Formula (2-1) is substituted with amine compound (2-2) in the presence of a base to form the sulfonamide compound of Formula (2-3).
  • the compound of Formula (1-3) is substituted with a compound of Formula (2-4) in the presence of palladium and base to form the protected indazole compound of Formula (2-5).
  • the protected indazole compound of Formula (2-5) is heated in the presence of acid to form the indazole compound of Formula (2-6).
  • the indazole compound of Formula (2-6) is substituted with thiadiazole-bromide compound of Formula (2-7) in the presence of a base to form a 1- indazole compound of Formula (2-8) and a 2-indazole compound of Formula (2-9).
  • an appropriately substituted indazole compound of Formula (3-1) is substituted with thiadiazole-bromide compound of Formula (3-2) in the presence of a base to form a 1-indazole compound of Formula (3-3) and a 2-indazole compound of Formula (3-4).
  • the 1-indazole compound of Formula (3-3) and a 2-indazole compound of Formula (3-4) are substituted with an amine compound of Formula (3-5) in the presence of potassium metabisulfite and then base to form a sulfonamide compound of Formula (3-6) and of Formula (3-7).
  • an appropriately substituted bromine-substituted indazole compound of Formula (4-1) is substituted with an alkyl halide compound of Formula (4-2) in the presence of potassium metabisulfite and palladium to form a sulfonamide compound of Formula (4-3).
  • Scheme 4 Attorney Docket No.: 53238-0003WO1 Methods of Use Compounds of the invention can inhibit the activity of PARG.
  • the compounds of the invention can be used to inhibit activity of PARG in a cell or in an individual or patient in need of inhibition of the enzyme by administering an inhibiting amount of a compound of the invention to the cell, individual, or patient.
  • the PARG is PARG1.
  • the compounds of the invention are useful in the treatment of various diseases or disorders associated with abnormal expression or activity of PARG.
  • the compounds of the invention are useful in the treatment of cancer.
  • the cancer is a stress-dependent cancer.
  • the cancer is selected from lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, mantle cell lymphoma, and renal cell carcinoma.
  • the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “contacting” PARG or “contacting” a cell with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having PARG, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing PARG.
  • the term “individual” or “patient,” used interchangeably, refers to mammals, and particularly humans. Typically, the individual or patient is in need of treatment.
  • the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to 1) inhibiting the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and/or symptomatology).
  • preventing refers to preventing the disease in an individual who may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease.
  • One or more additional pharmaceutical agents or treatment methods such as, for example, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, immunotherapies, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and/or kinase (tyrosine or serine/threonine), epigenetic or signal transduction inhibitors can be used in combination with the compounds of the present invention.
  • the agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • Suitable agents for use in combination with the compounds of the present invention for the treatment of cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapies or radiation therapy.
  • Compounds of this invention may be effective in combination with anti-hormonal agents for treatment of breast cancer and other tumors.
  • anti-estrogen agents including but not limited to tamoxifen and toremifene, aromatase inhibitors including but not limited to letrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g. prednisone), progestins (e.g. megastrol acetate), and estrogen receptor antagonists (e.g. fulvestrant).
  • Suitable anti-hormone agents used for treatment of prostate and other cancers may also be combined with compounds of the present invention.
  • anti-androgens including but not limited to flutamide, bicalutamide, and nilutamide, luteinizing hormone-releasing hormone (LHRH) analogs including leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g. degarelix), androgen receptor blockers (e.g. enzalutamide) and agents that inhibit androgen production (e.g. abiraterone).
  • Angiogenesis inhibitors may be efficacious in some tumors in combination with the compounds of the present invention.
  • Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept.
  • Inhibitors of VEGFR kinases and other anti-angiogenesis inhibitors include but are not limited to sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib
  • Suitable chemotherapeutic or other anti-cancer agents for use in combination with the compounds of the present invention include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan TM ), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethio- phosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine,
  • anti-cancer agent(s) for use in combination with the compounds of the present invention include antibody therapeutics to checkpoint or costimulatory molecules such as CTLA-4, PD-1, PD-L1 or 4-1BB, respectively, or antibodies to cytokines (IL-10, TGF- ⁇ , etc.).
  • Exemplary cancer immunotherapy antibodies include pembrolizumab, ipilimumab, nivolumab, atezolizumab and durvalumab.
  • Additional anti-cancer agent(s) for use in combination with the compounds of the present invention include antibody therapeutics directed to surface molecules of hematological cancers such as ofatumumab, rituximab, and alemtuzumab.
  • compositions refers to a combination of a compound of the invention, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.
  • compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be oral, topical (including ophthalmic and to mucous membranes Attorney Docket No.: 53238-0003WO1 including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, or parenteral.
  • Administration may be oral, topical (including ophthalmic and to mucous membranes Attorney Docket No.: 53238-0003WO1 including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epiderma
  • compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the compositions can be formulated in a unit dosage form.
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid pre-formulation is then subdivided into unit dosage forms of the type described above.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or Attorney Docket No.: 53238-0003WO1 pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • the amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration.
  • Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the compounds of the invention can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti- viral agents, anti-cancer agents, vaccines, antibodies, immune enhancers, immune suppressants, anti-inflammatory agents and the like.
  • ACN acetonitrile
  • AcOH acetic acid
  • BPO benzoyl peroxide
  • CH 3 CN acetonitrile
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • CH 2 Cl 2 diichloromethane
  • Cs 2 CO 3 cesium carbonate
  • d doublet
  • DCM diichloromethane
  • DEA diethylamine
  • DEAD diethyl azodicarboxylate
  • DIEA N,N-diisopropylethylamine
  • DMF N,N-dimethylformamide
  • DMAP 4-dimethyl aminopyridine
  • DMSO dimethylsulfoxide
  • DMSO-d 6 deuterated dimethylsulfoxide
  • EA ethyl acetate
  • equiv equivalents
  • ESI electrospray ionization
  • EtOAc ethyl acetate
  • EtOH eth
  • Step 2 1-[4-(6-bromo-1H-indazol-4-yl)piperazin-1-yl]-2-methylpropan-1-one
  • a mixture of 4-bromo-2-fluoro-6-[4-(2-methylpropanoyl)piperazin-1-yl]benzaldehyde (5 g, 13.997 mmol, 1 equiv) and hydrazine hydrate (2.80 g, 55.988 mmol, 4 equiv) in DMSO (50 mL) was stirred for 12 h at 100 °C.
  • the reaction was monitored by LCMS.
  • the mixture was allowed to cool down to room temperature.
  • the resulting mixture was quenched with water (150 mL).
  • Step 3 1-(4-(6-bromo-2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-2H-indazol-4- yl)piperazin-1-yl)-2-methylpropan-1-one
  • 1-[4-(6-bromo-1H-indazol-4-yl)piperazin-1-yl]-2-methylpropan-1-one (5 g, 14.235 mmol, 1 equiv)
  • 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (3.67 g, 17.082 mmol, 1.2 equiv) in DMF (30 mL) was added Cs 2 CO 3 (11.60 g, 35.587 mmol, 2.5 equiv) at room temperature.
  • the resulting mixture was stirred for 2 h at 70 °C.
  • the reaction was monitored by LCMS. added The mixture was allowed to cool down to room temperature.
  • the resulting mixture was quenched with water (150 mL).
  • the aqueous layer was extracted with EA (3 ⁇ 100 mL).
  • the combined organic layers were washed by brine (150 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Step 2 4-(6-bromo-1H-indazol-4-yl)piperazine-1-carboxylate
  • Step 3 tert-butyl 4- ⁇ 6-bromo-2-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4- yl ⁇ piperazine-1-carboxylate
  • Step 4 2-(6-bromo-4-(piperazin-1-yl)-2H-indazol-2-yl)-5-(difluoromethyl)-1,3,4-thiadiazole
  • tert-butyl 4-(6-bromo-2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)- 2H-indazol-4-yl)piperazine-1-carboxylate 0.5 g, 0.97 mmol, 1 equiv
  • 1,4-dioxane 4 mL
  • HCl 4M in 1,4-dioxane, 1 mL
  • Example 1A, 1B, and 1C 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((1S,2R)-1-cyano-2- methylcyclopropyl)-4-(4-isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide (1A), 2- (5-bromo-1,3,4-thiadiazol-2-yl)-N-((1R,2S)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide (1B), and rac 2-(5-bromo-1,3,4- thiadiazol-2-yl)-N-((trans)-1-cyano-2-methylcyclopropyl)-4-(4-isobutyrylpiperazin-1-yl)- 2H-indazole-6-sulfonamide (1C) Step 1: 4-chlor
  • Step 2 N-(1-cyano-2-methylcyclopropyl)-1-[(4-methoxyphenyl)methyl]-4-[4-(2- methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide
  • 4-chloro-N-(1-cyano-2-methylcyclopropyl)-1-[(4- methoxyphenyl)methyl] indazole-6-sulfonamide 130 mg, 0.302 mmol, 1 equiv
  • 2- Attorney Docket No.: 53238-0003WO1 methyl-1-(piperazin-1-yl)propan-1-one (94.26 mg, 0.604 mmol, 2 equiv) in dioxane (5 mL) were added RuPhos (4.33 mg, 0.009 mmol, 0.2 equiv), Cs 2 CO 3 (294.89 mg, 0.906 mmol, 3 equiv) and [2
  • Step 3 N-(1-cyano-2-methylcyclopropyl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]-1H- indazole-6-sulfonamide
  • N-(1-cyano-2-methylcyclopropyl)-1-[(4-methoxyphenyl)methyl]-4-[4-(2- methyl propanoyl)piperazin-1-yl]indazole-6-sulfonamide 130 mg, 0.236 mmol, 1 equiv
  • Step 4 1-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1-cyano-2-methylcyclopropyl)-4-[4-(2- methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide) and 2-(5-bromo-1,3,4-thiadiazol-2- yl)-N-(1-cyano-2-methylcyclopropyl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6- sulfonamide)
  • a mixture of N-(1-cyano-2-methylcyclopropyl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]- 1H-indazole-6-sulfonamide 130 mg, 0.302 mmol, 1 equiv)
  • Cs 2 CO 3 (295.15 mg, 0.906 mmol, 3 equiv) and dibromo-1
  • the reaction was monitored by LCMS. Desired product could be detected by LCMS.
  • the resulting mixture was diluted with water (30 mL).
  • the resulting mixture was extracted with EtOAc (3 ⁇ 30 mL).
  • the combined organic layers were washed with brine (2 ⁇ 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Example 2 1-(4-(2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(((1- methylcyclopropyl)methyl)sulfonyl)-2H-indazol-4-yl)piperazin-1-yl)-2-methylpropan-1- one
  • 1-(4- ⁇ 6-bromo-2-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4- yl ⁇ piperazin-1-yl)-2-methylpropan-1-one 50 mg, 0.103 mmol, 1 equiv
  • potassium metabisulfite 45.81 mg, 0.206 mmol, 2 equiv
  • PPh 3 8.11 mg, 0.031 mmol, 0.309 equiv
  • sodium formate 21.02 mg, 0.309 mmol, 3 equiv
  • phen 5.57 mg, 0.031 mmol
  • Example 3 2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide
  • Step 1 2-bromo-5-cyclopropyl-1,3,4-thiadiazole
  • a mixture of 2-methyl-2-propylnitrite (1.68 g, 16.291 mmol, 2.3 equiv) and CuBr 2 (3.64 g, 16.291 mmol, 2.3 equiv) in ACN (20 mL) was stirred for 10 min at room temperature.
  • Example 4 N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2-(5-methyl- 1,3,4-thiadiazol-2-yl)-2H-indazole-6-sulfonamide
  • Step 1 1-(4-(6-bromo-2-(5-methyl-1,3,4-thiadiazol-2-yl)-2H-indazol-4-yl) piperazin-1-yl)-2- methylpropan-1-one
  • a solution of 1-[4-(6-bromo-1H-indazol-4-yl) piperazin-1-yl]-2-methylpropan-1-one (1 g, 2.847 mmol, 1 equiv) and Cs 2 CO 3 (2.78 g, 8.541 mmol, 3 equiv) in DMF (10 mL) was added 2-bromo-5- methyl-1,3,4-thiadiazole (1.02 g,
  • Example 5 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-2-(1,3,4-thiadiazol-2- yl)-2H-indazole-6-sulfonamide
  • a solution of bis(1- ⁇ 4-[6-bromo-2-(1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1-yl ⁇ -2-meth ylpropan-1-one) (150 mg, 0.345 mmol, 1 equiv) in DMSO (5 mL) was treated with potassium metabisulfite (153.21 mg, 0.690 mmol, 2 equiv), tetraethylazanium bromide (79.65 mg, 0.38 0 mmol, 1.1 equiv), sodium formate (70.30 mg, 1.035 mmol, 3 equiv), PPh 3 (27.11 mg, 0.103
  • the crude produ ct was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(10 mmol/L NH 4 HCO 3 +0.1%NH 3 .
  • Example 6 N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2-(5-vinyl- 1,3,4-thiadiazol-2-yl)-2H-indazole-6-sulfonamide
  • Step 1 1-[4-(6-bromo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ indazol-4-yl)piperazin-1-yl]-2- methylpropan-1-one
  • DIEA (1.10 g, 8.541 mmol, 3 equiv) was added [2- (chloromethoxy)ethyl]trimethylsilane dropwise at 0 °C.
  • Step 2 4-[4-(2-methylpropanoyl)piperazin-1-yl]-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ indazole-6-sulfonyl fluoride
  • a mixture of 1-[4-(6-bromo-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ indazol-4-yl)piperazin-1- yl]-2-methylpropan-1-one (880 mg, 1.828 mmol, 1.00 equiv), potassium metabisulfite (811.45 mg, 3.656 mmol, 2 equiv), TEAB (422.17 mg, 2.011 mmol, 1.1 equiv), sodium formate (372.83 mg, 5.484 mmol, 3 equiv), palladium acetate (40.94 mg, 0.183 mmol, 0.1 equiv) and o-phenanthroline (98.69 mg, 0.548 mmol, 0.3 equiv)
  • Step 3 N-[3-(fluoromethyl)oxetan-3-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ indazole-6-sulfonamide
  • a solution of 4-[4-(2-methylpropanoyl)piperazin-1-yl]-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ indazole-6-sulfonyl fluoride 770 mg, 1.589 mmol, 1 equiv
  • HOBT 214.68 mg, 1.589 mmol, 1 equiv
  • DIEA 1437.38 mg, 11.123 mmol, 7 equiv
  • 3- (fluoromethyl)oxetan-3-amine 333.99 mg, 3.178 mmol, 2 equiv) in DMSO (8 mL) was stirred for 2 h at 25 °C.
  • reaction was monitored by LCMS. Then, the reaction was quenched with water (25 mL). The resulting mixture was extracted with EA (3 ⁇ 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 4 N-[3-(fluoromethyl)oxetan-3-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]-1H- indazole-6-sulfonamide
  • Step 5 1-(5-bromo-1,3,4-thiadiazol-2-yl)-N-[3-(fluoromethyl)oxetan-3-yl]-4-[4-(2-methyl propanoyl)piperazin-1-yl]indazole-6-sulfonamide and 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N- (3-(fluoromethyl) oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide
  • N-[3-(fluoromethyl)oxetan-3-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]- 1H-indazole-6-sulfonamide 230 mg, 0.523 mmol, 1 equiv
  • K 2 CO 3 216.97 mg, 1.569 mmol, 3 equi
  • Example 7 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1-cyanocyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide Attorney Docket No.: 53238-0003WO1
  • N-(1-cyanocyclopropyl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]- 1H-indazole-6-sulfonamide 95 mg, 0.228 mmol, 1 equiv
  • Cs 2 CO 3 74.32 mg, 0.228 mmol, 1 equiv
  • dibromo-1,3,4-thiadiazole 66.76 mg, 0.274 mmol, 1.2 equiv
  • Example 8 ethyl (E)-3-(5-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)acrylate Attorney Docket No.: 53238-0003WO1 To a stirred mixture of 1-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1-cyanocyclopropyl)-4-[4-(2- methylpropanoyl) piperazin-1-yl] indazole-6-sulfonamide (120 mg, 0.207mmol, 1equiv, from PH-RASE-068-1) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) prop-2- enoate (56.18 mg, 0.248m
  • IC 50 values were calculated using set control points for 100% inhibition as no enzyme and 0% inhibition 250 pM or 2 nM of PARG enzyme.
  • Data obtained for the Example compounds using the TFMU assay described in Example A is provided in Table A.

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Abstract

The present invention relates to sulfonamides and related compounds which are inhibitors of PARG and are useful in the treatment of cancer.

Description

Attorney Docket No.: 53238-0003WO1 INHIBITORS OF PARG FIELD OF THE INVENTION The present invention relates to sulfonamides and related compounds which are inhibitors of PARG and are useful in the treatment of cancer. BACKGROUND OF THE INVENTION Cancer is a disease caused by abnormal and unregulated cell division. One of the hallmarks of cancer is the up or downregulation of cellular stress pathways which the cancer cells or tumor use for a proliferative advantage. These cellular stress pathways often include, but are not limited to, oxidative stress, DNA damage stress, DNA replicative stress, transcriptional stress, hypoxia, and others. ADP-ribose, as well as the enzymes that generate ADP-ribose (Poly(ADP-ribose) polymerases or PARPs) and hydrolyze ADP-ribose (Poly(ADP-ribose) glycohydrolases or PARGs), play critical roles in regulating cellular stress responses. There are two forms of ADP-ribose in the cell, mono(ADP-ribose) (MAR) and Poly(ADP-ribose) (PAR). Both forms of ADP-ribose are generated by a family of 17 PARP proteins, whose key roles in the cell are to regulate cellular stress responses (Cohen MS, Chang P. Nat Chem Biol. 2018). In humans, PARG exists as a single gene with 3 splicing isoforms. These isoforms function in and are localized to the nucleus, cytoplasm, and mitochondria. The best understood function for PARG is in DNA damage repair. However, PARG also regulates gene splicing, transcriptional and epigenetic pathways (Bock FJ, Todorova TT, Chang P. Mol Cell 2015) (Le May, Litis et al. Mol Cell. 2012) (Dahl, Maturi et al. Plos One, 2014) (Guastafierro, Catizone et al. Biochem J 2013) (Caiafa, Guastafierro et al. FASEB J 2009), cell division (Chang and Mitchison Nature 2004), the cytoplasmic stress response (Leung, Chang et al. Mol Cell 2011), and other cellular stresses. Modulation of both MAR and PAR levels have been shown to be effective treatments for multiple cancers. Inhibiting ADP-ribose synthesis through the use of PARP inhibitors can be used for the treatment of multiple cancer types. PARG inhibitors work by modulating cellular stress responses such as the DNA damage response (DDR) and the replicative stress response. DDR and replicative stress are very important cellular stress responses for cancers because they are a consequence of all cellular stress responses, thus many cancers have them. Cancers accumulate DNA damage due to the upregulation of cellular stress pathways and Attorney Docket No.: 53238-0003WO1 subsequent errors in DNA replication. In cancers, single-strand breaks (SSBs) are the most common type of DNA damage lesion and PARG together with PARP1 play important roles in single strand break repair (SSBR) and another repair mechanism called base excision repair (BER). PARP1 recognizes the break, binds to it, and rapidly synthesizes PAR onto itself (automodification) and histone proteins. Multiple DNA repair proteins, including a master regulator XRCC1, bind to and are recruited to the newly synthesized PAR and then repair the break (Mortusewicz, Fouquerel et al. Nucleic Acid Res. 2011). Thus, the rapid increase in PAR acts as a key DNA repair signal. The signal initiated by PAR is transient as it becomes rapidly degraded by PARG. If PARG is absent or non-functional, PAR rapidly accumulates in the cancer cell and is toxic, resulting in cell death. When PARP1 is bound to or automodified by PAR, its catalytic activity is reduced and therefore PARG activity helps activate PARP1 and is an important regulator to keep the DNA damage repair signal “on” (Curtin and Szabo Mol Aspects Med. 2013). PARG depletion by RNA interference (RNAi) has been shown to kill cancer cells and to result in tumor regression in multiple murine cancer models. Human and murine cells that are null or depleted for PARG display an increased sensitivity to DNA damaging agents demonstrating a general defect in DNA damage related stress responses upon inhibition or depletion of PARG. Other cancer relevant stress pathways have also been shown to be defective upon PARG knockdown, suggesting PARG is an attractive target for the treatment of multiple cancer types. In humans, PARG depletion kills lung, ovarian, breast, cervical, and pancreatic cancer cells in vitro. Xenograft models of these human cancers implanted into mice show tumor regression when PARG protein expression is knocked down. Together, these results demonstrate that PARG is an effective target for the treatment of multiple stress- dependent cancers, and potentially cancers where cellular stress responses are not obviously present. This invention seeks to provide cell permeable inhibitors of PARG. SUMMARY OF THE INVENTION The present invention is directed to a compound of Formula I:
Figure imgf000003_0001
I or a pharmaceutically acceptable salt thereof, wherein constituent members are defined below. Attorney Docket No.: 53238-0003WO1 The present invention is further directed to a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The present invention is further directed to a method of inhibiting the activity of PARG comprising contacting a compound of Formula I, or a pharmaceutically acceptable salt thereof, with PARG. The present invention is further directed to a method of treating a disease or disorder in a patient in need of treatment, where the disease or disorder is characterized by overexpression or increased activity of PARG, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. The present invention is further directed to a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits PARG activity, such as a compound of Formula I, or a pharmaceutically acceptable salt thereof. The present disclosure also provides uses of the compounds described herein in the manufacture of a medicament for use in therapy. The present disclosure also provides the compounds described herein for use in therapy. DETAILED DESCRIPTION The present invention is directed to a compound of Formula I:
Figure imgf000004_0001
I or a pharmaceutically acceptable salt thereof, wherein: Q is NH or CH2; A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy1, Cy1-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, Attorney Docket No.: 53238-0003WO1 NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd, B is a group of formula (a), formula (b), formula (c), formula (d), formula (e), or
Figure imgf000005_0001
X1 is N or CR1; X2 is N or CR2; X3 is N or CR3; X4 is N or CR4; X5 is N or CR5; X6 is N or CR6; X7 is N or CR7; X8 is N or CR8; X9 is N or CR9; X10 is N or CR10; X11 is N or CR11; X12 is N or CR12; X13 is N or CR13; X14 is N or CR14; X15 is N or CR15; X16 is N or CR16; Attorney Docket No.: 53238-0003WO1 X17 is N or CR17; X18 is N or CR18; wherein no more than two of X1, X2, and X3 are simultaneously N; wherein no more than two of X4, X5, and X6 are simultaneously N; wherein no more than two of X7, X8, and X9 are simultaneously N; wherein no more than two of X10, X11, and X12 are simultaneously N; wherein no more than two of X13, X14, and X15 are simultaneously N; wherein no more than two of X16, X17, and X18 are simultaneously N; Z1 is N or C; Z2 is N or C; the symbol represents an optional bond; each Cy1 is independently selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy; each RCy is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1- 6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of RCy is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; R1, R2, R4, R5, R7, R8, R10, R11, R13, R14, R16, and R17 are each independently selected from H, halo, and C1-4 alkyl; R3, R6, R9, R12, R15, and R18 are each independently selected from H, halo, ORa2, NRc2Rd2, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4- 10 membered heterocycloalkyl of R3, R6, R9, R12, R15, and R18 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 Attorney Docket No.: 53238-0003WO1 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; RB1 is H, C1-4 alkyl, or C2-6 alkenyl, wherein said C1-4 alkyl or C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, halo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; RC1, RC2, RC3, RC4, and RC5 are each independently selected from C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 R’; RC6 is selected from H, C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 R’; RD1 is H, halo, or C1-4 alkyl; RE1 is H, C1-4 alkyl, or C2-6 alkenyl, wherein the C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, halo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; RE2 and RF1 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, and 5- membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl of RE2 and RF1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, Attorney Docket No.: 53238-0003WO1 NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; each R’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3- 7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl of R’ is optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; each Cy2 is independently selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Attorney Docket No.: 53238-0003WO1 Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, and Rd4 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5,
Figure imgf000009_0001
or Rc and Rd, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5, C(O)Rb5,
Figure imgf000009_0002
or Rc1 and Rd1, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5, C(O)Rb5,
Figure imgf000009_0003
or Rc2 and Rd2, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5, C(O)Rb5,
Figure imgf000009_0004
or Rc3 and Rd3, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5, C(O)Rb5,
Figure imgf000009_0005
or Rc4 and Rd4, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, Attorney Docket No.: 53238-0003WO1
Figure imgf000010_0001
each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; and each Re, Re1, Re2, Re3, Re4, and Re5 is independently selected from H, C1-4 alkyl, and CN. In some embodiments, Q is NH. In some embodiments, Q is CH2. In some embodiments, A is C1-6 alkyl. In some embodiments, A is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, C(=NRe)NRcRd, NRcC(=NRe)NRcRd, NRcRd, NRcC(O)Rb, NRcC(O)ORa, NRcC(O)NRcRd, NRcS(O)Rb, NRcS(O)2Rb, NRcS(O)2NRcRd, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd. In some embodiments, A is C2-6 alkenyl. In some embodiments, A is C2-6 alkenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa,
Figure imgf000010_0002
embodiments, A is C2-6 alkynyl. In some embodiments, A is C2-6 alkynyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 Attorney Docket No.: 53238-0003WO1 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa,
Figure imgf000011_0005
embodiments, A is Cy1. In some embodiments, A is Cy1-C1-4 alkyl-. In some embodiments,
Figure imgf000011_0001
Figure imgf000011_0002
integer selected from 0, 1, 2, 3, 4, and 5.
Figure imgf000011_0003
In some embodiments, B is a group of formula (a):
Figure imgf000011_0004
In some embodiments, B is a group of formula (b): Attorney Docket No.: 53238-0003WO1
Figure imgf000012_0001
(b). In some embodiments, B is a group of formula (c):
Figure imgf000012_0005
(c). In some embodiments, B is a group of formula (d):
Figure imgf000012_0002
In some embodiments, B is a group of formula (e):
Figure imgf000012_0003
In some embodiments, B is a group of formula (f):
Figure imgf000012_0004
In some embodiments, B is a group of formula (a), formula (c), or formula (f): Attorney Docket No.: 53238-0003WO1
Figure imgf000013_0001
Figure imgf000013_0002
integer selected from 0, 1, 2, 3, 4, and 5; and B is a group of formula (a), formula (c), or formula (f):
Figure imgf000013_0003
integer selected from 0, 1, 2, 3, 4, and 5; and B is a group of formula (a):
Figure imgf000013_0004
In some embodiments,
Figure imgf000013_0005
3, 4, and 5; and B is a group of formula (c): Attorney Docket No.: 53238-0003WO1
Figure imgf000014_0001
In some embodiments,
Figure imgf000014_0002
integer selected from 0, 1,, 3, 4, and 5; and B is a group of formula (f):
Figure imgf000014_0003
In some embodiments, X1 is N. In some embodiments, X1 is CR1. In some embodiments, X2 is N. In some embodiments, X2 is CR2. In some embodiments, X3 is N. In some embodiments, X3 is CR3. In some embodiments, X4 is N. In some embodiments, X4 is CR4. In some embodiments, X5 is N. In some embodiments, X5 is CR5. In some embodiments, X6 is N. In some embodiments, X6 is CR6. In some embodiments, X7 is N. In some embodiments, X7 is CR7. In some embodiments, X8 is N. In some embodiments, X8 is CR8. In some embodiments, X9 is N. In some embodiments, X9 is CR9. In some embodiments, X10 is N. In some embodiments, X10 is CR10. In some embodiments, X11 is N. In some embodiments, X11 is CR11. In some embodiments, X12 is N. In some embodiments, X12 is CR12. In some embodiments, X13 is N. In some embodiments, X13 is CR13. In some embodiments, X14 is N. In some embodiments, X14 is CR14. In some embodiments, X15 is N. In some embodiments, X15 is CR15. In some embodiments, X16 is N. In some embodiments, X16 is CR16. In some embodiments, X17 is N. In some embodiments, X17 is CR17. In some embodiments, X18 is N. In some embodiments, X18 is CR18. In some embodiments, X1 is CR1, X2 is CR2, and X3 is CR3. In some embodiments, X4 is CR4, X5 is CR5, and X6 is CR6. In some embodiments, X7 is CR7, X8 is CR8, and X9 is CR9. Attorney Docket No.: 53238-0003WO1 In some embodiments, X10 is CR10, X11 is CR11, and X12 is CR12. In some embodiments, X13 is CR13, X14 is CR14, and X15 is CR15. In some embodiments, X16 is CR16, X17 is CR17, and X18 is CR18. In some embodiments, Z1 is N. In some embodiments, Z1 is C. In some embodiments, Z2 is N. In some embodiments, Z2 is C. In some embodiments, at least one Cy1 is C6-10 aryl. In some embodiments, at least one Cy1 is C6-10 aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy. In some embodiments, at least one Cy1 is C3-7 cycloalkyl. In some embodiments, at least one Cy1 is C3-7 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy. In some embodiments, at least one Cy1 is 5-10 membered heteroaryl. In some embodiments, at least one Cy1 is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy. In some embodiments, at least one Cy1 is 4-10 membered heterocycloalkyl. In some embodiments, at least one Cy1 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy. In some embodiments, at least one Cy1 is C3-7 cycloalkyl or 4-10 membered heterocycloalkyl. In some embodiments, at least one Cy1 is C3-7 cycloalkyl or 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy. In some embodiments, at least one Cy1 is cyclopropyl. In some embodiments, at least one Cy1 is cyclopropyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy. In some embodiments, at least one Cy1 is cyclopropyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, and CN. In some embodiments, at least one Cy1 is 4-membered heterocycloalkyl. In some embodiments, at least one Cy1 is 4-membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy. In some embodiments, at least one Cy1 is oxetanyl. In some embodiments, at least one Cy1 is oxetanyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy. In some embodiments, at least one Cy1 is oxetanyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, and CN. In some embodiments, R1 is H. In some embodiments, R1 is halo. In some embodiments, R1 is C1-4 alkyl. Attorney Docket No.: 53238-0003WO1 In some embodiments, R2 is H. In some embodiments, R2 is halo. In some embodiments, R2 is C1-4 alkyl. In some embodiments, R4 is H. In some embodiments, R4 is halo. In some embodiments, R4 is C1-4 alkyl. In some embodiments, R5 is H. In some embodiments, R5 is halo. In some embodiments, R5 is C1-4 alkyl. In some embodiments, R7 is H. In some embodiments, R7 is halo. In some embodiments, R7 is C1-4 alkyl. In some embodiments, R8 is H. In some embodiments, R8 is halo. In some embodiments, R8 is C1-4 alkyl. In some embodiments, R10 is H. In some embodiments, R10 is halo. In some embodiments, R10 is C1-4 alkyl. In some embodiments, R11 is H. In some embodiments, R11 is halo. In some embodiments, R11 is C1-4 alkyl. In some embodiments, R13 is H. In some embodiments, R13 is halo. In some embodiments, R13 is C1-4 alkyl. In some embodiments, R14 is H. In some embodiments, R14 is halo. In some embodiments, R14 is C1-4 alkyl. In some embodiments, R16 is H. In some embodiments, R16 is halo. In some embodiments, R16 is C1-4 alkyl. In some embodiments, R17 is H. In some embodiments, R17 is halo. In some embodiments, R17 is C1-4 alkyl. In some embodiments, R3 is H. In some embodiments, R3 is halo. In some embodiments, R3 is ORa2. In some embodiments, R3 is NRc2Rd2. In some embodiments, R3 is C6-10 aryl. In some embodiments, R3 is C3-7 cycloalkyl. In some embodiments, R3 is C3-7 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R3 is 5-10 membered heteroaryl. In some embodiments, R3 is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 Attorney Docket No.: 53238-0003WO1 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R3 is 4-10 membered heterocycloalkyl. In some embodiments, R3 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R3 is H or 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-6 alkyl and C(O)Rb2. In some embodiments, R3 is piperazinyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-6 alkyl
Figure imgf000017_0001
In some embodiments, R6 is H. In some embodiments, R6 is halo. In some embodiments, R6 is ORa2. In some embodiments, R6 is NRc2Rd2. In some embodiments, R6 is C6-10 aryl. In some embodiments, R6 is C3-7 cycloalkyl. In some embodiments, R6 is C3-7 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, Attorney Docket No.: 53238-0003WO1 S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R6 is 5-10 membered heteroaryl. In some embodiments, R6 is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R6 is 4-10 membered heterocycloalkyl. In some embodiments, R6 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R9 is H. In some embodiments, R9 is halo. In some embodiments, R9 is ORa2. In some embodiments, R9 is NRc2Rd2. In some embodiments, R9 is C6-10 aryl. In some embodiments, R9 is C3-7 cycloalkyl. In some embodiments, R9 is C3-7 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R9 is 5-10 membered heteroaryl. In some embodiments, R9 is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and Attorney Docket No.: 53238-0003WO1 S(O)2NRc2Rd2. In some embodiments, R9 is 4-10 membered heterocycloalkyl. In some embodiments, R9 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R12 is H. In some embodiments, R12 is halo. In some embodiments, R12 is ORa2. In some embodiments, R12 is NRc2Rd2. In some embodiments, R12 is C6-10 aryl. In some embodiments, R12 is C3-7 cycloalkyl. In some embodiments, R12 is C3-7 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R12 is 5-10 membered heteroaryl. In some embodiments, R12 is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R12 is 4-10 membered heterocycloalkyl. In some embodiments, R12 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, Attorney Docket No.: 53238-0003WO1 NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R15 is H. In some embodiments, R15 is halo. In some embodiments, R15 is ORa2. In some embodiments, R15 is NRc2Rd2. In some embodiments, R15 is C6-10 aryl. In some embodiments, R15 is C3-7 cycloalkyl. In some embodiments, R15 is C3-7 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R15 is 5-10 membered heteroaryl. In some embodiments, R15 is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R15 is 4-10 membered heterocycloalkyl. In some embodiments, R15 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R18 is H. In some embodiments, R18 is halo. In some embodiments, R18 is ORa2. In some embodiments, R18 is NRc2Rd2. In some embodiments, R18 is C6-10 aryl. In some embodiments, R18 is C3-7 cycloalkyl. In some embodiments, R18 is C3-7 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, Attorney Docket No.: 53238-0003WO1 CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R18 is 5-10 membered heteroaryl. In some embodiments, R18 is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R18 is 4-10 membered heterocycloalkyl. In some embodiments, R18 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, R1 is H and R2 is H. In some embodiments, R1 is H, R2 is H, and R3 is H. In some embodiments, R1 is H, R2 is H, and R3 is H or 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-6 alkyl and C(O)Rb2. In some embodiments, R1 is H, R2 is H, and R3 is piperazinyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-6 alkyl and C(O)Rb2. In some embodiments, R1 is
Figure imgf000021_0001
In some embodiments, R4 is H and R5 is H. In some embodiments, R4 is H, R5 is H, and R6 is H. Attorney Docket No.: 53238-0003WO1 In some embodiments, R7 is H and R8 is H. In some embodiments, R7 is H, R8 is H, and R9 is H. In some embodiments, R10 is H and R12 is H. In some embodiments, R11 is H, R12 is H, and R13 is H. In some embodiments, R13 is H and R14 is H. In some embodiments, R13 is H, R14 is H, and R15 is H. In some embodiments, R16 is H and R17 is H. In some embodiments, R16 is H, R17 is H, and R18 is H. In some embodiments, RB1 is H. In some embodiments, RB1 is C1-4 alkyl. In some embodiments, RB1 is C1-4 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, halo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl,
Figure imgf000022_0001
S(O)2Rb3, and S(O)2NRc3Rd3. In some embodiments, RB1 is C2-6 alkenyl. In some embodiments, RB1 is C2-6 alkenyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, halo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl,
Figure imgf000022_0002
In some embodiments, RC1 is C1-6 alkyl. In some embodiments, RC1 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC1 is C2-6 alkenyl. In some embodiments, RC1 is C2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC1 is 5-membered heteroaryl. In some embodiments, RC1 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC1 is C1-6 alkyl or C2-6 alkenyl, wherein the C1-6 alkyl or C2-6 alkenyl is optionally substituted with 1, 2, 3, or 4 R’ C(O)NRc4Rd4, C(O)ORa4, and NRc4Rd4. In some embodiments, RC1 is 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C3-7 cycloalkyl, and NRc4C(O)Rb4. In some embodiments, RC1 is thiazolyl or 1,3,4-thiadiazolyl, optionally substituted with 1, 2, 3, or 4 halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C3-7 Attorney Docket No.: 53238-0003WO1 cycloalkyl, and NRc4C(O)Rb4. In some embodiments,
Figure imgf000023_0001
Figure imgf000023_0002
; wherein m is an integer selected from 0, 1, and 2. In some embodiments,
Figure imgf000023_0003
In some embodiments, RC2 is C1-6 alkyl. In some embodiments, RC2 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC2 is C2-6 alkenyl. In some embodiments, RC2 is C2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC2 is 5-membered heteroaryl. In some embodiments, RC2 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC3 is C1-6 alkyl. In some embodiments, RC3 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC3 is C2-6 alkenyl. In some embodiments, RC3 is C2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC3 is 5-membered heteroaryl. In some embodiments, RC3 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC3 is C1-6 alkyl or C2-6 alkenyl, wherein the C1-6 alkyl or C2-6 alkenyl is optionally substituted with 1, 2, 3, or 4 R’ C(O)NRc4Rd4, C(O)ORa4, and NRc4Rd4. In some embodiments, RC3 is 5-membered heteroaryl, wherein the 5-membered heteroaryl is Attorney Docket No.: 53238-0003WO1 optionally substituted with 1, 2, 3, or 4 halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C3-7 cycloalkyl, and NRc4C(O)Rb4. In some embodiments, RC3 is thiazolyl or 1,3,4-thiadiazolyl, optionally substituted with 1, 2, 3, or 4 halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C3-7 cycloalkyl, and NRc4C(O)Rb4. In some embodiments,
Figure imgf000024_0001
Figure imgf000024_0002
; wherein m is an integer selected from 0, 1, and 2. In some embodiments,
Figure imgf000024_0003
In some embodiments, RC4 is C1-6 alkyl. In some embodiments, RC4 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC4 is C2-6 alkenyl. In some embodiments, RC4 is C2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC4 is 5-membered heteroaryl. In some embodiments, RC4 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC5 is C1-6 alkyl. In some embodiments, RC5 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC5 is C2-6 alkenyl. In some embodiments, RC5 is C2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC5 is 5-membered heteroaryl. In some embodiments, RC5 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’. Attorney Docket No.: 53238-0003WO1 In some embodiments, RC6 is H. In some embodiments, RC6 is C1-6 alkyl. In some embodiments, RC6 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC6 is C2-6 alkenyl. In some embodiments, RC6 is C2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RC6 is 5-membered heteroaryl. In some embodiments, RC6 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, RD1 is H. In some embodiments, RD1 is halo. In some embodiments, RD1 is C1-4 alkyl. In some embodiments, RE1 is H. In some embodiments, RE1 is C1-4 alkyl. In some embodiments, RE1 is C1-4 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, halo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl,
Figure imgf000025_0001
S(O)2Rb3, and S(O)2NRc3Rd3. In some embodiments, RE1 is C2-6 alkenyl. In some embodiments, RE1 is C2-6 alkenyl optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, halo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl,
Figure imgf000025_0002
In some embodiments, RE2 is H. In some embodiments, RE2 is C1-6 alkyl. In some embodiments, RE2 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, RE2 is C2-6 alkenyl. In some embodiments, RE2 is C2-6 alkenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, Attorney Docket No.: 53238-0003WO1 SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, RE2 is 5-membered heteroaryl. In some embodiments, RE2 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, RF1 is H. In some embodiments, RF1 is C1-6 alkyl. In some embodiments, RF1 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, RF1 is C2-6 alkenyl. In some embodiments, RF1 is C2-6 alkenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, RF1 is 5-membered heteroaryl. In some embodiments, RF1 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered Attorney Docket No.: 53238-0003WO1 heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, at least one R’ is halo. In some embodiments, at least one R’ is C1-6 alkyl. In some embodiments, at least one R’ is C1-6 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4. In some embodiments, at least one R’ is C2-6 alkenyl. In some embodiments, at least one R’ is C2-6 alkenyl optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4. In some embodiments, at least one R’ is C2-6 alkynyl. In some embodiments, at least one R’ is C2-6 alkynyl optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4. In some embodiments, at least one R’ is C1-6 haloalkyl. In some embodiments, at least one R’ is C1-6 haloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4. In some embodiments, at least one R’ is C6-10 aryl. In some embodiments, at least one R’ is C6-10 aryl optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4. In some embodiments, at least one R’ is C3-7 cycloalkyl. In some embodiments, at least one R’ is C3-7 cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, Attorney Docket No.: 53238-0003WO1 NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4. In some embodiments, at least one R’ is 5-10 membered heteroaryl. In some embodiments, at least one R’ is 5-10 membered heteroaryl optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4. In some embodiments, at least one R’ is 4-10 membered heterocycloalkyl. In some embodiments, at least one R’ is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4. In some embodiments, at least one R’ is C6-10 aryl-C1-4 alkyl. In some embodiments, at least one R’ is C6-10 aryl-C1-4 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4. In some embodiments, at least one R’ is C3-7 cycloalkyl-C1-4 alkyl. In some embodiments, at least one R’ is C3-7 cycloalkyl-C1-4 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4. In some embodiments, at least one R’ is 5-10 membered heteroaryl-C1-4 alkyl. In some embodiments, at least one R’ is 5-10 membered heteroaryl-C1-4 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4. In some embodiments, at least one R’ is 4-10 membered heterocycloalkyl-C1-4 alkyl. In some embodiments, at least one R’ is 4-10 Attorney Docket No.: 53238-0003WO1 membered heterocycloalkyl-C1-4 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4. In some embodiments, at least one R’ is CN. In some embodiments, at least one R’ is NO2. In some embodiments, at least one R’ is ORa4. In some embodiments, at least one R’ is SRa4. In some embodiments, at least one R’ is C(O)Rb4. In some embodiments, at least one R’ is C(O)NRc4Rd4. In some embodiments, at least one R’ is C(O)ORa4. In some embodiments, at least one R’ is OC(O)Rb4. In some embodiments, at least one R’ is OC(O)NRc4Rd4. In some embodiments, at least one R’ is C(=NRe4)NRc4Rd4. In some embodiments, at least one R’ is NRc4C(=NRe4)NRc4Rd4. In some embodiments, at least one R’ is NRc4Rd4. In some embodiments, at least one R’ is NRc4C(O)Rb4. In some embodiments, at least one R’ is NRc4C(O)ORa4. In some embodiments, at least one R’ is NRc4C(O)NRc4Rd4. In some embodiments, at least one R’ is NRc4S(O)Rb4. In some embodiments, at least one R’ is NRc4S(O)2Rb4. In some embodiments, at least one R’ is NRc4S(O)2NRc4Rd4. In some embodiments, at least one R’ is S(O)Rb4. In some embodiments, at least one R’ is S(O)NRc4Rd4. In some embodiments, at least one R’ is S(O)2Rb4. In some embodiments, at least one R’ is S(O)2NRc4Rd4. In some embodiments, at least one Cy2 is C6-10 aryl. In some embodiments, at least one Cy2 is C6-10 aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3. In some embodiments, at least one Cy2 is C3-7 cycloalkyl. In some embodiments, at least one Cy2 is C3-7 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl- C1-4 alkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, Attorney Docket No.: 53238-0003WO1 S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3. In some embodiments, at least one Cy2 is 5-10 membered heteroaryl. In some embodiments, at least one Cy2 is 5-10 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl,
Figure imgf000030_0001
S(O)2Rb3, and S(O)2NRc3Rd3. In some embodiments, at least one Cy2 is 4-10 membered heterocycloalkyl. In some embodiments, at least one Cy2 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2,
Figure imgf000030_0002
In some embodiments, Rc and Rd, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5,
Figure imgf000030_0003
In some embodiments, Rc1 and Rd1, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5,
Figure imgf000030_0004
In some embodiments, Rc2 and Rd2, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, Attorney Docket No.: 53238-0003WO1
Figure imgf000031_0001
In some embodiments, Rc3 and Rd3, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5,
Figure imgf000031_0002
In some embodiments, Rc4 and Rd4, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5,
Figure imgf000031_0003
In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula II-A:
Figure imgf000031_0004
II-A or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula II-B:
Figure imgf000031_0005
II-B or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula III-A:
Figure imgf000031_0006
Attorney Docket No.: 53238-0003WO1 III-A or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula III-B:
Figure imgf000032_0001
III-B or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula III-C:
Figure imgf000032_0002
III-C or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula III-A-1:
Figure imgf000032_0003
III-A-1 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula III-A-2:
Figure imgf000032_0004
III-A-2 Attorney Docket No.: 53238-0003WO1 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula III-B-1:
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula III-B-2:
Figure imgf000033_0002
or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula III-C-1:
Figure imgf000033_0003
III-C-1 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula III-C-2:
Figure imgf000033_0004
Attorney Docket No.: 53238-0003WO1 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-A:
Figure imgf000034_0001
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-B:
Figure imgf000034_0002
IV-B or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-C:
Figure imgf000034_0003
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula I V-D: Attorney Docket No.: 53238-0003WO1
Figure imgf000035_0001
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula I V-E:
Figure imgf000035_0002
IV-E or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-F:
Figure imgf000035_0003
or a pharmaceutically acceptable salt thereof, wherein p is an integer selected from 0, 1, 2, 3, and 4; and each R3’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, Attorney Docket No.: 53238-0003WO1 NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-A-1:
Figure imgf000036_0001
IV-A-1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-B-1:
Figure imgf000036_0002
IV-B-1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-C-1:
Figure imgf000036_0003
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-D-1: Attorney Docket No.: 53238-0003WO1
Figure imgf000037_0001
IV-D-1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-E-1:
Figure imgf000037_0002
IV-E-1 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-F-1:
Figure imgf000037_0003
IV-F-1 or a pharmaceutically acceptable salt thereof, wherein p is an integer selected from 0, 1, 2, 3, and 4; and each R3’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, Attorney Docket No.: 53238-0003WO1 NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-A-2:
Figure imgf000038_0001
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-B-2:
Figure imgf000038_0002
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-C-2:
Figure imgf000038_0003
IV-C-2 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula I V-D-2: Attorney Docket No.: 53238-0003WO1
Figure imgf000039_0001
IV-D-2 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-E-2:
Figure imgf000039_0002
or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-F-2:
Figure imgf000039_0003
or a pharmaceutically acceptable salt thereof, wherein p is an integer selected from 0, 1, 2, 3, and 4; and each R3’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, Attorney Docket No.: 53238-0003WO1 NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-A:
Figure imgf000040_0001
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-B:
Figure imgf000040_0002
V-B or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-C:
Figure imgf000040_0003
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-D: Attorney Docket No.: 53238-0003WO1
Figure imgf000041_0001
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-E:
Figure imgf000041_0002
V-E or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-A-1:
Figure imgf000041_0003
V-A-1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-B-1:
Figure imgf000041_0004
or a pharmaceutically acceptable salt thereof. Attorney Docket No.: 53238-0003WO1 In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-C-1:
Figure imgf000042_0001
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-D-1:
Figure imgf000042_0002
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-E-1:
Figure imgf000042_0003
or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-A-2: Attorney Docket No.: 53238-0003WO1
Figure imgf000043_0001
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-B-2:
Figure imgf000043_0002
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-C-2:
Figure imgf000043_0003
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-D-2:
Figure imgf000043_0004
or a pharmaceutically acceptable salt thereof. Attorney Docket No.: 53238-0003WO1 In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-E-2:
Figure imgf000044_0001
or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-A:
Figure imgf000044_0002
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-B:
Figure imgf000044_0003
VI-B or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-C:
Figure imgf000044_0004
Attorney Docket No.: 53238-0003WO1 VI-C or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-D:
Figure imgf000045_0001
VI-D or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-A-1:
Figure imgf000045_0002
VI-A-1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-B-1:
Figure imgf000045_0003
VI-B-1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-C-1: Attorney Docket No.: 53238-0003WO1
Figure imgf000046_0001
VI-C-1 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-D-1:
Figure imgf000046_0002
VI-D-1 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-A-2:
Figure imgf000046_0003
or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-B-2:
Figure imgf000046_0004
VI-B-2 or a pharmaceutically acceptable salt thereof. Attorney Docket No.: 53238-0003WO1 In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-C-2:
Figure imgf000047_0001
VI-C-2 or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-D-2:
Figure imgf000047_0002
VI-D-2 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: Q is NH or CH2; A is C1-6 alkyl, C2-6 alkenyl, Cy1, Cy1-C1-4 alkyl-, wherein said C1-6 alkyl, and C2-6 alkenyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
Figure imgf000047_0003
and S(O)2NRcRd, B is a group of formula (a), formula (b), formula (c), formula (d), formula (e), or formula (f): Attorney Docket No.: 53238-0003WO1
Figure imgf000048_0001
X2 is N or CR2; X3 is N or CR3; X4 is N or CR4; X5 is N or CR5; X6 is N or CR6; X7 is N or CR7; X8 is N or CR8; X9 is N or CR9; X10 is N or CR10; X11 is N or CR11; X12 is N or CR12; X13 is N or CR13; X14 is N or CR14; X15 is N or CR15; X16 is N or CR16; X17 is N or CR17; X18 is N or CR18; wherein no more than two of X1, X2, and X3 are simultaneously N; wherein no more than two of X4, X5, and X6 are simultaneously N; wherein no more than two of X7, X8, and X9 are simultaneously N; Attorney Docket No.: 53238-0003WO1 wherein no more than two of X10, X11, and X12 are simultaneously N; wherein no more than two of X13, X14, and X15 are simultaneously N; wherein no more than two of X16, X17, and X18 are simultaneously N; Z1 is N or C; Z2 is N or C; the symbol represents an optional bond; each Cy1 is independently selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy; each RCy is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6 alkyl and C2-6 alkenyl of RCy is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; R1, R2, R4, R5, R7, R8, R10, R11, R13, R14, R16, and R17 are each independently selected from H, halo, and C1-4 alkyl; R3, R6, R9, R12, R15, and R18 are each independently selected from H, halo, ORa2, NRc2Rd2, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4- 10 membered heterocycloalkyl of R3, R6, and R9 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; RB1 is H, C1-4 alkyl, or C2-6 alkenyl, wherein said C1-4 alkyl or C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, Attorney Docket No.: 53238-0003WO1 2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3,
Figure imgf000050_0001
selected from C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 R’; RC6 is selected from H, C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 R’; RD1 is H, halo, or C1-4 alkyl; RE1 is H, C1-4 alkyl, or C2-6 alkenyl, each optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, halo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6
Figure imgf000050_0002
RE2 and RF1 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, and 5- membered heteroaryl, wherein said C1-6 alkyl, C1-6 alkyl substituted with R’, C2-6 alkenyl, and 5-membered heteroaryl of RE2 and RF1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; each R’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3- 7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 Attorney Docket No.: 53238-0003WO1 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl of R’ is optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; each Cy2 is independently selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa3, SRa3, C(O)Rb3,
Figure imgf000051_0001
each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, and Rd4 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5,
Figure imgf000051_0002
each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered Attorney Docket No.: 53238-0003WO1 heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; and each Re, Re1, Re2, Re3, Re4, and Re5 is independently selected from H, C1-4 alkyl, and CN. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: Q is NH or CH2; A is C1-6 alkyl, C2-6 alkenyl, Cy1, Cy1-C1-4 alkyl-, wherein said C1-6 alkyl, and C2-6 alkenyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb,
Figure imgf000052_0001
B is a group of formula (a), formula (c), or formula (f):
Figure imgf000052_0002
X2 is N or CR2; X3 is N or CR3; X7 is N or CR7; X8 is N or CR8; X9 is N or CR9; X16 is N or CR16; X17 is N or CR17; X18 is N or CR18; wherein no more than two of X1, X2, and X3 are simultaneously N; wherein no more than two of X7, X8, and X9 are simultaneously N; Attorney Docket No.: 53238-0003WO1 wherein no more than two of X16, X17, and X18 are simultaneously N; Z1 is N or C; Z2 is N or C; the symbol represents an optional bond; each Cy1 is independently selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy; each RCy is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; R1, R2, R7, R8, R16, and R17 are each independently selected from H, halo, and C1-4 alkyl; R3, R9, and R18 are each independently selected from H, halo, ORa2, NRc2Rd2, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R3, R9, and R18 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; RB1 is H, C1-4 alkyl, or C2-6 alkenyl; RC1 and RC3 are each independently selected from C1-6 alkyl, C2-6 alkenyl, and 5- membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 R’; RC6 is selected from H, C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 R’; RD1 is H, halo, or C1-4 alkyl; each R’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 Attorney Docket No.: 53238-0003WO1 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl of R’ is optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra4, Rb4, Rc4, and Rd4 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa5,
Figure imgf000054_0001
each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl; and each Re, Re1, Re2, Re4, and Re5 is independently selected from H, C1-4 alkyl, and CN. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: Q is NH or CH2; A is Cy1 or Cy1-C1-4 alkyl-; Attorney Docket No.: 53238-0003WO1 B is a group of formula (a), formula (c), or formula (f):
Figure imgf000055_0001
X2 is N or CR2; X3 is N or CR3; X7 is N or CR7; X8 is N or CR8; X9 is N or CR9; X16 is N or CR16; X17 is N or CR17; X18 is N or CR18; wherein no more than two of X1, X2, and X3 are simultaneously N; wherein no more than two of X7, X8, and X9 are simultaneously N; wherein no more than two of X16, X17, and X18 are simultaneously N; Z1 is N or C; Z2 is C; the symbol represents an optional bond; each Cy1 is independently selected from C3-7 cycloalkyl and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy; each RCy is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, and CN; R1, R2, R7, R8, R16, and R17 are each H; R3, R9, and R18 are each independently selected from H and 4-10 membered heterocycloalkyl, wherein said 4-10 membered heterocycloalkyl of R3, R9, and R18 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-6 alkyl and C(O)Rb2; RC1 and RC3 are each independently selected from C1-6 alkyl, C2-6 alkenyl, and 5- membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 R’; Attorney Docket No.: 53238-0003WO1 RC6 is selected from H, C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 R’; RD1 is H; each R’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C3-7 cycloalkyl, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, wherein the C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, and C3-7 cycloalkyl of R’ is optionally substituted with 1, 2, or 3 groups independently selected from C(O)ORa4 and NRc4Rd4; and each Rb2, Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C1-6 alkyl, and C2-6 alkenyl, wherein said C1-6 alkyl and C2-6 alkenyl of Rb2, Ra4, Rb4, Rc4, and Rd4 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from CN. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, selected from: 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((1S,2R)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide; 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((1R,2S)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide; 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((1R,2R)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide; 1-(4-(2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(((1- methylcyclopropyl)methyl)sulfonyl)-2H-indazol-4-yl)piperazin-1-yl)-2-methylpropan-1-one; 2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide; N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2-(5-methyl-1,3,4- thiadiazol-2-yl)-2H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-2-(1,3,4-thiadiazol-2-yl)-2H- indazole-6-sulfonamide; N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2-(5-vinyl-1,3,4- thiadiazol-2-yl)-2H-indazole-6-sulfonamide; N-(3-methyloxetan-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6- sulfonamide; 2-(5-bromo-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan- 3-yl)-2H-indazole-6-sulfonamide; Attorney Docket No.: 53238-0003WO1 (E)-4-(5-(N-(1-methylcyclopropyl)sulfamoyl)-1,3-dioxoisoindolin-2-yl)but-2- enamide; ethyl (E)-4-(5-(N-(1-methylcyclopropyl)sulfamoyl)-1,3-dioxoisoindolin-2-yl)but-2- enoate; (E)-4-(5-(N-(1-methylcyclopropyl)sulfamoyl)-1,3-dioxoisoindolin-2-yl)but-2-enoic acid; N-(4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-2H-indazol-2-yl)thiazol-5- yl)acrylamide; 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1-cyanocyclopropyl)-4-(4-isobutyrylpiperazin- 1-yl)-2H-indazole-6-sulfonamide; ethyl (E)-3-(5-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-4-(4-isobutyrylpiperazin-1-yl)- 2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)acrylate; N-(1-cyanocyclopropyl)-2-(2-((cyanomethyl)amino)ethyl)-4-(4-isobutyrylpiperazin- 1-yl)-2H-indazole-6-sulfonamide; 2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-2H-indazole-6- sulfonamide; N-(1-cyanocyclopropyl)-2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-2H-indazole-6- sulfonamide; (S)-2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyryl-3-methylpiperazin-1- yl)-N-(3-methyloxetan-3-yl)-2H-indazole-6-sulfonamide; and 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-2-(5-vinyl-1,3,4-thiadiazol-2- yl)-2H-indazole-6-sulfonamide. It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. At various places in the present specification various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached Attorney Docket No.: 53238-0003WO1 to the rest of the molecule at any ring member as permitted by valency. For example, the term “pyridinyl,” “pyridyl,” or “a pyridine ring” may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring. The term “n-membered,” where “n” is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is “n”. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group. For compounds of the invention in which a variable appears more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties independently selected from the group defined for R. As used herein, the phrase “optionally substituted” means unsubstituted or substituted. As used herein, the term “substituted” means that a hydrogen atom is replaced by a non-hydrogen group. It is to be understood that substitution at a given atom is limited by valency. As used herein, the term “C1-j,” where i and j are integers, employed in combination with a chemical group, designates a range of the number of carbon atoms in the chemical group with i-j defining the range. For example, C1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. As used herein, the term “alkyl,” employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched. In some embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3- pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, and the like. In some embodiments, the alkyl group is methyl, ethyl, or propyl. As used herein, “alkenyl,” employed alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon double bonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. As used herein, “alkynyl,” employed alone or in combination with other terms, refers to an alkyl group having one or more carbon-carbon triple bonds. Example alkynyl groups Attorney Docket No.: 53238-0003WO1 include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms. As used herein, “halo” or “halogen”, employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, halo is F or Cl. As used herein, the term “haloalkyl,” employed alone or in combination with other terms, refers to an alkyl group having up to the full valency of halogen atom substituents, which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like. As used herein, the term “alkoxy,” employed alone or in combination with other terms, refers to a group of formula -O-alkyl. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. As used herein, “haloalkoxy,” employed alone or in combination with other terms, refers to a group of formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An example haloalkoxy group is -OCF3. As used herein, “amino,” employed alone or in combination with other terms, refers to NH2. As used herein, the term “cycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclohexene, cyclohexane, and the like, or pyrido derivatives of cyclopentane or cyclohexane. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo. Cycloalkyl groups also include cycloalkylidenes. The term “cycloalkyl” also includes bridgehead cycloalkyl groups (e.g., non-aromatic cyclic hydrocarbon moieties containing at least one bridgehead carbon, such as admantan-1-yl) and spirocycloalkyl groups (e.g., non-aromatic hydrocarbon moieties containing at least two rings fused at a single carbon atom, such as spiro[2.5]octane and the like). In some embodiments, the cycloalkyl group has 3 to 10 ring members, or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is a C3-7 monocyclic cycloalkyl Attorney Docket No.: 53238-0003WO1 group. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. As used herein, the term “heterocycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a bond in common with) to the non-aromatic heterocycloalkyl ring, for example, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least one bridgehead atom, such as azaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., a heterocycloalkyl moiety containing at least two rings fused at a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like). In some embodiments, the heterocycloalkyl group has 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring forming atoms. In some embodiments, the heterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl portion is a C2-7 monocyclic heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is a morpholine ring, pyrrolidine ring, piperazine ring, piperidine ring, tetrahydropyran ring, tetrahyropyridine, azetidine ring, or tetrahydrofuran ring. As used herein, the term “aryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., a fused ring system) aromatic hydrocarbon moiety, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms or 6 carbon atoms. In some Attorney Docket No.: 53238-0003WO1 embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl. As used herein, the term “heteroaryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., a fused ring system) aromatic hydrocarbon moiety, having one or more heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group is a monocyclic or a bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. Example heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl, azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl or the like. The carbon atoms or heteroatoms in the ring(s) of the heteroaryl group can be oxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized, provided the aromatic nature of the ring is preserved. In some embodiments, the heteroaryl group has from 3 to 10 carbon atoms, from 3 to 8 carbon atoms, from 3 to 5 carbon atoms, from 1 to 5 carbon atoms, or from 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring- forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention may be isolated as a mixture of isomers or as separated isomeric forms. Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example Attorney Docket No.: 53238-0003WO1 prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. An example of tautomeric forms, pyridazin-3(2H)-one and pyridazin-3-ol, is depicted below:
Figure imgf000062_0001
. Compounds of the invention also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the invention include at least one deuterium atom. The term, “compound,” as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted, unless otherwise specified. All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates) or can be isolated. In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art. As used herein, and unless otherwise specified, the term "about", when used in connection with a numeric value or range of values which is provided to describe a particular solid form (e.g., a specific temperature or temperature range, such as describing a melting, dehydration, or glass transition; a mass change, such as a mass change as a function of Attorney Docket No.: 53238-0003WO1 temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak position, such as in analysis by, for example, 13C NMR, DSC, TGA and XRPD), indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular solid form. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. Synthesis Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., Attorney Docket No.: 53238-0003WO1 temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety. Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. The expressions, “ambient temperature,” “room temperature,” and “RT”, as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 ºC to about 30 ºC. Compounds of Formula I can be prepared according to numerous preparatory routes known in the literature. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below. Unless noted otherwise, all substituents are as defined herein. In the process depicted in Scheme 1, an appropriately substituted, aldehyde fluoride- containing compound of Formula (1-1) is substituted with amine compound (1-2) in the presence of a base to form the aldehyde compound of Formula (1-3). The compound of Formula (1-3) is reacted with a hydrazine compound of Formula (1-4) to form the indazole compound of Formula (1-5). The indazole compound of Formula (1-5) is substituted with thiadiazole-bromide compound of Formula (1-6) in the presence of a base to form a 1- indazole compound of Formula (1-7) and a 2-indazole compound of Formula (1-8). Scheme 1 Attorney Docket No.: 53238-0003WO1
Figure imgf000065_0001
wherein Z1 is a heterocycloalkyl, comprising 3–9 ring members in addition to the N atom; each R3’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; and q is an integer selected from 0, 1, 2, 3, and 4. In the process depicted in Scheme 2, an appropriately substituted, sulfonic acid chloride containing compound of Formula (2-1) is substituted with amine compound (2-2) in the presence of a base to form the sulfonamide compound of Formula (2-3). The compound of Formula (1-3) is substituted with a compound of Formula (2-4) in the presence of palladium and base to form the protected indazole compound of Formula (2-5). The protected indazole compound of Formula (2-5) is heated in the presence of acid to form the indazole compound of Formula (2-6). The indazole compound of Formula (2-6) is substituted with thiadiazole-bromide compound of Formula (2-7) in the presence of a base to form a 1- indazole compound of Formula (2-8) and a 2-indazole compound of Formula (2-9). Scheme 2 Attorney Docket No.: 53238-0003WO1
Figure imgf000066_0002
Figure imgf000066_0001
wherein Z1 is a heterocycloalkyl, comprising 3–9 ring members in addition to the N atom; each R3’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; q is an integer selected from 0, 1, 2, 3, and 4; and PG represents an appropriate protecting group. In the process depicted in Scheme 3, an appropriately substituted indazole compound of Formula (3-1) is substituted with thiadiazole-bromide compound of Formula (3-2) in the presence of a base to form a 1-indazole compound of Formula (3-3) and a 2-indazole compound of Formula (3-4). The 1-indazole compound of Formula (3-3) and a 2-indazole compound of Formula (3-4) are substituted with an amine compound of Formula (3-5) in the presence of potassium metabisulfite and then base to form a sulfonamide compound of Formula (3-6) and of Formula (3-7). Scheme 3 Attorney Docket No.: 53238-0003WO1
Figure imgf000067_0001
Figure imgf000067_0004
Figure imgf000067_0002
wherein Z1 is a heterocycloalkyl, comprising 3–9 ring members in addition to the N atom; each R3’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; and q is an integer selected from 0, 1, 2, and 3. In the process depicted in Scheme 4, an appropriately substituted bromine-substituted indazole compound of Formula (4-1) is substituted with an alkyl halide compound of Formula (4-2) in the presence of potassium metabisulfite and palladium to form a sulfonamide compound of Formula (4-3). Scheme 4
Figure imgf000067_0003
Attorney Docket No.: 53238-0003WO1 Methods of Use Compounds of the invention can inhibit the activity of PARG. For example, the compounds of the invention can be used to inhibit activity of PARG in a cell or in an individual or patient in need of inhibition of the enzyme by administering an inhibiting amount of a compound of the invention to the cell, individual, or patient. In some embodiments, the PARG is PARG1. As PARG inhibitors, the compounds of the invention are useful in the treatment of various diseases or disorders associated with abnormal expression or activity of PARG. For example, the compounds of the invention are useful in the treatment of cancer. In some embodiments, the cancer is a stress-dependent cancer. In some embodiments, the cancer is selected from lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, mantle cell lymphoma, and renal cell carcinoma. As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal. As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” PARG or “contacting” a cell with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having PARG, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing PARG. As used herein, the term “individual” or “patient,” used interchangeably, refers to mammals, and particularly humans. Typically, the individual or patient is in need of treatment. As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. Attorney Docket No.: 53238-0003WO1 As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and/or symptomatology). As used herein the term “preventing” or “prevention” refers to preventing the disease in an individual who may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease. Combination Therapy One or more additional pharmaceutical agents or treatment methods such as, for example, chemotherapeutics or other anti-cancer agents, immune enhancers, immunosuppressants, immunotherapies, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.), and/or kinase (tyrosine or serine/threonine), epigenetic or signal transduction inhibitors can be used in combination with the compounds of the present invention. The agents can be combined with the present compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. Suitable agents for use in combination with the compounds of the present invention for the treatment of cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapies or radiation therapy. Compounds of this invention may be effective in combination with anti-hormonal agents for treatment of breast cancer and other tumors. Suitable examples are anti-estrogen agents including but not limited to tamoxifen and toremifene, aromatase inhibitors including but not limited to letrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g. prednisone), progestins (e.g. megastrol acetate), and estrogen receptor antagonists (e.g. fulvestrant). Suitable anti-hormone agents used for treatment of prostate and other cancers may also be combined with compounds of the present invention. These include anti-androgens including but not limited to flutamide, bicalutamide, and nilutamide, luteinizing hormone-releasing hormone (LHRH) analogs including leuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists (e.g. degarelix), androgen receptor blockers (e.g. enzalutamide) and agents that inhibit androgen production (e.g. abiraterone). Angiogenesis inhibitors may be efficacious in some tumors in combination with the compounds of the present invention. These include antibodies against VEGF or VEGFR, or Attorney Docket No.: 53238-0003WO1 kinase inhibitors of VEGFR. Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept. Inhibitors of VEGFR kinases and other anti-angiogenesis inhibitors include but are not limited to sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib Suitable chemotherapeutic or other anti-cancer agents for use in combination with the compounds of the present invention include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uracil mustard, chlormethine, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethio- phosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide. Other anti-cancer agent(s) for use in combination with the compounds of the present invention include antibody therapeutics to checkpoint or costimulatory molecules such as CTLA-4, PD-1, PD-L1 or 4-1BB, respectively, or antibodies to cytokines (IL-10, TGF-β, etc.). Exemplary cancer immunotherapy antibodies include pembrolizumab, ipilimumab, nivolumab, atezolizumab and durvalumab. Additional anti-cancer agent(s) for use in combination with the compounds of the present invention include antibody therapeutics directed to surface molecules of hematological cancers such as ofatumumab, rituximab, and alemtuzumab. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety. Pharmaceutical Formulations and Dosage Forms When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions. A pharmaceutical composition refers to a combination of a compound of the invention, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be oral, topical (including ophthalmic and to mucous membranes Attorney Docket No.: 53238-0003WO1 including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, or parenteral. This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. The compositions can be formulated in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these pre-formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above. The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or Attorney Docket No.: 53238-0003WO1 pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner. The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like. The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. Attorney Docket No.: 53238-0003WO1 The therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. The compounds of the invention can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti- viral agents, anti-cancer agents, vaccines, antibodies, immune enhancers, immune suppressants, anti-inflammatory agents and the like. EXAMPLES Definitions: ACN (acetonitrile); AcOH (acetic acid); BPO (benzoyl peroxide); CH3CN (acetonitrile); CDCl3 (deuterated chloroform); CD3OD (deuterated methanol); CH2Cl2 (dichloromethane); Cs2CO3 (cesium carbonate); d (doublet); DCM (dichloromethane); DEA (diethylamine); DEAD (diethyl azodicarboxylate); DIEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); DMAP (4-dimethyl aminopyridine); DMSO (dimethylsulfoxide); DMSO-d6 (deuterated dimethylsulfoxide); EA(ethyl acetate); equiv (equivalents); ESI (electrospray ionization); EtOAc (ethyl acetate); EtOH (ethanol); g (gram); h (hour); 1H NMR (proton nuclear magnetic resonance); HCl (hydrochloric acid); Hz (hertz); IPA (iso- propyl alcohol); K2CO3 (potassium carbonate); L (liter); LiCl (lithium chloride); LiOH (lithium hydroxide); LCMS (liquid chromatography-mass spectrometry); M (molar); MeMgBr (methyl magnesium bromide); MeOH (methanol); mg (milligrams); MHz (megahertz); min (minutes); mL (milliliters), mmol (millimoles); MTBE (methyl tert-butyl ether); m/z (mass per charge); m (multiplet); N2 (nitrogen); NaCl (sodium chloride); Na2SO4 (sodium sulfate); NH4Cl (ammonium chloride); NaN3 (sodium azide); NH3 (ammonia); NH4HCO3 (ammonium bicarbonate); nm (nanometers); PE (petroleum ether); PPh3 (triphenylphosphine); prep-HPLC (preparative high-performance liquid chromatography); ppm (parts per million); q (quartet); RT (room temperature); RT (retention time); RuPhos (2- Attorney Docket No.: 53238-0003WO1 Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl); RuPhos-G3-Palladacycle ((2- Dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)[2-(2-amino-1,1- biphenyl)]palladium(II) methanesulfonate); s (singlet); TEA (triethylamine); TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl); THF (tetrahydrofuran); t (triplet); TsCl (tosyl chloride); Rt (retention time); TLC (thin layer chromatography); TMSCN (trimethylsilyl cyanide); UV (ultraviolet); v/v (volume/volume); Xantphos ((9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane). Intermediate 1: 1-(4-(6-bromo-2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-2H-indazol- 4-yl)piperazin-1-yl)-2-methylpropan-1-one
Figure imgf000074_0001
Step 1: 4-bromo-2-fluoro-6-[4-(2-methylpropanoyl)piperazin-1-yl]benzaldehyde A mixture of 4-bromo-2,6-difluorobenzaldehyde (5 g, 22.624 mmol, 1 equiv), 2-methyl-1- (piperazin-1-yl)propan-1-one (5.30 g, 33.936 mmol, 1.5 equiv) and K2CO3 (6.25 g, 45.248 mmol, 2 equiv) in DMF (50 mL) was stirred for 16 h at 80 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. Then water (200 mL) was added. The mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (eluting with 1:2 EA/PE) to afford 4-bromo-2-fluoro-6-[4-(2-methylpropanoyl)piperazin-1-yl]benzaldehyde (5 g, 55.68%) as a yellow solid. LCMS (ESI, m/z): 357, 359 [M+H] +. Step 2: 1-[4-(6-bromo-1H-indazol-4-yl)piperazin-1-yl]-2-methylpropan-1-one A mixture of 4-bromo-2-fluoro-6-[4-(2-methylpropanoyl)piperazin-1-yl]benzaldehyde (5 g, 13.997 mmol, 1 equiv) and hydrazine hydrate (2.80 g, 55.988 mmol, 4 equiv) in DMSO (50 mL) was stirred for 12 h at 100 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was quenched with water (150 mL). The aqueous layer was extracted with EA (3×100 mL). The combined organic layers were washed by brine (150 mL), dried over anhydrous Na2SO4. After Attorney Docket No.: 53238-0003WO1 filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 1:1 EA/PE) to afford 1-[4-(6-bromo-1H- indazol-4-yl)piperazin-1-yl]-2-methylpropan-1-one (4 g, 73.22%) as a yellow solid. LCMS (ESI, m/z): 351, 353 [M+H] +. Step 3: 1-(4-(6-bromo-2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-2H-indazol-4- yl)piperazin-1-yl)-2-methylpropan-1-one To a stirred mixture of 1-[4-(6-bromo-1H-indazol-4-yl)piperazin-1-yl]-2-methylpropan-1-one (5 g, 14.235 mmol, 1 equiv) and 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (3.67 g, 17.082 mmol, 1.2 equiv) in DMF (30 mL) was added Cs2CO3 (11.60 g, 35.587 mmol, 2.5 equiv) at room temperature. The resulting mixture was stirred for 2 h at 70 °C. The reaction was monitored by LCMS. added The mixture was allowed to cool down to room temperature. The resulting mixture was quenched with water (150 mL). The aqueous layer was extracted with EA (3×100 mL). The combined organic layers were washed by brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue silica gel column chromatography (eluting with 2:1 EA/PE) to afford 1-(4-{6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazin-1- yl)-2-methylpropan-1-one (3 g, 44%) as a light yellow solid and 1-(4-(6-bromo-2-(5- (difluoromethyl)-1,3,4-thiadiazol-2-yl)-2H-indazol-4-yl)piperazin-1-yl)-2-methylpropan-1- one (0.5 g, 7.3%) as a light yellow solid. LCMS (ESI, m/z): 485, 487 [M+H] +. 1H NMR (300 MHz, d6-DMSO) δ 8.80 (s, 1H), 8.11 (s, 1H), 7.72-7.45 (m, 1H), 6.91 (s, 1H), 6.81-6.69 (m, 4H), 6.48-6.36 (m, 4H), 2.99-2.87 (m, 1H), 1.04 (d, J=6.8 Hz, 6H). Intermediate 2: 2-(6-bromo-4-(piperazin-1-yl)-2H-indazol-2-yl)-5-(difluoromethyl)- 1,3,4-thiadiazole
Figure imgf000075_0001
Step 1: 4-(5-bromo-3-fluoro-2-formylphenyl)piperazine-1-carboxylate A mixture of 4-bromo-2,6-difluorobenzaldehyde (5 g, 22.624 mmol, 1 equiv), tert-butyl piperazine-1-carboxylate (5.06 g, 27.149 mmol, 1.2 equiv) and K2CO3 (6.25 g, 45.248 mmol, 2 equiv) in DMF (50 mL) was stirred for 12 h at 80 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. Then water (150 mL) Attorney Docket No.: 53238-0003WO1 was added. The mixture was extracted with EA (3×100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (eluting with 1:1 EA/PE) to afford tert-butyl 4-(5-bromo-3-fluoro-2-formylphenyl)piperazine-1-carboxylate (5 g, 51.36%) as a yellow solid. LCMS (ESI, m/z): 387, 389 [M+H] +. Step 2: 4-(6-bromo-1H-indazol-4-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(5-bromo-3-fluoro-2-formylphenyl)piperazine-1-carboxylate (5 g, 12.912 mmol, 1 equiv) and hydrazine hydrate (80%, 2.59 g, 51.648 mmol, 4 equiv) in DMSO (40 mL) was stirred for 30 h at 100 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. Then water (150 mL) was added. The mixture was extracted with EA (3×100 mL), the combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (eluting with 1:1 EA/PE) to afford tert-butyl 4-(6-bromo- 1H-indazol-4-yl)piperazine-1-carboxylate (4 g, 73.13%) as a yellow solid. LCMS (ESI, m/z): 381, 383[M+H]+. Step 3: tert-butyl 4-{6-bromo-2-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4- yl}piperazine-1-carboxylate A mixture of tert-butyl 4-(6-bromo-1H-indazol-4-yl)piperazine-1-carboxylate (4 g, 10.491 mmol, 1 equiv), 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (2.71 g, 12.589 mmol, 1.2 equiv) and Cs2CO3 (6.84 g, 20.982 mmol, 2 equiv) in DMF (40 mL) was stirred for 2 h at 70 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. Then water (100 mL) was added. The mixture was extracted with EA (3×80 mL), the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (eluting with 1:1 EA/PE) to afford tert-butyl 4-{6-bromo-1-[5-(difluoromethyl)-1,3,4- thiadiazol-2-yl]indazol-4-yl}piperazine-1-carboxylate (3.0 g, 55%) as a yellow solid. tert- butyl 4-{6-bromo-2-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4-yl}piperazine-1- carboxylate (0.5 g, 9.2%) as a yellow solid. LCMS (ESI, m/z): 515, 517 [M+H]+. Step 4: 2-(6-bromo-4-(piperazin-1-yl)-2H-indazol-2-yl)-5-(difluoromethyl)-1,3,4-thiadiazole To a stirred solution of tert-butyl 4-(6-bromo-2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)- 2H-indazol-4-yl)piperazine-1-carboxylate (0.5 g, 0.97 mmol, 1 equiv) in 1,4-dioxane (4 mL) was added HCl (4M in 1,4-dioxane, 1 mL) dropwise. The resulting mixture was stirred Attorney Docket No.: 53238-0003WO1 for 1 h at rt. The reaction was monitored by LCMS. The reaction was monitored by LCMS. The mixture was concentrated. The residue was purified by silica gel column chromatography (eluting with 3:1 EA/PE) to afford 2-(6-bromo-4-(piperazin-1-yl)-2H- indazol-2-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (1 g, 74.47%) as a yellow solid. LCMS (ESI, m/z): 415, 417 [M+H] +. Example 1A, 1B, and 1C: 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((1S,2R)-1-cyano-2- methylcyclopropyl)-4-(4-isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide (1A), 2- (5-bromo-1,3,4-thiadiazol-2-yl)-N-((1R,2S)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide (1B), and rac 2-(5-bromo-1,3,4- thiadiazol-2-yl)-N-((trans)-1-cyano-2-methylcyclopropyl)-4-(4-isobutyrylpiperazin-1-yl)- 2H-indazole-6-sulfonamide (1C)
Figure imgf000077_0001
Step 1: 4-chloro-N-(1-cyano-2-methylcyclopropyl)-1-[(4-methoxyphenyl)methyl]indazole-6- sulfonamide A solution of 1-amino-2-methylcyclopropane-1-carbonitrile (258.96 mg, 2.694 mmol, 2 equiv) in DCM (5 mL) and pyridine (5 mL) was treated with 4-chloro-1-[(4- methoxyphenyl)methyl]indazole-6-sulfonyl chloride (500 mg, 1.347 mmol, 1 equiv) in portions at 0 °C. The resulting mixture was stirred for overnight at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 4-chloro-N-(1-cyano-2-methylcyclopropyl)-1-[(4- methoxyphenyl)methyl]indazole-6-sulfonamide; methane (150 mg, 22.43%) as a yellow solid. LCMS (ESI, m/z): 431, 433 [M+H] +. Step 2: N-(1-cyano-2-methylcyclopropyl)-1-[(4-methoxyphenyl)methyl]-4-[4-(2- methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide To a stirred solution of 4-chloro-N-(1-cyano-2-methylcyclopropyl)-1-[(4- methoxyphenyl)methyl] indazole-6-sulfonamide (130 mg, 0.302 mmol, 1 equiv) and 2- Attorney Docket No.: 53238-0003WO1 methyl-1-(piperazin-1-yl)propan-1-one (94.26 mg, 0.604 mmol, 2 equiv) in dioxane (5 mL) were added RuPhos (4.33 mg, 0.009 mmol, 0.2 equiv), Cs2CO3 (294.89 mg, 0.906 mmol, 3 equiv) and [2',6'-bis(propan-2-yloxy)-[1,1'-biphenyl]-2-yl]dicyclohexylphosphane; {2'- amino-[1,1'-biphenyl]-2-yl}palladio methanesulfonate (25.23 mg, 0.030 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filter cake was washed with DCM (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford N-(1-cyano-2-methylcyclopropyl)-1-[(4-methoxyphenyl)methyl]-4-[4-(2- methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide (150 mg, 81.26%) as a yellow solid. LCMS (ESI, m/z): 551 [M+H] +. Step 3: N-(1-cyano-2-methylcyclopropyl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]-1H- indazole-6-sulfonamide A solution of N-(1-cyano-2-methylcyclopropyl)-1-[(4-methoxyphenyl)methyl]-4-[4-(2- methyl propanoyl)piperazin-1-yl]indazole-6-sulfonamide (130 mg, 0.236 mmol, 1 equiv) in TFA (5 mL) was stirred for 8 h at 70 °C. The resulting mixture was concentrated under reduced pressure to afford N-(1-cyano-2-methylcyclopropyl)-4-[4-(2- methylpropanoyl)piperazin-1-yl]-1H-indazole-6-sulfonamide (120 mg, crude) as a yellow oil. LCMS (ESI, m/z): 431[M+H] +. Step 4: 1-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1-cyano-2-methylcyclopropyl)-4-[4-(2- methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide) and 2-(5-bromo-1,3,4-thiadiazol-2- yl)-N-(1-cyano-2-methylcyclopropyl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6- sulfonamide) A mixture of N-(1-cyano-2-methylcyclopropyl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]- 1H-indazole-6-sulfonamide (130 mg, 0.302 mmol, 1 equiv) , Cs2CO3 (295.15 mg, 0.906 mmol, 3 equiv) and dibromo-1,3,4-thiadiazole (147.29 mg, 0.604 mmol, 2 equiv) in DMF (5 mL) was stirred for 8 h at room temperature. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC Attorney Docket No.: 53238-0003WO1 with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 75% B in 7 min, 75% B; Wave Length: 254 nm; RT1(min): 6.4; Number Of Runs: 0) to afford 40 mg a mixture of 1-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1- cyano-2-methylcyclopropyl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6- sulfonamide) and 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1-cyano-2-methylcyclopropyl)-4-[4- (2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide) as a yellow solid. LCMS (ESI, m/z): 593, 595[M+H] +. Step 5: 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((1S,2R)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide and 2-(5-bromo-1,3,4-thiadiazol-2-yl)- N-((1R,2S)-1-cyano-2-methylcyclopropyl)-4-(4-isobutyrylpiperazin-1-yl)-2H-indazole-6- sulfonamide 2-(5-Bromo-1,3,4-thiadiazol-2-yl)-N-[(1S,2R)-1-cyano-2-methylcyclopropyl]-4-[4-(2-methyl propanoyl)piperazin-1-yl]indazole-6-sulfonamide was separated by Prep-chiral-HPLC with the following conditions (Column: CHIRALPAK IE, 2*25 cm, 5 μm ; Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 25 min; Wave Length: 220/254 nm; RT1(min): 13.872; RT2(min): 15.572; Sample Solvent: EtOH--HPLC; Injection Volume: 0.5 mL; Number Of Runs: 8) to afford 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-[(1S,2R)-1-cyano-2- methylcyclopropyl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide (3.0 mg) as a yellow solid and 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((1R,2S)-1-cyano-2- methylcyclopropyl)-4-(4-isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide (2.8 mg, stereochemistry assumed) as a yellow solid. 2-(5-Bromo-1,3,4-thiadiazol-2-yl)-N-((1S,2R)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide (stereochemistry assumed): LCMS (ESI, m/z): 364.00 [M+H]+; 1H NMR (300 MHz, Chloroform-d) δ=9.12(s, 1H), 8.00 (s, 1H), 6.78 (s, 1H), 5.39 (s, 1H), 3.92-3.75 (m, 4H), 3.43-3.33 (m, 4H), 2.93-2.78 (m, 1H), 1.60- 1.55 (m, 3H), 1.36-1.23 (m, 3H), 1.18 (d, J=6.3 Hz, 6H). rac 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((trans)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide(stereochemistry assumed): LCMS (ES, m/z): 593.10, 595.10 [M+H]+, RT: 0.936 min. 1H NMR (400 MHz, Chloroform-d) δ 9.00 (s, 1H), 7.99 (s, 1H), 6.77 (s, 1H), 5.95 (s, 1H), 3.99-3.72 (m, 4H), 3.53-3.22 (m, 4H), Attorney Docket No.: 53238-0003WO1 2.95-2.72 (m, 1H), 2.00-1.81 (m, 1H), 1.81-1.72 (m, 1H), 1.28 (d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.8 Hz, 6H), 1.16-1.08 (m, 1H).
Figure imgf000080_0001
Example 2: 1-(4-(2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(((1- methylcyclopropyl)methyl)sulfonyl)-2H-indazol-4-yl)piperazin-1-yl)-2-methylpropan-1- one
Figure imgf000080_0002
To a stirred mixture of 1-(4-{6-bromo-2-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazol-4- yl}piperazin-1-yl)-2-methylpropan-1-one (50 mg, 0.103 mmol, 1 equiv), potassium metabisulfite (45.81 mg, 0.206 mmol, 2 equiv) , PPh3 (8.11 mg, 0.031 mmol, 0.309 equiv), sodium formate (21.02 mg, 0.309 mmol, 3 equiv), phen (5.57 mg, 0.031 mmol, 0.3 equiv) and Pd(OAc)2 (2.31 mg, 0.010 mmol, 0.1 equiv) in DMSO (1.5 mL) was added TEAB (16.44 mg, 0.113 mmol, 1.1 equiv). The mixture was stirred for 4 h at 70 °C under N2 atmosphere. To the above was added 1-(bromomethyl)-1-methylcyclopropane (61.41 mg, 0.412 mmol, 4 equiv) in DMSO (0.5 mL) dropwise. The mixture was stirred at 0 °C for other 1 h. Desired product could be detected by LCMS. The reaction was quenched with brine (15 mL). The mixture was washed with EA (2×15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following condition: (Column: YMC-Actus Triart C18 ExRS, 20*250 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 6.23 mL/min; Gradient: 60% B to 80% B in 7 min, 80% B; Wave Attorney Docket No.: 53238-0003WO1 Length: 254 nm; RT1(min): 5; Injection Volume: 0.5 mL; Number Of Runs: 5) to afford 1- (4-(2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(((1-methylcyclopropyl)methyl)sulfonyl)- 2H-indazol-4-yl)piperazin-1-yl)-2-methylpropan-1-one (5.4 mg, 9.65%) as a yellow solid. LCMS (ESI, m/z): 539.20 [M+H]+, 1H NMR (300 MHz, DMSO-d6) δ=9.74 (s, 1H), 7.77- 7.64 (m, 2H), 6.68 (s, 1H), 3.78-3.76 (m, 4H), 3.47-3.34 (m, 6H), 2.99-2.90 (m, 1H), 1.15 (s, 3H), 1.05 (d, J=6.6 Hz, 6H), 0.42-0.39 (m, 2H), 0.27-0.26 (m, 2H). Example 3: 2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide
Figure imgf000081_0001
Step 1: 2-bromo-5-cyclopropyl-1,3,4-thiadiazole A mixture of 2-methyl-2-propylnitrite (1.68 g, 16.291 mmol, 2.3 equiv) and CuBr2 (3.64 g, 16.291 mmol, 2.3 equiv) in ACN (20 mL) was stirred for 10 min at room temperature. To the above mixture was added 5-cyclopropyl-1,3,4-thiadiazol-2-amine (1 g, 7.083 mmol, 1 equiv) in portions. The mixture was stirred for additional 3 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford 2-bromo-5-cyclopropyl-1,3,4-thiadiazole (700 mg, 48.19%) as a yellow oil. LCMS (ESI, m/z): 205, 207[M+H]+ Step 2: 1-{4-[6-bromo-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1-yl}-2- methylpropan-1-one and 1-{4-[6-bromo-2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)indazol-4- yl]piperazin-1-yl}-2-methylpropan-1-one A mixture of 1-[4-(6-bromo-1H-indazol-4-yl)piperazin-1-yl]-2-methylpropan-1-one (1 g, 2.85 mmol, 1 equiv), 2-bromo-5-cyclopropyl-1,3,4-thiadiazole (701 mg, 3.42 mmol, 1.2 equiv) and Cs2CO3 (2.31 g, 7.12 mmol, 2.5 equiv) in DMF (10 mL) was stirred for 3 h at 70℃. The reaction was monitored by LCMS. The resulting mixture was quenched with water (100 mL). The aqueous layer was extracted with EA (3×100 mL). The combined organic layers were washed by brine (100 mL), dried over anhydrous Na2SO4. After Attorney Docket No.: 53238-0003WO1 filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford the mixture of 1-{4-[6- bromo-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1-yl}-2-methylpropan- 1-one and 1-{4-[6-bromo-2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1- yl}-2-methylpropan-1-one (600 mg, 44%) as a yellow solid. LCMS (ESI, m/z): 475, 477[M+H]+ Step 3: 2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide A mixture of 1-{4-[6-bromo-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1- yl}-2-methylpropan-1-one and 1-{4-[6-bromo-2-(5-cyclopropyl-1,3,4-thiadiazol-2- yl)indazol-4-yl]piperazin-1-yl}-2-methylpropan-1-one (300 mg, 0.631 mmol, 1 equiv), potassium metabisulfite (280.59 mg, 1.262 mmol, 2 equiv), tetraethylazanium bromide (145.88 mg, 0.694 mmol, 1.1 equiv), sodium formate (128.74 mg, 1.893 mmol, 3 equiv), PPh3 (49.65 mg, 0.189 mmol, 0.3 equiv), phen (34.12 mg, 0.189 mmol, 0.3 equiv) and Pd(AcO)2 (14.17 mg, 0.063 mmol, 0.1 equiv) in DMSO (2 mL) was stirred for 4 h at 70℃ under nitrogen atmosphere. To the above mixture was added 3- (fluoromethyl)oxetan-3-amine (265.32 mg, 2.524 mmol, 4 equiv), pyridine (0.5 mL, 0.006 mmol, 0.01 equiv) and NBS (449.26 mg, 2.524 mmol, 4 equiv) in THF (2 mL) dropwise at 0℃. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was monitored withe LCMS. The resulting mixture was quenched with water (50 mL). The aqueous layer was extracted with EA (3×50 mL). The combined organic layers were washed by brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by Prep-HPLC with the following conditions ( Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 60% B in 7 min, 60% B; Wave Length: 254 nm; RT1(min): 6.17; Injection Volume: 0.8 mL; Number Of Runs: 2) to afford 1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-[3- (fluoromethyl)oxetan-3-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide (24.6 mg, 6.85%) and 2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3- yl)-4-(4-isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide (13.6 mg, 3.79%) as a white solid. LCMS (ESI, m/z): 564.25[M+H]+. 1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-[3-(fluoromethyl)oxetan-3-yl]-4-[4-(2- methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide: 1HNMR (300 MHz, DMSO-d6) Attorney Docket No.: 53238-0003WO1 δ=8.89 (br, 1H), 8.84 (s, 1H), 8.43 (s, 1H), 7.12 (s, 1H), 4.68 (s, 1H), 4.61-4.48 (m, 3H), 4.33 (d, J=6.9 Hz, 2H), 3.77-3.74 (m, 4H), 3.43-3.32 (m, 4H), 2.97-2.89 (m, 1H), 2.59-2.51 (m, 1H), 1.28-1.25 (m, 2H), 1.24-1.21 (m, 2H), 1.06 (d, J=6.6 Hz, 6H). 2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide: 1H NMR (300 MHz, DMSO-d6) ¥ 9.52 (s, 1H), 8.69 (br, 1H), 7.65 (s, 1H), 6.72 (s, 1H), 4.68 (s, 1H), 4.59-4.50 (m, 3H), 4.33 (d, J=6.6 Hz, 2H), 3.76-3.71 (m, 4H), 3.38-3.29 (m, 4H), 2.99-2.90 (m, 1H), 2.73-2.50 (m, 1H), 1.35-1.28 (m, 2H), 1.21-1.11 (m, 2H), 1.06 (d, J=6.6 Hz, 6H). Example 4: N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2-(5-methyl- 1,3,4-thiadiazol-2-yl)-2H-indazole-6-sulfonamide
Figure imgf000083_0001
Step 1: 1-(4-(6-bromo-2-(5-methyl-1,3,4-thiadiazol-2-yl)-2H-indazol-4-yl) piperazin-1-yl)-2- methylpropan-1-one A solution of 1-[4-(6-bromo-1H-indazol-4-yl) piperazin-1-yl]-2-methylpropan-1-one (1 g, 2.847 mmol, 1 equiv) and Cs2CO3 (2.78 g, 8.541 mmol, 3 equiv) in DMF (10 mL) was added 2-bromo-5- methyl-1,3,4-thiadiazole (1.02 g, 5.694 mmol, 2 equiv) in portions. The resulting mixture was stirred for 2 h at 70oC. Desired product could be detected by LCMS. The reaction was with quenched with brine (100 mL). The resulting mixture extracted with EA (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (1:1) to afford 1-(4-(6-bromo-2-(5-methyl-1,3,4-thiadiazol-2-yl)-2H-indazol-4-yl) piperazin-1-yl)-2-methylpropan-1-one (200 mg, 15.63%) as a yellow solid. LCMS (ES, m/z): 449, 451[M+H]+, Step 2: N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2-(5-methyl-1,3,4- thiadiazol-2-yl)-2H-indazole-6-sulfonamide To a stirred mixture of 1-{4-[6-bromo-2-(5-methyl-1,3,4-thiadiazol-2-yl)indazol-4- Attorney Docket No.: 53238-0003WO1 yl]piperazin- 1-yl}-2-methylpropan-1-one (150 mg, 0.334 mmol, 1 equiv) in DMSO (2 mL) was added dipotassium sulfinosulfonate (148.42 mg, 0.668 mmol, 2 equiv), PPh3 (26.27 mg, 0.100 mmol, 0.3 equiv), sodium formate (68.11 mg, 1.002 mmol, 3 equiv), Pd(OAc)2 (7.49 mg, 0.033 mmol, 0.1 equiv) and phen (18.05 mg, 0.100 mmol, 0.3 equiv). The resulting mixture was stirred for 4 h at 70 °C under N2 atmosphere. Then 3-(fluoromethyl) oxetan-3- amine hydrochloride (141.77 mg, 1.002 mmol, 3 equiv) in pyridine (1 mL) and NBS (237.65 mg, 1.336 mmol, 4 equiv) in THF (2 mL) were added dropwise at 0oC. The mixture was stirred for other 1 h at room temperature. Desired product could be detected by LCMS. The reaction was quenched with water (20 mL). The mixture was washed with EA (3×15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following condition: (Column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 31% B to 61% B in 7 min, 61% B; Wave Length: 254 nm; RT1(min): 6.78; Injection Volume: 0.7 mL; Number Of Runs: 2) to afford N-(3-(fluoromethyl)oxetan-3-yl)-4-(4- isobutyrylpiperazin-1-yl)-2-(5-methyl-1,3,4-thiadiazol-2-yl)-2H-indazole-6-sulfonamide (0.8 mg, 0.43%) as a yellow solid. LCMS (ES, m/z): 538 [M+H]+, 1H NMR (300 MHz, DMSO- d6) δ=9.58-9.57 (m, 1H), 8.83 (br, 1H), 7.68 (s 1H), 6.71 (s, 1H), 4.70 (s, 1H), 4.57-4.54 (m, 3H), 4.33 (d, J=6.9 Hz, 2H), 3.76-3.73 (m, 4H), 3.76-3.50 (m, 4H), 2.97-2.92 (m, 1H), 2.80 (s, 3H), 1.05 (d, J=6.6 Hz, 6H). Example 5: 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-2-(1,3,4-thiadiazol-2- yl)-2H-indazole-6-sulfonamide
Figure imgf000084_0001
A solution of bis(1-{4-[6-bromo-2-(1,3,4-thiadiazol-2-yl)indazol-4-yl]piperazin-1-yl}-2-meth ylpropan-1-one) (150 mg, 0.345 mmol, 1 equiv) in DMSO (5 mL) was treated with potassium metabisulfite (153.21 mg, 0.690 mmol, 2 equiv), tetraethylazanium bromide (79.65 mg, 0.38 0 mmol, 1.1 equiv), sodium formate (70.30 mg, 1.035 mmol, 3 equiv), PPh3 (27.11 mg, 0.103 Attorney Docket No.: 53238-0003WO1 mmol, 0.3 equiv), 1,10-phenanthroline (18.63 mg, 0.103 mmol, 0.3 equiv) and palladium ace tate (7.74 mg, 0.034 mmol, 0.1 equiv). The mixture was stirred for 4 h at 70 °C under nitroge n atmosphere. To the above was added 3-methyloxetan-3-amine (90.06 mg, 1.035 mmol, 3 eq uiv) in pyridine (2 mL) in portions. Then 1-bromopyrrolidine-2,5-dione (183.98 mg, 1.035 m mol, 3 equiv) in THF (5 mL) was added dropwise at 0 °C. The resulting mixture was stirred f or 1 h at 25 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The reacti on mixture was diluted with water (30 mL). The resulting mixture was extracted with EA (3× 30 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydro us Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude produ ct was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.1%NH3. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 54% B in 7 min, 5 4% B; Wave Length: 254 nm; RT1(min): 5.87; Injection Volume: 0.7 mL; Number Of Runs: 3) to afford 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-2-(1,3,4-thiadiazol-2-yl)- 2H-indazole-6-sulfonamide (13.2 mg, 7.54%) as a yellow solid. LCMS (ESI, m/z): 506.05 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ=9.64-9.60 (m, 2H), 8.45 (s, 1H), 7.67 (s, 1H), 6.7 1 (s, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.12 (d, J=6.0 Hz, 2H), 3.84-3.71 (m, 4H), 3.45-3.33 (m, 4 H), 2.97-2.94 (m, 1H), 1.44 (s, 3H), 1.05 (d, J = 6.8 Hz, 6H). Example 6: N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2-(5-vinyl- 1,3,4-thiadiazol-2-yl)-2H-indazole-6-sulfonamide
Figure imgf000085_0001
Step 1: 1-[4-(6-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl} indazol-4-yl)piperazin-1-yl]-2- methylpropan-1-one To a solution of 1-[4-(6-bromo-1H-indazol-4-yl)piperazin-1-yl]-2-methylpropan-1-one (1 g, 2.847 mmol, 1 equiv) and DIEA (1.10 g, 8.541 mmol, 3 equiv)was added [2- (chloromethoxy)ethyl]trimethylsilane dropwise at 0 °C. The resulting mixture was stirred for 2 h at 25 °C. The reaction was monitored by LCMS. Then the reaction was quenched with water (100 mL). The resulting mixture was extracted with EA (3×100 mL). The combined Attorney Docket No.: 53238-0003WO1 organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford 1-[4-(6-bromo-1-{[2- (trimethylsilyl)ethoxy]methyl} indazol-4-yl)piperazin-1-yl]-2-methylpropan-1-one (950 mg, 69.30%) as a white solid. LCMS (ES, m/z): 481ˈ483 [M+H] +. Step 2: 4-[4-(2-methylpropanoyl)piperazin-1-yl]-1-{[2- (trimethylsilyl)ethoxy]methyl}indazole-6-sulfonyl fluoride A mixture of 1-[4-(6-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}indazol-4-yl)piperazin-1- yl]-2-methylpropan-1-one (880 mg, 1.828 mmol, 1.00 equiv), potassium metabisulfite (811.45 mg, 3.656 mmol, 2 equiv), TEAB (422.17 mg, 2.011 mmol, 1.1 equiv), sodium formate (372.83 mg, 5.484 mmol, 3 equiv), palladium acetate (40.94 mg, 0.183 mmol, 0.1 equiv) and o-phenanthroline (98.69 mg, 0.548 mmol, 0.3 equiv) in DMSO (10 mL) was stirred for 4 h at 70 ℃ under nitrogen atmosphere. Then to the above mixture was added N- (benzenesulfonyl)-N-fluorobenzenesulfonamide (576.29 mg, 1.828 mmol, 1.00 equiv) in THF (2 mL) dropwise over 2 min at 0 °C. The resulting mixture was stirred for additional 25 °C at 2 h. The reaction was monitored by LCMS. Then, the reaction was quenched with water (40 mL). The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford 4-[4-(2- methylpropanoyl)piperazin-1-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}indazole-6-sulfonyl fluoride (770 mg, 86.87%) as an off-white solid. LCMS (ES, m/z): 485.30[M+H] +. Step 3: N-[3-(fluoromethyl)oxetan-3-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]-1-{[2- (trimethylsilyl)ethoxy]methyl}indazole-6-sulfonamide A solution of 4-[4-(2-methylpropanoyl)piperazin-1-yl]-1-{[2- (trimethylsilyl)ethoxy]methyl}indazole-6-sulfonyl fluoride (770 mg, 1.589 mmol, 1 equiv), HOBT (214.68 mg, 1.589 mmol, 1 equiv), DIEA (1437.38 mg, 11.123 mmol, 7 equiv) and 3- (fluoromethyl)oxetan-3-amine (333.99 mg, 3.178 mmol, 2 equiv) in DMSO (8 mL) was stirred for 2 h at 25 °C. The reaction was monitored by LCMS. Then, the reaction was quenched with water (25 mL). The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified Attorney Docket No.: 53238-0003WO1 by silica gel column chromatography, eluted with PE/EA (1:3) to afford N-[3- (fluoromethyl)oxetan-3-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]-1-{[2- (trimethylsilyl)ethoxy]methyl}indazole-6-sulfonamide (530 mg, 58.55%) as an off-white solid. LCMS (ES, m/z): 570.35 [M+H] +. Step 4: N-[3-(fluoromethyl)oxetan-3-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]-1H- indazole-6-sulfonamide A mixture of N-[3-(fluoromethyl)oxetan-3-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]-1- {[2-(trimethylsilyl)ethoxy]methyl}indazole-6-sulfonamide (530 mg, 0.930 mmol, 1 equiv) and TFA (2 mL, 24.686 mmol, 26.54 equiv) in DCM (1 mL, 15.731 mmol, 16.91 equiv) was stirred at 0 °C for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in N-[3-(fluoromethyl)oxetan-3-yl]-4-[4- (2-methylpropanoyl)piperazin-1-yl]-1H-indazole-6-sulfonamide (400 mg, crude) as a white solid. LCMS (ES, m/z): 440.20 [M+H] +. Step 5: 1-(5-bromo-1,3,4-thiadiazol-2-yl)-N-[3-(fluoromethyl)oxetan-3-yl]-4-[4-(2-methyl propanoyl)piperazin-1-yl]indazole-6-sulfonamide and 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N- (3-(fluoromethyl) oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide Into a mixture of N-[3-(fluoromethyl)oxetan-3-yl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]- 1H-indazole-6-sulfonamide (230 mg, 0.523 mmol, 1 equiv) and K2CO3 (216.97 mg, 1.569 mmol, 3 equiv) in DMF (5 mL) was added dibromo-1,3,4-thiadiazole (153.16 mg, 0.628 mmol, 1.2 equiv). The resulting mixture was stirred for additional 16 h at 60 °C. The reaction was monitored by LCMS. Then, the reaction was quenched with water (50 mL). The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA(1:1) to afford the mixture of 1-(5-bromo-1,3,4- thiadiazol-2-yl)-N-[3-(fluoromethyl)oxetan-3-yl]-4-[4-(2-methyl propanoyl)piperazin-1- yl]indazole-6-sulfonamide and 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl) oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide (61 mg, 19.35%) as an off-white solid. LCMS (ES, m/z): 601, 603 [M+H] +. Step 6: N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2-(5-vinyl-1,3,4- thiadiazol-2-yl)-2H-indazole-6-sulfonamide A mixture of 1-(5-bromo-1,3,4-thiadiazol-2-yl)-N-[3-(fluoromethyl)oxetan-3-yl]-4-[4-(2- Attorney Docket No.: 53238-0003WO1 methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide (30 mg, 0.050 mmol, 1 equiv) and 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin- 1-yl)-2H-indazole-6-sulfonamide (30 mg, 0.050 mmol, 1 equiv) and 2-ethenyl-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (15.34 mg, 0.100 mmol, 2 equiv), Pd(dppf)Cl2 (3.64 mg, 0.005 mmol, 0.1 equiv) and Na2CO3 (15.83 mg, 0.150 mmol, 3 equiv) in 1,4-dioxane (2 mL) and H2O (0.5 mL) was stirred for 16 h at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. Then, the reaction was quenched with water (20 mL). The resulting mixture was washed with EA (3×20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with PE/EA (1:1). The crude product was purified by Prep-HPLC with the following conditions (Column: Agilent Poroshell HPH- C18; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 32% B to 58% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.31) to afford N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(5-vinyl- 1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (3.1 mg, 11.16%) as a white solid and N- (3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2-(5-vinyl-1,3,4-thiadiazol-2- yl)-2H-indazole-6-sulfonamide (1.6 mg, 8.62%) as a yellow solid. N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-1-(5-vinyl-1,3,4- thiadiazol-2-yl)-1H-indazole-6-sulfonamide˖LCMS (ES, m/z): 550.15 [M+H] +. Rt 0.886 min. 1H NMR (400 MHz, Chloroform-d) δ=8.82 (s, 1H), 8.26 (s, 1H), 7.19 (s, 1H), 7.09-7.01 (m, 1H), 6.07-6.01 (m, 1H), 5.84 (d, J = 8.8 Hz, 1H), 5.40 (s, 1H), 4.81-4.88 (m, 3H), 4.73 (s, 1H), 4.45 (d, J = 7.2 Hz, 2H), 3.95-3.76 (m, 4H), 3.46-3.34 (m, 4H), 2.89-2.81 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H). N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2-(5-vinyl-1,3,4- thiadiazol-2-yl)-2H-indazole-6-sulfonamide˖LCMS (ES, m/z): 550.10 [M+H] +. Rt 0.865 min. 1H NMR (400 MHz, Chloroform-d) δ=9.03 (s, 1H), 7.92 (s, 1H), 7.09-7.01 (m, 1H), 6.71 (s, 1H), 6.14-6.09 (m, 1H), 5.92-5.86 (m, 1H), 5.16 (s, 1H), 4.88-4.81 (m, 3H), 4.73 (s, 1H), 4.45 (d, J = 6.8 Hz, 2H), 3.92-3.75 (m, 4H), 3.43-3.36 (m, 4H), 2.89-2.81 (m, 1H), 1.19 (d, J = 6.8 Hz, 6H). Example 7: 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1-cyanocyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide Attorney Docket No.: 53238-0003WO1
Figure imgf000089_0001
To a stirred solution of N-(1-cyanocyclopropyl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]- 1H-indazole-6-sulfonamide (95 mg, 0.228 mmol, 1 equiv) and Cs2CO3 (74.32 mg, 0.228 mmol, 1 equiv) in DMF was added dibromo-1,3,4-thiadiazole (66.76 mg, 0.274 mmol, 1.2 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for additional 24h at room temperature. Desired product could be detected by LCMS. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol/L NH4HCO3), 10% to 60% gradient in 20 min; detector, UV 254 nm to afford the crude. The crude product was purified by reverse phase flash with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 44% B to 64% B in 7 min, 64% B; Wave Length: 254 nm; RT1(min): 5.83/6.27; Number Of Runs: 0) to afford 1-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1- cyanocyclopropyl)-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide (7.2 mg, 5.20%) as a light yellow solid and 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1- cyanocyclopropyl)-4-(4-isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide (4.9 mg, 3.57%) as a yellow solid. LCMS (ESI, m/z): 579 [M+H]+. 1-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1-cyanocyclopropyl)-4-[4-(2- methylpropanoyl)piperazin-1-yl]indazole-6-sulfonamide:
Figure imgf000089_0002
MHz, DMSO-d6) δ 8.94 (s, 1H), 8.41 (s, 1H), 7.15 (d, J = 1.4 Hz, 1H), 3.77 (d, J = 14.6 Hz, 4H), 3.46 (s, 4H), 2.95 (p, J = 6.7 Hz, 1H), 1.45 – 1.35 (m, 2H), 1.33 – 1.25 (m, 2H), 1.05 (d, J = 6.7 Hz, 6H). 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1-cyanocyclopropyl)-4-(4-isobutyrylpiperazin-1- yl)-2H-indazole-6-sulfonamide: 1H NMR (300 MHz, DMSO-d6) δ 9.67 (d, J = 1.1 Hz, 1H), 9.21 (s, 1H), 7.73 (s, 1H), 6.68 (d, J = 1.3 Hz, 1H), 3.75 (s, 4H), 3.43 (s, 4H), 3.01 – 2.90 (m, 2H), 1.49 – 1.38 (m, 2H), 1.38 – 1.26 (m, 2H), 1.05 (d, J = 6.7 Hz, 6H). Example 8: ethyl (E)-3-(5-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)acrylate Attorney Docket No.: 53238-0003WO1
Figure imgf000090_0001
To a stirred mixture of 1-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1-cyanocyclopropyl)-4-[4-(2- methylpropanoyl) piperazin-1-yl] indazole-6-sulfonamide (120 mg, 0.207mmol, 1equiv, from PH-RASE-068-1) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) prop-2- enoate (56.18 mg, 0.248mmol, 1.2equiv) in 1,4-dioxane and H20. To the above mixture were added K2CO3 (57.24 mg, 0.414mmol, 2equiv) and pd(dppf)Cl2 (30.30 mg, 0.041mmol, 0.2equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3h at 80 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 20mL). The combined organic layers were washed with water (3x5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford ethyl (2E)-3-(5-{6-[(1-cyanocyclopropyl) sulfamoyl]-4-[4-(2- methylpropanoyl) piperazin-1-yl] indazol-2-yl}-1,3,4-thiadiazol-2-yl) prop-2-enoate as a yellow solid. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column, 19*250 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 35% B to 61% B in 10 min, 61% B; Wave Length: 254 nm; RT1(min): 8.98/9.48) to afford ethyl (2E)-3-(5-{6- [(1-cyanocyclopropyl)sulfamoyl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazol-2-yl}- 1,3,4-thiadiazol-2-yl)prop-2-enoate (5.7 mg, 4.60%) and ethyl (2E)-3-(5-{6-[(1- cyanocyclopropyl)sulfamoyl]-4-[4-(2-methylpropanoyl)piperazin-1-yl]indazol-1-yl}-1,3,4- thiadiazol-2-yl)prop-2-enoate (7.1 mg, 5.73%) as a light yellow solid and orange solid. LCMS (ES. m/z): 599 [M+H]+. Ethyl (2E)-3-(5-{6-[(1-cyanocyclopropyl)sulfamoyl]-4-[4-(2-methylpropanoyl)piperazin- 1-yl]indazol-2-yl}-1,3,4-thiadiazol-2-yl)prop-2-enoate: 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.26-9.22 (m, 1H), 8.28-7.86 (m, 1H), 7.74 (s, 1H), 7.10-7.05 (m, 1H), 6.67 (d, J = 1.3 Hz, 1H), 4.30-4.23 (m, 2H), 3.78-3.74 (m, 4H), 2.97-2.93 (m, 1H), 2.07 (s, 1H), 1.45 – 1.36 (m, 2H), 1.33-1.23 (m, 5H), 1.06-0.85 (m, 6H). Ethyl (2E)-3-(5-{6-[(1-cyanocyclopropyl)sulfamoyl]-4-[4-(2-methylpropanoyl)piperazin- 1-yl]indazol-1-yl}-1,3,4-thiadiazol-2-yl)prop-2-enoate: 1H NMR (300 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.53 (s, 1H), 7.86-7.81 (m, 1H), 7.15 (s, 1H), 7.01-6.96 (m, 1H), 4.29-4.22 (m, Attorney Docket No.: 53238-0003WO1 2H), 3.99-3.75 (m, 4H), 3.45-3.36 (m, 6H), 2.99-2.91 (m, 1H), 1.51 (s, 2H), 1.40-1.27 (m, 5H), 1.06-0.83 (m, 6H). The compounds of the below table were prepared in a manner similar to the compounds of Examples 1–8.
Figure imgf000091_0001
Attorney Docket No.: 53238-0003WO1
Figure imgf000092_0001
Attorney Docket No.: 53238-0003WO1
Figure imgf000093_0001
Example A. Inhibition of PARG TFMU Assay Attorney Docket No.: 53238-0003WO1 The ability of the compounds of the Examples to inhibit PARG activity in 4- (trifluoromethyl)umbelliferone (TFMU) assay was determined as described below. PARG inhibitors were added into 384 well plate for a 10-point dose response curve at 1:3 dilutions. TFMU PARG substrate and PARG (250 pM or 2 nM) were then added to the plate to initiate enzymatic reaction. After incubation with the reagent, luminescence was read. IC50 values were calculated using set control points for 100% inhibition as no enzyme and 0% inhibition 250 pM or 2 nM of PARG enzyme. Compounds of the present disclosure showed IC50 values in the following ranges: **** = IC50 < 50 nM; *** = 50 nM ≤ IC50 < 500 nM; ** = 500 nM ≤ IC50 < 5000 nM; * = 5000 nM ≤ IC50. Data obtained for the Example compounds using the TFMU assay described in Example A is provided in Table A. Table A
Figure imgf000094_0001
Attorney Docket No.: 53238-0003WO1
Figure imgf000095_0001
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

Attorney Docket No.: 53238-0003WO1 What is claimed is: 1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: Q is NH or CH2; A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy1, Cy1-C1-4 alkyl-, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl- C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb,
Figure imgf000096_0001
B is a group of formula (a), formula (b), formula (c), formula (d), formula (e), or formula (f):
Figure imgf000096_0002
X1 is N or CR1; X2 is N or CR2; Attorney Docket No.: 53238-0003WO1 X3 is N or CR3; X4 is N or CR4; X5 is N or CR5; X6 is N or CR6; X7 is N or CR7; X8 is N or CR8; X9 is N or CR9; X10 is N or CR10; X11 is N or CR11; X12 is N or CR12; X13 is N or CR13; X14 is N or CR14; X15 is N or CR15; X16 is N or CR16; X17 is N or CR17; X18 is N or CR18; wherein no more than two of X1, X2, and X3 are simultaneously N; wherein no more than two of X4, X5, and X6 are simultaneously N; wherein no more than two of X7, X8, and X9 are simultaneously N; wherein no more than two of X10, X11, and X12 are simultaneously N; wherein no more than two of X13, X14, and X15 are simultaneously N; wherein no more than two of X16, X17, and X18 are simultaneously N; Z1 is N or C; Z2 is N or C; the symbol represents an optional bond; each Cy1 is independently selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy; each RCy is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1- 6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and Attorney Docket No.: 53238-0003WO1 S(O)2NRc1Rd1, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of RCy is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; R1, R2, R4, R5, R7, R8, R10, R11, R13, R14, R16, and R17 are each independently selected from H, halo, and C1-4 alkyl; R3, R6, R9, R12, R15, and R18 are each independently selected from H, halo, ORa2, NRc2Rd2, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4- 10 membered heterocycloalkyl of R3, R6, R9, R12, R15, and R18 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; RB1 is H, C1-4 alkyl, or C2-6 alkenyl, wherein said C1-4 alkyl or C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, halo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; RC1, RC2, RC3, RC4, and RC5 are each independently selected from C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 R’; RC6 is selected from H, C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 R’; RD1 is H, halo, or C1-4 alkyl; Attorney Docket No.: 53238-0003WO1 RE1 is H, C1-4 alkyl, or C2-6 alkenyl, wherein the C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, halo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; RE2 and RF1 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, and 5- membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl of RE2 and RF1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; each R’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3- 7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl of R’ is optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; each Cy2 is independently selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, Attorney Docket No.: 53238-0003WO1 or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa3, SRa3, C(O)Rb3,
Figure imgf000100_0001
each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, and Rd4 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5,
Figure imgf000100_0002
or Rc and Rd, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5, C(O)Rb5,
Figure imgf000100_0003
or Rc1 and Rd1, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5, C(O)Rb5,
Figure imgf000100_0004
Attorney Docket No.: 53238-0003WO1 or Rc2 and Rd2, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5, C(O)Rb5,
Figure imgf000101_0001
or Rc3 and Rd3, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5, C(O)Rb5,
Figure imgf000101_0002
or Rc4 and Rd4, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, CN, ORa5, SRa5, C(O)Rb5,
Figure imgf000101_0003
each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; and each Re, Re1, Re2, Re3, Re4, and Re5 is independently selected from H, C1-4 alkyl, and CN. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is NH. Attorney Docket No.: 53238-0003WO1 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is CH2. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein A is Cy1. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein Cy1 is C3-7 cycloalkyl or 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy. 6. The compound of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein Cy1 is cyclopropyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy. 7. The compound of claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein Cy1 is oxetanyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy. 8. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000102_0001
and n is an integer selected from 0, 1, 2, 3, 4, and 5. 9. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000102_0002
Attorney Docket No.: 53238-0003WO1
Figure imgf000103_0001
10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein B is a group of formula (a):
Figure imgf000103_0002
11. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein B is a group of formula (b):
Figure imgf000103_0003
12. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein B is a group of formula (c):
Figure imgf000103_0004
Attorney Docket No.: 53238-0003WO1 13. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein B is a group of formula (d):
Figure imgf000104_0001
14. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein B is a group of formula (e):
Figure imgf000104_0002
15. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein B is a group of formula (f):
Figure imgf000104_0003
16. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000104_0004
is an integer selected from 0, 1, 2, 3, 4, and 5; and B is a group of formula (a), formula (c), or
Figure imgf000104_0005
Attorney Docket No.: 53238-0003WO1 17. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000105_0001
integer selected from 0, 1, 2, 3, 4, and 5; and B is a group of formula (a):
Figure imgf000105_0002
18. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000105_0003
integer selected from 0, 1, 2, 3, 4, and 5; and B is a group of formula (c):
Figure imgf000105_0004
19. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000105_0005
integer selected from 0, 1, 2, 3, 4, and 5; and B is a group of formula (f):
Figure imgf000105_0006
Attorney Docket No.: 53238-0003WO1 20. The compound of any one of claims 1 to 10 and 16 to 17, or a pharmaceutically acceptable salt thereof, wherein X1 is CR1, X2 is CR2, and X3 is CR3. 21. The compound of any one of claims 1 to 10, 16, and 18, or a pharmaceutically acceptable salt thereof, wherein X7 is CR7, X8 is CR8, and X9 is CR9. 22. The compound of any one of claims 1 to 10, 16, 18, and 21, or a pharmaceutically acceptable salt thereof, wherein Z2 is N. 23. The compound of any one of claims 1 to 10, 16, 18, and 21, or a pharmaceutically acceptable salt thereof, wherein Z2 is C. 24. The compound of any one of claims 1 to 10, 16, and 19, or a pharmaceutically acceptable salt thereof, wherein X7 is CR7, X8 is CR8, and X9 is CR9. 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein at least one RCy is C1-6 alkyl, C1-6 haloalkyl, or CN. 26. The compound of any one of claims 1 to 10, 16 to 17, and 20, or a pharmaceutically acceptable salt thereof, wherein R1 is H and R2 is H. 27. The compound of any one of claims 1 to 10, 16, 18, and 21 to 23, or a pharmaceutically acceptable salt thereof, wherein R4 is H and R5 is H. 28. The compound of any one of claims 1 to 10, 16, 19, and 24, or a pharmaceutically acceptable salt thereof, wherein R7 is H and R8 is H. 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R3, R6, R9, R12, R15, or R18 is H or 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-6 alkyl and C(O)Rb2. Attorney Docket No.: 53238-0003WO1 30. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R3, R6, R9, R12, R15, or R18 is piperazinyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-6 alkyl and C(O)Rb2. 31. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R3, R6, R9, R12, R15, or R18 is H. 32. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt
Figure imgf000107_0001
33. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, RC3, RC4, RC5, or RC6 is C1-6 alkyl, C2-6 alkenyl, or 5-membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, or 5-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 R’. 34. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, RC3, RC4, RC5, or RC6 is C1-6 alkyl or C2-6 alkenyl, wherein the C1-6 alkyl or C2-6 alkenyl is optionally substituted with 1, 2, 3, or 4 R’ C(O)NRc4Rd4, C(O)ORa4, and NRc4Rd4. 35. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, RC3, RC4, RC5, or RC6 is 5-membered heteroaryl, wherein the 5- membered heteroaryl is optionally substituted with 1, 2, 3, or 4 halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C3-7 cycloalkyl, and NRc4C(O)Rb4. 36. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein RC1, RC2, RC3, RC4, RC5, or RC6 is thiazolyl or 1,3,4-thiadiazolyl, optionally Attorney Docket No.: 53238-0003WO1 substituted with 1, 2, 3, or 4 halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C3-7 cycloalkyl, and NRc4C(O)Rb4. 37. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000108_0001
wherein m is an integer selected from 0, 1, and 2. 38. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt
Figure imgf000108_0002
39. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein RC6 is H. 40. The compound of any one of claims 1 to 10, 16 to 17, 20, 25 to 26, and 29 to 39, or a pharmaceutically acceptable salt thereof, wherein RD1 is H. Attorney Docket No.: 53238-0003WO1 41. The compound of claim 1 having Formula II-A or II-B:
Figure imgf000109_0001
II-A II-B or a pharmaceutically acceptable salt thereof. 42. The compound of claim 1 having Formula III-A, III-B, or III-C:
Figure imgf000109_0002
or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. 43. The compound of claim 1 having Formula III-A-1 or III-A-2:
Figure imgf000109_0003
III-A-1 III-A-2 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. 44. The compound of claim 1 having Formula III-B-1 or III-B-2:
Figure imgf000109_0004
or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. 45. The compound of claim 1 having Formula III-C-1 or III-C-2: Attorney Docket No.: 53238-0003WO1
Figure imgf000110_0001
or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. 46. The compound of claim 1 having Formula IV-A, IV-B, IV-C, IV-D, IV-E, or IV-F:
Figure imgf000110_0002
Attorney Docket No.: 53238-0003WO1 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5; p is an integer selected from 0, 1, 2, 3, and 4; and each R3’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl- C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. 47. The compound of claim 1 having Formula IV-A-1, IV-B-1, IV-C-1, IV-D-1, IV-E-1, or IV-F-1:
Figure imgf000111_0001
Attorney Docket No.: 53238-0003WO1
Figure imgf000112_0001
IV-E-1 IV-F-1 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5; p is an integer selected from 0, 1, 2, 3, and 4; and each R3’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl- C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. 48. The compound of claim 1 having Formula IV-A-2, IV-B-2, IV-C-2, IV-D-2, IV-E-2, or IV-F-2:
Figure imgf000112_0002
Attorney Docket No.: 53238-0003WO1 IV-C-2 IV-D-2
Figure imgf000113_0001
or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5; p is an integer selected from 0, 1, 2, 3, and 4; and each R3’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl- C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2. 49. The compound of claim 1 having Formula V-A, VI-B, V-C, V-D, or V-E:
Figure imgf000113_0002
Attorney Docket No.: 53238-0003WO1
Figure imgf000114_0001
V-E or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. 50. The compound of claim 1 having Formula V-A-1, V-B-1, V-C-1, V-D-1, or V-E-1:
Figure imgf000114_0002
Attorney Docket No.: 53238-0003WO1
Figure imgf000115_0001
or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. 51. The compound of claim 1 having Formula V-A-2, V-B-2, V-C-2, V-D-2, or V-E-2:
Figure imgf000115_0002
or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. 52. The compound of claim 1 having Formula VI-A, VI-B, VI-C, or VI-D: Attorney Docket No.: 53238-0003WO1
Figure imgf000116_0001
VI-C VI-D or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. 53. The compound of claim 1 having Formula VI-A-1, VI-B-1, VI-C-1, or VI-D-1:
Figure imgf000116_0002
VI-C-1 VI-D-1 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. Attorney Docket No.: 53238-0003WO1 54. The compound of claim 1 having Formula VI-A-2, VI-B-2, VI-C-2, or VI-D-2:
Figure imgf000117_0001
or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, 2, 3, 4, and 5. 55. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: Q is NH or CH2; A is C1-6 alkyl, C2-6 alkenyl, Cy1, Cy1-C1-4 alkyl-, wherein said C1-6 alkyl, and C2-6 alkenyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
Figure imgf000117_0003
and S(O)2NRcRd, B is a group of formula (a), formula (b), formula (c), formula (d), formula (e), or formula (f):
Figure imgf000117_0002
Attorney Docket No.: 53238-0003WO1 (a) (b) (c)
Figure imgf000118_0001
X1 is N or CR1; X2 is N or CR2; X3 is N or CR3; X4 is N or CR4; X5 is N or CR5; X6 is N or CR6; X7 is N or CR7; X8 is N or CR8; X9 is N or CR9; X10 is N or CR10; X11 is N or CR11; X12 is N or CR12; X13 is N or CR13; X14 is N or CR14; X15 is N or CR15; X16 is N or CR16; X17 is N or CR17; X18 is N or CR18; wherein no more than two of X1, X2, and X3 are simultaneously N; wherein no more than two of X4, X5, and X6 are simultaneously N; wherein no more than two of X7, X8, and X9 are simultaneously N; wherein no more than two of X10, X11, and X12 are simultaneously N; wherein no more than two of X13, X14, and X15 are simultaneously N; wherein no more than two of X16, X17, and X18 are simultaneously N; Z1 is N or C; Z2 is N or C; Attorney Docket No.: 53238-0003WO1 the symbol represents an optional bond; each Cy1 is independently selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy; each RCy is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein the C1-6 alkyl and C2-6 alkenyl of RCy is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; R1, R2, R4, R5, R7, R8, R10, R11, R13, R14, R16, and R17 are each independently selected from H, halo, and C1-4 alkyl; R3, R6, R9, R12, R15, and R18 are each independently selected from H, halo, ORa2, NRc2Rd2, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4- 10 membered heterocycloalkyl of R3, R6, and R9 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; RB1 is H, C1-4 alkyl, or C2-6 alkenyl, wherein said C1-4 alkyl or C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; RC1, RC2, RC3, RC4, and RC5 are each independently selected from C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 R’; Attorney Docket No.: 53238-0003WO1 RC6 is selected from H, C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 R’; RD1 is H, halo, or C1-4 alkyl; RE1 is H, C1-4 alkyl, or C2-6 alkenyl, wherein the C1-6 alkyl and C2-6 alkenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, halo, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(=NRe3)NRc3Rd3, NRc3C(=NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3; RE2 and RF1 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, and 5- membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl of RE2 and RF1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; each R’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3- 7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl of R’ is optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, Attorney Docket No.: 53238-0003WO1 NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; each Cy2 is independently selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa3, SRa3, C(O)Rb3,
Figure imgf000121_0001
each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, and Rd4 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5,
Figure imgf000121_0002
each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; and Attorney Docket No.: 53238-0003WO1 each Re, Re1, Re2, Re3, Re4, and Re5 is independently selected from H, C1-4 alkyl, and CN. 56. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: Q is NH or CH2; A is C1-6 alkyl, C2-6 alkenyl, Cy1, Cy1-C1-4 alkyl-, wherein said C1-6 alkyl, and C2-6 alkenyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered
Figure imgf000122_0002
and S(O)2NRcRd, B is a group of formula (a), formula (c), or formula (f):
Figure imgf000122_0001
X2 is N or CR2; X3 is N or CR3; X7 is N or CR7; X8 is N or CR8; X9 is N or CR9; X16 is N or CR16; X17 is N or CR17; X18 is N or CR18; wherein no more than two of X1, X2, and X3 are simultaneously N; wherein no more than two of X7, X8, and X9 are simultaneously N; wherein no more than two of X16, X17, and X18 are simultaneously N; Z1 is N or C; Z2 is N or C; the symbol represents an optional bond; Attorney Docket No.: 53238-0003WO1 each Cy1 is independently selected from C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy; each RCy is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1; R1, R2, R7, R8, R16, and R17 are each independently selected from H, halo, and C1-4 alkyl; R3, R9, and R18 are each independently selected from H, halo, ORa2, NRc2Rd2, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of R3, R9, and R18 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRcC(O)ORa2, NRcC(O)NRc2Rd2, NRcS(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2; RB1 is H, C1-4 alkyl, or C2-6 alkenyl; RC1 and RC3 are each independently selected from C1-6 alkyl, C2-6 alkenyl, and 5- membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 R’; RC6 is selected from H, C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 R’; RD1 is H, halo, or C1-4 alkyl; each R’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein the C1-6 Attorney Docket No.: 53238-0003WO1 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl of R’ is optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; each Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl of Ra, Rb, Rc, Rd, Ra1, Rb1, Rc1, Rd1, Ra2, Rb2, Rc2, Rd2, Ra4, Rb4, Rc4, and Rd4 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, ORa5,
Figure imgf000124_0001
each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, and 4-10 membered heterocycloalkyl-C1-4 alkyl; and each Re, Re1, Re2, Re4, and Re5 is independently selected from H, C1-4 alkyl, and CN. 57. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: Q is NH or CH2; A is Cy1 or Cy1-C1-4 alkyl-; B is a group of formula (a), formula (c), or formula (f): Attorney Docket No.: 53238-0003WO1
Figure imgf000125_0001
X2 is N or CR2; X3 is N or CR3; X7 is N or CR7; X8 is N or CR8; X9 is N or CR9; X16 is N or CR16; X17 is N or CR17; X18 is N or CR18; wherein no more than two of X1, X2, and X3 are simultaneously N; wherein no more than two of X7, X8, and X9 are simultaneously N; wherein no more than two of X16, X17, and X18 are simultaneously N; Z1 is N or C; Z2 is C; the symbol represents an optional bond; each Cy1 is independently selected from C3-7 cycloalkyl and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from RCy; each RCy is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, and CN; R1, R2, R7, R8, R16, and R17 are each H; R3, R9, and R18 are each independently selected from H and 4-10 membered heterocycloalkyl, wherein said 4-10 membered heterocycloalkyl of R3, R9, and R18 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-6 alkyl and C(O)Rb2; RC1 and RC3 are each independently selected from C1-6 alkyl, C2-6 alkenyl, and 5- membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 R’; Attorney Docket No.: 53238-0003WO1 RC6 is selected from H, C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, and 5-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 R’; RD1 is H; each R’ is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C3-7 cycloalkyl, C(O)NRc4Rd4, C(O)ORa4, NRc4Rd4, NRc4C(O)Rb4, wherein the C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, and C3-7 cycloalkyl of R’ is optionally substituted with 1, 2, or 3 groups independently selected from C(O)ORa4 and NRc4Rd4; and each Rb2, Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C1-6 alkyl, and C2-6 alkenyl, wherein said C1-6 alkyl and C2-6 alkenyl of Rb2, Ra4, Rb4, Rc4, and Rd4 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from CN. 58. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from: 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((1S,2R)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide; 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((1R,2S)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide; 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-((1R,2R)-1-cyano-2-methylcyclopropyl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide; 1-(4-(2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(((1- methylcyclopropyl)methyl)sulfonyl)-2H-indazol-4-yl)piperazin-1-yl)-2-methylpropan-1-one; 2-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-4-(4- isobutyrylpiperazin-1-yl)-2H-indazole-6-sulfonamide; N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2-(5-methyl-1,3,4- thiadiazol-2-yl)-2H-indazole-6-sulfonamide; 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-2-(1,3,4-thiadiazol-2-yl)-2H- indazole-6-sulfonamide; N-(3-(fluoromethyl)oxetan-3-yl)-4-(4-isobutyrylpiperazin-1-yl)-2-(5-vinyl-1,3,4- thiadiazol-2-yl)-2H-indazole-6-sulfonamide; N-(3-methyloxetan-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6- sulfonamide; 2-(5-bromo-1,3,4-thiadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan- 3-yl)-2H-indazole-6-sulfonamide; Attorney Docket No.: 53238-0003WO1 (E)-4-(5-(N-(1-methylcyclopropyl)sulfamoyl)-1,3-dioxoisoindolin-2-yl)but-2- enamide; ethyl (E)-4-(5-(N-(1-methylcyclopropyl)sulfamoyl)-1,3-dioxoisoindolin-2-yl)but-2- enoate; (E)-4-(5-(N-(1-methylcyclopropyl)sulfamoyl)-1,3-dioxoisoindolin-2-yl)but-2-enoic acid; N-(4-(6-(N-(1-methylcyclopropyl)sulfamoyl)-2H-indazol-2-yl)thiazol-5- yl)acrylamide; 2-(5-bromo-1,3,4-thiadiazol-2-yl)-N-(1-cyanocyclopropyl)-4-(4-isobutyrylpiperazin- 1-yl)-2H-indazole-6-sulfonamide; ethyl (E)-3-(5-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-4-(4-isobutyrylpiperazin-1-yl)- 2H-indazol-2-yl)-1,3,4-thiadiazol-2-yl)acrylate; N-(1-cyanocyclopropyl)-2-(2-((cyanomethyl)amino)ethyl)-4-(4-isobutyrylpiperazin- 1-yl)-2H-indazole-6-sulfonamide; 2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan-3-yl)-2H-indazole-6- sulfonamide; N-(1-cyanocyclopropyl)-2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-2H-indazole-6- sulfonamide; (S)-2-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(4-isobutyryl-3-methylpiperazin-1- yl)-N-(3-methyloxetan-3-yl)-2H-indazole-6-sulfonamide; and 4-(4-isobutyrylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)-2-(5-vinyl-1,3,4-thiadiazol-2- yl)-2H-indazole-6-sulfonamide. 59. A method of inhibiting the activity of PARG comprising contacting a compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, with said PARG. 60. The method of claim 59, wherein the contacting is contacting in vitro. 61. A method of treating a disease or disorder in a patient in need of treatment comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof. 62. The method of claim 61, wherein the disease or disorder is cancer. Attorney Docket No.: 53238-0003WO1 63. The method of claim 62, wherein the cancer is a stress-dependent cancer. 64. The method of claim 62, wherein said cancer is selected from lung cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, skin cancer, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, mantle cell lymphoma, and renal cell carcinoma.
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