WO2025035108A2 - Inhibiteurs de parg - Google Patents

Inhibiteurs de parg Download PDF

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Publication number
WO2025035108A2
WO2025035108A2 PCT/US2024/041747 US2024041747W WO2025035108A2 WO 2025035108 A2 WO2025035108 A2 WO 2025035108A2 US 2024041747 W US2024041747 W US 2024041747W WO 2025035108 A2 WO2025035108 A2 WO 2025035108A2
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alkyl
formula
independently selected
cycloalkyl
halo
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WO2025035108A3 (fr
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Paul Chang
Katherine Widdowson
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ARase Therapeutics Inc
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ARase Therapeutics Inc
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    • 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
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • 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.
  • PARG inhibitors work by modulating Attorney Docket No.: 53238-0005WO1 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 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.
  • SSBR single strand break repair
  • BER base excision repair
  • RNA interference RNA interference
  • 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.
  • 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.
  • the present invention is directed to a compound of Formula I: Attorney Docket No.: 53238-0005WO1 or a pharmaceutically acceptable salt constituent members are defined below.
  • 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 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, or Cy-C1-4 alkyl-, wherein said C1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of A 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 Attorney Docket No.: 53238-0005WO1 haloalkyl, C6-10 aryl, C3-7 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-
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ;
  • X 5 is N or CR 5 ;
  • X 6 is N or CR 6 ;
  • X 7 is N or CR 7 ;
  • X 8 is N or CR 8 ;
  • X 9 is N or CR 9 ;
  • X 10 is N or CR 10 ;
  • X 11 is N or CR 11 ;
  • X 12 is N or CR 12 ;
  • X 13 is N or CR 13 ;
  • X 14 is N or CR 14 ;
  • X 15 is N or CR 15 ;
  • X 16 is N or CR 16 ;
  • X 17 is N or CR 17 ;
  • X 18 is N or CR 18 ;
  • X 19 is N or CR 19 ;
  • X 20 is N or CR 20 ;
  • X 21 is N or
  • the present invention is also directed to a compound of Formula I: or a pharmaceutically acceptable salt Q is NH or CH 2;
  • A is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy, or Cy-C 1-4 alkyl-, wherein said C 1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of A 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, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 member
  • the present invention is also directed to a compound of Formula I: or a pharmaceutically acceptable salt Q is NH or CH 2 ;
  • A is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, or Cy-C1-4 alkyl-, wherein said C1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of A 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, C 6-10 aryl, C 3-7 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- C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl,
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ;
  • X 5 is N or CR 5 ;
  • X 6 is N or CR 6 ;
  • X 7 is N or CR 7 ;
  • X 8 is N or CR 8 ;
  • X 9 is N or CR 9 ;
  • X 10 is N or CR 10 ;
  • X 11 is N or CR 11 ;
  • X 12 is N or CR 12 ;
  • Attorney Docket No.: 53238-0005WO1 X 13 is N or CR 13 ;
  • X 14 is N or CR 14 ;
  • X 15 is N or CR 15 ;
  • X 16 is N or CR 16 ;
  • X 17 is N or CR 17 ;
  • X 18 is N or CR 18 ;
  • X 19 is N
  • Q is NH. In some embodiments, Q is CH 2 .
  • 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-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 , OC(O)R
  • 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, C1-6 alkyl, C2-6 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, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 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 , OC(O)R b , OC(O)NR c R d ,
  • A is Cy. In some embodiments, A is Cy-C1-4 alkyl-. In some embodiments, A is selected from C 3-7 cycloalkyl and 4-10 membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy . In some embodiments, A is C 3-7 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy . In some embodiments, A is cyclopropyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy , wherein at least one R Cy is C1-6 alkyl.
  • A is cyclopropyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy , wherein at least one R Cy is methyl. In some embodiments, A is cyclopropyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy , wherein at least one R Cy is CN. In some embodiments, A is cyclopropyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy , wherein the cyclopropyl is substituted with methyl and CN. In some embodiments, A is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • A is oxetanyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy . In some embodiments, A is oxetanyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy , In some embodiments, A is oxetanyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy , wherein at least one R Cy is C1-6 alkyl, C1-6 haloalkyl, or CN. In some embodiments, A is oxetanyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy , wherein at least one R Cy is methyl, fluoromethyl, or CN.
  • A is selected , O , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)2NR c1 R d1 ; m is an integer selected from 0, 1, 2, 3, 4, and 5; and o is an integer selected from 0, 1, 2, and 3.
  • A is selected ; and m is an integer selected from 0, 1, 2, 3, In some embodiments, A m is an integer selected 5. In some embodiments, A is selected Attorney Docket No.: 53238-0005WO1 m is an integer selected from 0, 1, 2, 3, 4, and 5. In some embodiments, A is selected , , In some embodiments, A is selected .
  • B is of formula (a): In some embodiments, In some embodiments, B is of formula (d): Attorney Docket No.: 53238-0005WO1 (d). In some embodiments, B is of formula (e): In some embodiments, In some embodiments, In some embodiments, B In some embodiments, Attorney Docket No.: 53238-0005WO1 In some embodiments, B In some embodiments, B In some embodiments, B is of formula (a), formula (c), formula (d), formula (e), formula (f), formula (g), formula (i), or formula (k): Attorney Docket No.: 53238-0005WO1 , formula (e), formula (f), formula (g), or formula (h):
  • B is of formula (i) or formula (k): Attorney Docket No.: 53238-0005WO1 some , , formula (i), formula (j), or formula (k): In some embodiments, B is of formula (c), formula (g), formula (i), or formula (k):
  • X 1 is CR 1 .
  • X 2 is CR 2 .
  • X 3 is N.
  • X 3 is CR 3 .
  • X 1 is CR 1 ;
  • X 2 is CR 2 ;
  • X 3 is CR 3 .
  • R 1 is H.
  • R 1 is halo.
  • R 1 is C1-4 alkyl.
  • R 2 is H.
  • R 2 is halo.
  • R 2 is C1-4 alkyl.
  • R 3 is H. In some embodiments, R 3 is halo. In some embodiments, R 3 is OR a2 . In some embodiments, R 3 is NR c2 R d2 . In some embodiments, R 3 is C 6-10 aryl.
  • R X1 is 5-membered heteroaryl. In some embodiments, R X1 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, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 ,
  • R Y1 is H. In some embodiments, R Y1 is halo. In some embodiments, R Y1 is C1-6 alkyl. In some embodiments, R Y1 is C1-6 alkyl optionally substituted with 1, 2, 3, substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 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- 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
  • R Y1 is C 2-6 alkenyl. In some embodiments, R Y1 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, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 ,
  • R Y1 is 5-membered heteroaryl. In some embodiments, R Y1 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 Attorney Docket No.: 53238-0005WO1 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C 6-10 aryl, C 3-7 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- 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 a
  • R Z1 is H. In some embodiments, R Z1 is halo. In some embodiments, R Z1 is C 1-6 alkyl. In some embodiments, R Z1 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 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- 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
  • R Z1 is C2-6 alkenyl. In some embodiments, R Z1 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, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 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)
  • R Z1 is 5-membered heteroaryl. In some embodiments, R Z1 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, C 6-10 aryl, C 3-7 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- 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)R
  • B is of formula (b): In some embodiments, some X 4 is CR 4 . In some embodiments, X 5 is N. In some embodiments, X 5 is CR 5 . In some embodiments, X 6 is N. In some embodiments, X 6 is CR 6 . In some embodiments, X 4 is CR 4 ; X 5 is CR 5 ; and X 6 is CR 6 . In some embodiments, R 4 is H. In some embodiments, R 4 is halo. In some embodiments, R 4 is C1-4 alkyl. In some embodiments, R 5 is H. In some embodiments, R 5 is halo. In some embodiments, R 5 is C1-4 alkyl.
  • R 6 is H. In some embodiments, R 6 is halo. In some embodiments, R 6 is OR a2 . In some embodiments, R 6 is NR c2 R d2 . In some embodiments, R 6 is C 6-10 aryl.
  • R 6 is 5-10 membered heteroaryl.
  • R X2 is H. In some embodiments, R X2 is halo. In some embodiments, R X2 is C1-6 alkyl. In some embodiments, R X2 is C1-6 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, C1-6 haloalkyl, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C
  • R X2 is C2-6 alkenyl.
  • R X1 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, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 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
  • R X2 is 5-membered heteroaryl.
  • R X2 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, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a
  • R Y2 is C 2-6 alkenyl. In some embodiments, R Y2 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, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 ,
  • R Y2 is 5-membered heteroaryl. In some embodiments, R Y2 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, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 ,
  • B is of formula (c): In some embodiments, X 7 some X 7 is CR 7 . In some embodiments, X 8 is N. In some embodiments, X 8 is CR 8 . In some embodiments, X 9 is N. In some embodiments, X 9 is CR 9 . In some embodiments, X 7 is CR 7 ; X 8 is CR 8 ; and X 9 is CR 9 . In some embodiments, R 7 is H. In some embodiments, R 7 is halo. In some embodiments, R 7 is C 1-4 alkyl. In some embodiments, R 8 is H. In some embodiments, R 8 is halo. In some embodiments, R 8 is C 1-4 alkyl.
  • R 8 is selected from H, fluoro, and bromo.
  • 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.
  • R X3 is C1-6 alkyl.
  • R X3 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, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 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- 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 X3 is C 2-6 alkenyl. In some embodiments, R X3 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, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 ,
  • R X3 is 5-membered heteroaryl. In some embodiments, R X3 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 Attorney Docket No.: 53238-0005WO1 haloalkyl, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2
  • R X3 is selected from C 1-6 alkyl and 5-membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, R X3 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’, selected from halo, OR a3 , and CN. In some embodiments, R X3 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 C1-6 alkyl. In some embodiments, R X3 is selected from , embodiments, R Z3 is C 1-6 alkyl.
  • R Z3 is 5-membered heteroaryl. In some embodiments, R Z3 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, C 6-10 aryl, C 3-7 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- 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)R
  • R Z3 is selected from H and halo. In some embodiments, R Z3 is selected from H and chloro.
  • B is of formula (d): In some embodiments, 10 10 X is CR . 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 10 is CR 10 ; X 11 is CR 11 ; and X 12 is CR 12 . In some embodiments, R 10 is H. In some embodiments, R 10 is halo. In some embodiments, R 10 is C 1-4 alkyl. In some embodiments, R 11 is H.
  • R 11 is halo. In some embodiments, R 11 is C1-4 alkyl. In some embodiments, 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.
  • R X4 is H. In some embodiments, R X4 is halo. In some embodiments, R X4 is C1-6 alkyl. In some embodiments, R X4 is C1-6 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, C1-6 haloalkyl, C6-10 aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered Attorney Docket No.: 53238-0005WO1 heterocycloalkyl, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl-C1-4 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
  • R X4 is C 2-6 alkenyl. In some embodiments, R X4 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, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 ,
  • R X4 is 5-membered heteroaryl.
  • R X4 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- 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 Y4 is C 2-6 alkenyl. In some embodiments, R Y4 is C 2-6 alkenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, Attorney Docket No.: 53238-0005WO1 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, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2
  • B is of formula (e): In some embodiments, 13 13 X is CR . 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 13 is CR 13 ; X 14 is CR 14 ; and X 15 is CR 15 . In some embodiments, R 13 is H. In some embodiments, R 13 is halo. In some embodiments, R 13 is C1-4 alkyl. In some embodiments, R 14 is H. In some embodiments, R 14 is halo. In some embodiments, R 14 is C1-4 alkyl. In some embodiments, R 15 is H.
  • 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 Attorney Docket No.: 53238-0005WO1 is C6-10 aryl.
  • R X5 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 Attorney Docket No.: 53238-0005WO1 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, 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
  • R X5 is C2-6 alkenyl. In some embodiments, R X5 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, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 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
  • R X5 is 5-membered heteroaryl. In some embodiments, R X5 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, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)R
  • R Y5 is H. In some embodiments, R Y5 is halo. In some embodiments, R Y5 is C1-6 alkyl. In some embodiments, R Y5 is C1-6 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, C1-6 haloalkyl, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C
  • R Y5 is C2-6 alkenyl. In some embodiments, R Y5 is C2-6 Attorney Docket No.: 53238-0005WO1 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, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR
  • R Y5 is 5-membered heteroaryl. In some embodiments, R Y5 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, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 ,
  • R Z5 is C 2-6 alkenyl. In some embodiments, R Z5 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, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC
  • R Z5 is 5-membered heteroaryl.
  • R Z5 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, C 6-10 aryl, C 3-7 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- 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)R b2
  • X 16 is CR 16 .
  • X 17 is N.
  • X 17 is CR 17 .
  • X 18 is N.
  • X 18 is CR 18 .
  • X 16 is CR 16 ;
  • X 17 is CR 17 ;
  • X 18 is CR 18 .
  • R 16 is H.
  • R 16 is halo.
  • R 16 is C 1-4 alkyl.
  • R 17 is H.
  • R 17 is halo.
  • R 17 is C 1-4 alkyl.
  • R 18 is H.
  • 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 C6-10 aryl. In some embodiments, R 18 is C6-10 aryl 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, 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, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC
  • R X6 is H. In some embodiments, R X6 is halo. In some embodiments, R X6 is C1-6 alkyl. In some embodiments, R X6 is C1-6 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, C1-6 haloalkyl, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C
  • R X6 is C2-6 alkenyl. In some embodiments, R X6 is C2-6 Attorney Docket No.: 53238-0005WO1 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, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR
  • R X6 is 5-membered heteroaryl.
  • R X6 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, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 ,
  • R Y6 is C 2-6 alkenyl. In some embodiments, R Y6 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, C6-10 aryl-C1-4 alkyl, C3-7 cycloalkyl- C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 ,
  • R Y6 is 5-membered heteroaryl. In some embodiments, R Y6 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, C 6-10 aryl, C 3-7 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- 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 ,
  • X 19 is CR 19 .
  • X 20 is N.
  • X 20 is CR 20 .
  • X 21 is N.
  • X 21 is CR 21 .
  • R 19 is H.
  • R 19 is halo.
  • R 19 is C 1-4 alkyl.
  • R 20 is H.
  • R 20 is halo.
  • R 20 is C1-4 alkyl.
  • R 21 is H.
  • R 21 is halo.
  • R 21 is OR a2 . In some embodiments, R 21 is NR c2 R d2 . In some embodiments, R 21 is C6-10 aryl. In some embodiments, R 21 is C6-10 aryl 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, 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-C1-4 alkyl, CN, NO2, 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
  • R 21 is C 3-7 cycloalkyl. In some embodiments, R 21 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- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 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 c2 C NR c C or 4 6 6 6 6
  • R X7 is H. In some embodiments, R X7 is halo. In some embodiments, R X7 is C 1-6 alkyl. In some embodiments, R X7 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 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- 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 d
  • R X7 is C2-6 alkenyl. In some embodiments, R X7 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, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 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
  • R X7 is 5-membered heteroaryl.
  • 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C 6-10 aryl, C 3-7 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- 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 d
  • R Z7 is H. In some embodiments, R Z7 is halo. In some embodiments, R Z7 is C1-6 alkyl. In some embodiments, R Z7 is C1-6 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, C1-6 haloalkyl, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR
  • R Z7 is C2-6 alkenyl. In some embodiments, R Z7 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, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 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)
  • R Z7 is 5-membered heteroaryl. In some embodiments, R Z7 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, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)R
  • B is of formula (h):
  • X 22 is N.
  • X 22 is CR 22 .
  • X 23 is N.
  • X 23 is CR 23 .
  • X 24 is N.
  • X 24 is CR 24 .
  • X 22 is CR 22 ;
  • X 23 is CR 23 ;
  • X 24 is CR 24 .
  • R 22 is H.
  • R 22 is halo.
  • R 22 is C 1-4 alkyl.
  • R 23 is H.
  • R 23 is halo.
  • R 23 is C 1-4 alkyl.
  • R 24 is H.
  • R 24 is halo.
  • R 24 is OR a2 .
  • R 24 is NR c2 R d2 .
  • R 24 is C6-10 aryl.
  • R 24 is C 3-7 cycloalkyl. In some embodiments, R 24 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- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 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 c2 C NR c C or 4 6 6 6 6
  • R X8 is H. In some embodiments, R X8 is halo. In some embodiments, R X8 is C 1-6 alkyl. In some embodiments, R X8 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 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- 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 d
  • R X8 is C2-6 alkenyl. In some embodiments, R X8 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, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 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
  • R X8 is 5-membered heteroaryl.
  • 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C 6-10 aryl, C 3-7 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- 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 d
  • R Y8 is H. In some embodiments, R Y8 is halo. In some embodiments, R Y8 is C1-6 alkyl. In some embodiments, R Y8 is C1-6 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, C1-6 haloalkyl, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C
  • R Y8 is C2-6 alkenyl. In some embodiments, R Y8 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, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl- C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 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
  • R Y8 is 5-membered heteroaryl. In some embodiments, R Y8 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, C6-10 aryl, C3-7 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- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 ,
  • B is of formula (i): In some embodiments, X 25 is N. In some embodiments, X 25 is CR 25 . In some embodiments, X 26 is N. In some embodiments, X 26 is CR 26 . In some embodiments, X 27 is N. In some embodiments, X 27 is CR 27 . In some embodiments, X 25 is CR 25 ; X 26 is CR 26 ; and X 27 is CR 27 . In some embodiments, R 25 is H. In some embodiments, R 25 is halo. In some embodiments, R 25 is C1-4 alkyl. In some embodiments, R 26 is H. In some embodiments, R 26 is halo.
  • R 26 is C1-4 alkyl. In some embodiments, R 26 is selected from H, fluoro, and bromo. In some embodiments, R 27 is H. In some embodiments, R 27 is halo. In some embodiments, R 27 is OR a2 . In some embodiments, R 27 is NR c2 R d2 . In some embodiments, R 27 is C6-10 aryl.
  • R W1 is C2-6 alkenyl. In some embodiments, R W1 is C2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, R W1 is 5-membered heteroaryl. In some embodiments, R W1 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, R W1 is selected from C 1-6 alkyl and 5-membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, R W1 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’, selected from halo, OR a3 , and CN.
  • R W1 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 C1-6 alkyl. In some embodiments, R W1 is selected from , Attorney Docket No.: 53238-0005WO1
  • X 28 is CR 28 . In some embodiments, X 29 is N. In some embodiments, X 29 is CR 29 . In some embodiments, X 30 is N. In some embodiments, X 30 is CR 30 . In some embodiments, X 28 is CR 28 ; X 29 is CR 29 ; and X 30 is CR 30 . In some embodiments, R 28 is H. In some embodiments, R 28 is halo.
  • R 28 is C1-4 alkyl.
  • R 29 is H.
  • R 29 is halo.
  • R 29 is C1-4 alkyl.
  • R 30 is H.
  • R 30 is halo.
  • R 30 is OR a2 .
  • R 30 is NR c2 R d2 .
  • R 30 is C6-10 aryl.
  • R 30 is 4-10 membered heterocycloalkyl.
  • R W2 is 5-membered heteroaryl. In some embodiments, R W2 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’.
  • B is of formula (k): In some embodiments, X 31 is N. In some embodiments, X 31 is CR 31 . In some embodiments, X 32 is N. In some embodiments, X 32 is CR 32 . In some embodiments, X 33 is N. In some embodiments, X 33 is CR 33 . In some embodiments, X 31 is CR 31 ; X 32 is CR 32 ; and X 33 is CR 33 . In some embodiments, R 31 is H. In some embodiments, R 31 is halo.
  • R 31 is C1-4 alkyl. Attorney Docket No.: 53238-0005WO1
  • R 32 is H.
  • R 32 is halo.
  • R 32 is C 1-4 alkyl.
  • R 32 is selected from H, fluoro, and bromo.
  • R 33 is H.
  • R 33 is halo.
  • R 33 is OR a2 .
  • R 33 is NR c2 R d2 .
  • R 33 is C 6-10 aryl.
  • R 33 is H. In some embodiments, R 33 is halo. In some embodiments, R 33 is OR a2 . In some embodiments, R 33 is NR c2 R d2 . In some embodiments, R 33 is C6-10 aryl.
  • R 33 is selected from H, halo, OR a2 , NR c2 R d2 , 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 R 3 , R 6 , R 9 , R 12 , R 15 , R 18 , R 21 , R 24 , R 27 , R 30 , and R 33 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 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
  • R W3 and R W4 are selected from C1-6 alkyl and 5-membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 R’.
  • R W3 and R W4 are C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’, selected from halo, OR a3 , and CN.
  • R W3 and R W4 are 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 C 1-6 alkyl. In some embodiments, at least one of R W3 and R W4 is 1,3,4-thiadiazolyl optionally substituted with 1 R’. In some embodiments, at least one of R W3 and R W4 is 1,3,4-thiadiazolyl optionally substituted with difluoromethyl, trifluoromethyl, or methanol. In some embodiments, R W3 and R W4 are selected from H, methyl, , .
  • R W3 and R W4 are selected from , 6 7 are or R W4 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’.
  • R W3 is H.
  • R W3 is C 1-6 alkyl.
  • R W3 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’.
  • R W3 is C 2-6 alkenyl.
  • R W3 is C 2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’.
  • R W3 is 5-membered heteroaryl.
  • R W2 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’.
  • R W3 is C 1-6 alkyl.
  • R W3 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’.
  • R W3 is C2-6 alkenyl.
  • R W3 is C 2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’.
  • R W3 is 5-membered heteroaryl.
  • R W2 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’.
  • R W3 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’, selected from halo, OR a3 , NR c3 R d3 , and CN.
  • R W3 is elected from H, methyl, , each optionally substituted with 1, 2, 3, or 4 R’.
  • R W3 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’, selected from halo, OR a3 , and CN.
  • R W4 is C1-6 alkyl.
  • R W4 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’.
  • R W4 is C 2-6 alkenyl.
  • R W4 is C2-6 alkenyl optionally substituted with 1, 2, 3, or 4 R’.
  • R W4 is 5-membered heteroaryl. In some embodiments, R W4 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’. In some embodiments, R W4 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 C1-6 alkyl. In some embodiments, R W3 is elected from ; and .
  • R W3 is selected from Attorney Docket No.: 53238-0005WO1
  • B is of formula (a), formula (c), formula (d), formula (e), formula (f), formula (g), formula (i), or formula (k): ; Attorney Docket No.: 53238-0005WO1 NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; m is an integer selected from 0, 1, 2, 3, 4, and 5; and
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula II-A: or a
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula III-B: Attorney Docket No.: 53238-0005WO1 or a from 0, 1, 2, 3, and 4.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IV-1: Attorney Docket No.: 53238-0005WO1 or a from 0, 1, 2, 3, and 4.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula V-A: or a
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VI-A: or a
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VII-A: or a
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VII-B: or a pharmaceutically acceptable salt thereof having Formula VII-1: Attorney Docket No.: 53238-0005WO1 or a n an from 0, 1, 2, 3, and 4.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VIII-A: or a pharmaceutically
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula VIII-1: Attorney Docket No.: 53238-0005WO1 or a from 0, 1, 2, 3, and 4.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula IX-A: or a
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula X-1: or a selected from 0, 1, 2, 3, and 4.
  • provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula XI-A: or a Attorney Docket No.: 53238-0005WO1
  • the compound is of Formula XII-A and Q is NH.
  • the compound is of Formula XII-A and R Cy is selected from C1-6 alkyl and C1-6 haloalkyl. In some embodiments, the compound is of Formula XII-A and R Cy is C 1-6 alkyl. In some embodiments, the compound is of Formula XII-A and R Cy is C 1-6 haloalkyl. In some embodiments, the compound is of Formula XII-A and R Cy is methyl. In some embodiments, the compound is of Formula XII-A and R Cy is fluoromethyl. In some embodiments, the compound is of Formula XII-A and m is 1. In some embodiments, the compound is of Formula XII-A and X 31 is CR 31 .
  • the compound is of Formula XII-A and X 31 is CH. In some embodiments, the compound is of Formula XII-A and X 32 is CR 32 . In some embodiments, the compound is of Formula XII-A and X 32 is CH. In some embodiments, the compound is of Formula XII-A and X 33 is CR 33 . Attorney Docket No.: 53238-0005WO1 In some embodiments, the compound is of Formula XII-A and CR 33 is 4-10 membered heterocycloalkyl. In some embodiments, the compound is of Formula XII-A and CR 33 is 6-9 membered heterocycloalkyl.
  • the compound is of Formula XII-A and CR 33 is 6 membered heterocycloalkyl. In some embodiments, the compound is of Formula XII-A and CR 33 is 7 membered heterocycloalkyl. In some embodiments, the compound is of Formula XII-A and CR 33 is 9 membered heterocycloalkyl.
  • the compound is of Formula XII-A and CR 33 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, CN, NO2, (CH2)mOR a2 , 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 , and CR 33 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-6 alkyl, (CH2)mOR a2 , C(O)R b2 , and C(O)NR c2 R d2 .
  • the compound is of Formula XII-A and R W3 is C 1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’, selected from halo, OR a3 , NR c3 R d3 , and CN.
  • the compound is of Formula XII-A and R W4 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 C1-6 alkyl.
  • the compound is of Formula XII-A and R W3 and R W4 are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, and 5-membered heteroaryl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, and 5-membered heteroaryl are optionally substituted with 1, 2, 3, or 4 R’.
  • the compound is of Formula XII-A and R W3 is selected from H, C1-6 alkyl, and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with 1, 2, 3, or 4 R’; and R W4 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’.
  • R W3 is selected from H, C1-6 alkyl, and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with 1, 2, 3, or 4 R’; and R W4 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’.
  • Attorney Docket No.: 53238-0005WO1 provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having Formula XII-B: or a pharmaceutically
  • the compound is of Formula XII-B and Q is NH.
  • the compound is of Formula XII-B and R Cy is selected from C1-6 alkyl and C1-6 haloalkyl. In some embodiments, the compound is of Formula XII-B and R Cy is C 1-6 alkyl. In some embodiments, the compound is of Formula XII-B and R Cy is C 1-6 haloalkyl. In some embodiments, the compound is of Formula XII-B and R Cy is methyl. In some embodiments, the compound is of Formula XII-B and R Cy is fluoromethyl. In some embodiments, the compound is of Formula XII-B and m is 1. In some embodiments, the compound is of Formula XII-B and X 31 is CR 31 .
  • the compound is of Formula XII-B and X 31 is CH. In some embodiments, the compound is of Formula XII-B and X 32 is CR 32 . In some embodiments, the compound is of Formula XII-B and X 32 is CH. In some embodiments, the compound is of Formula XII-B and X 33 is CR 33 . In some embodiments, the compound is of Formula XII-B and CR 33 is 4-10 membered heterocycloalkyl. In some embodiments, the compound is of Formula XII-B and CR 33 is 6-9 membered heterocycloalkyl.
  • the compound is of Formula XII-B and CR 33 is 6 membered heterocycloalkyl. In some embodiments, the compound is of Formula XII-B and CR 33 is 7 membered heterocycloalkyl. In some embodiments, the compound is of Formula XII-B and CR 33 is 9 membered heterocycloalkyl.
  • the compound is of Formula XII-B and CR 33 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl, (CH 2 ) m OR a2 , C(O)R b2 , and C(O)NR c2 R d2 .
  • the compound is of Formula XII-B and R W3 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’, selected from halo, OR a3 , NR c3 R d3 , and CN.
  • the compound is of Formula XII-B and R’ is C1-6 haloalkyl.
  • the compound is of Formula XII-B and R W3 is selected from H, C1-6 alkyl, and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with 1, 2, 3, or 4 R’; and R’ is C1-6 haloalkyl.
  • R W3 is selected from H, C1-6 alkyl, and C3-7 cycloalkyl, wherein the C1-6 alkyl and C3-7 cycloalkyl are optionally substituted with 1, 2, 3, or 4 R’; and R’ is C1-6 haloalkyl.
  • the compound is of Formula XII-C and R Cy is selected from C1-6 alkyl and C1-6 haloalkyl.
  • the compound is of Formula XII-A and R Cy is C 1-6 alkyl. In some embodiments, the compound is of Formula XII-C and R Cy is C 1-6 Attorney Docket No.: 53238-0005WO1 haloalkyl. In some embodiments, the compound is of Formula XII-C and R Cy is methyl. In some embodiments, the compound is of Formula XII-C and R Cy is fluoromethyl. In some embodiments, the compound is of Formula XII-C and n is 0. In some embodiments, the compound is of Formula XII-C and R 31 is H. In some embodiments, the compound is of Formula XII-C and R 32 is H.
  • the compound is of Formula XII-C and R 33 is 4-10 membered heterocycloalkyl. In some embodiments, the compound is of Formula XII-C and R 33 is 6-9 membered heterocycloalkyl. In some embodiments, the compound is of Formula XII-C and R 33 is 6 membered heterocycloalkyl. In some embodiments, the compound is of Formula XII- C and R 33 is 7 membered heterocycloalkyl. In some embodiments, the compound is of Formula XII-C and R 33 is 9 membered heterocycloalkyl.
  • the compound is of Formula XII-C and R 33 is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl, (CH 2 ) m OR a2 , C(O)R b2 , and C(O)NR c2 R d2 .
  • the compound is of Formula XII-C and R W3 is C1-6 alkyl optionally substituted with 1, 2, 3, or 4 R’, selected from halo, OR a3 , NR c3 R d3 , and CN.
  • the compound is of Formula XII-C and R W4 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 C 1-6 alkyl.
  • the compound is of Formula XII-C and R W3 and R W4 are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, and 5-membered Attorney Docket No.: 53238-0005WO1 heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, and 5-membered heteroaryl are optionally substituted with 1, 2, 3, or 4 R’.
  • the compound is of Formula XII-C and R W3 is selected from H, C 1-6 alkyl, and C 3-7 cycloalkyl, wherein the C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with 1, 2, 3, or 4 R’; and R W4 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’.
  • R W3 is selected from H, C 1-6 alkyl, and C 3-7 cycloalkyl, wherein the C 1-6 alkyl and C 3-7 cycloalkyl are optionally substituted with 1, 2, 3, or 4 R’; and R W4 is 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 R’.
  • m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is an integer selected from 0, 2, 3, 4, and 5.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, o is 0.
  • o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, p is 0. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein: Q is NH or CH2; A is Cy or Cy-C 1-4 alkyl-; B is of formula (c), formula (g), formula (i), formula (j), or formula (k): X 7 is N or CR 7 ; X 8 is N or CR 8 ; X 9 is N or CR 9 ; X 19 is N or CR 19 ; X 20 is N or CR 20 ; X 21 is N or CR 21 ; X 25 is N or CR 25 ; X 26 is N or CR 26 ; Attorney Docket No.: 53238-0005WO1 X 27 is N or CR 27 ; X 28 is N or CR 28 ; X 29 is N or CR 29 ; X 30 is N or CR 30 ; X 31 is N or CR 31 ; X 32 is N or CR 32 ; X 33 is N or CR 33 ;
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein: Q is NH or CH2; A is Cy or Cy-C 1-4 alkyl-; B is of formula (c), formula (i), or formula (k): Attorney Docket No.: 53238-0005WO1 or X 25 is N or CR 25 ; X 26 is N or CR 26 ; X 27 is N or CR 27 ; X 31 is N or CR 31 ; X 32 is N or CR 32 ; X 33 is N or CR 33 ; wherein no more than two of X 7 , X 8 , and X 9 are simultaneously N; wherein no more than two of X 25 , X 26 , and X 27 are simultaneously N; wherein no more than two of X 31 , X 32 , and X 33 are simultaneously N; each Cy is independently selected from C 3-7 cycloalkyl and 4-10 membered heterocycloalkyl, each optional
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein: Q is NH; A is Cy; B is of formula (c), formula (i), or formula (k): Attorney Docket No.: 53238-0005WO1 X 25 is CR 25 ; X 26 is CR 26 ; X 27 is CR 27 ; X 31 is CR 31 ; X 32 is CR 32 ; X 33 is CR 33 ; each Cy 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 R Cy ; each R Cy is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and CN; R 7 , R 8 , R 25 , R 26 , R 31 , and R 32 are each independently selected from H and halo; R 9 , R 27 , and R 33 are each independently selected from H,
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein: Q is NH; A is Cy or Cy-C1-4 alkyl-; B is of formula (c), formula (g), formula (i), formula (j), or formula (k): X 7 is N or CR 7 ; X 8 is N or CR 8 ; X 9 is N or CR 9 ; X 19 is N or CR 19 ; X 20 is N or CR 20 ; Attorney Docket No.: 53238-0005WO1 X 21 is N or CR 21 ; X 25 is N or CR 25 ; X 26 is N or CR 26 ; X 27 is N or CR 27 ; X 28 is N or CR 28 ; X 29 is N or CR 29 ; X 30 is N or CR 30 ; X 31 is N or CR 31 ; X 32 is N or CR 32 ; X 33 is N or CR 33 ; wherein no
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein: Q is NH; A is Cy or Cy-C1-4 alkyl-; B is a group of formula (c), formula (i) or formula (k): X 9 is N or CR 9 ; X 25 is N or CR 25 ; X 26 is N or CR 26 ; X 27 is N or CR 27 ; X 31 is N or CR 31 ; X 32 is N or CR 32 ; X 33 is N or CR 33 ; Attorney Docket No.: 53238-0005WO1 wherein no more than two of X 7 , X 8 , and X 9 are simultaneously N; wherein no more than two of X 25 , X 26 , and X 27 are simultaneously N; wherein no more than two of X 31 , X 32 , and X 33 are simultaneously N; each Cy is independently selected from C 3-7 cycloalkyl and 4-10 membered
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein: Q is NH; A is Cy; B is a group of formula (c), formula (i), or formula (k): X 9 is CR 9 ; X 25 is CR 25 ; X 26 is CR 26 ; X 27 is CR 27 ; X 31 is CR 31 ; X 32 is CR 32 ; X 33 is CR 33 ; each Cy 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 R Cy ; each R Cy is independently selected from C1-6 alkyl, C1-6 haloalkyl, and CN; R 7 , R 8 , R 25 , R 26 , R 31 , and R 32 are each independently selected from H and halo; R 9 , R 27 , and R 33 are each independently selected from H, halo, and 4
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein: Q is NH; A is Cy or Cy-C1-4 alkyl-;, B is of formula (c), formula (g), formula (i), formula (j), or formula (k):
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein: Q is NH; A is Cy or Cy-C 1-4 alkyl-; B is a group of formula (c), formula (i) or formula (k): X 9 is N or CR 9 ; X 25 is N or CR 25 ; X 26 is N or CR 26 ; X 27 is N or CR 27 ; X 31 is N or CR 31 ; Attorney Docket No.: 53238-0005WO1 X 32 is N or CR 32 ; X 33 is N or CR 33 ; wherein no more than two of X 7 , X 8 , and X 9 are simultaneously N; wherein no more than two of X 25 , X 26 , and X 27 are simultaneously N; wherein no more than two of X 31 , X 32 , and X 33 are simultaneously N; each Cy is independently selected from C 3-7 cycloalkyl and 4-10 membere
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein: Q is NH; A is Cy; B is a group of formula (c), formula (i), or formula (k): X 9 is CR 9 ; X 25 is CR 25 ; X 26 is CR 26 ; X 27 is CR 27 ; X 31 is CR 31 ; X 32 is CR 32 ; X 33 is CR 33 ; each Cy 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 R Cy ; each R Cy is independently selected from C1-6 alkyl, C1-6 haloalkyl, and CN; R 7 , R 8 , R 25 , R 26 , R 31 , and R 32 are each independently selected from H and halo; R 9 , R 27 , and R 33 are each independently selected from H, halo, and 4
  • B when B is formula (a), formula (c), formula (d), formula (e), formula (f), formula (g), or formula (k); A is Cy; and Cy is C3-7 cycloalkyl, then Cy is substituted with 0, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • B when B is formula (a), formula (c), formula (d), formula (e), formula (f), formula (g), or formula (k); and A is Cy; then Cy is C4-7 cycloalkyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Cy .
  • A is not 1-methylcyclopropyl, 1-cyanocyclopropyl, or 1- (fluoromethyl)cyclopropyl.
  • A is not 1-methylcyclopropyl. In some embodiments, A is not 1-cyanocyclopropyl. In some embodiments, A is not 1- (fluoromethyl)cyclopropyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof selected from: ⁇ 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-2-oxo-1,3-dihydro- 1,3-benzimidazol-5-ylsulfonyl ⁇ (3-methyl-3-oxetanyl)amine; ⁇ 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-2-oxo-1,3-dihydro- 1,3-benzimidazol-5-ylsulfonyl ⁇ [3-(fluoromethyl)-3-oxetanyl]amine; ⁇ 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-6-fluoro-2-oxo-1
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof selected from: ⁇ 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-2-oxo-1,3-dihydro- 1,3-benzimidazol-5-ylsulfonyl ⁇ (3-methyl-3-oxetanyl)amine; ⁇ 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-2-oxo-1,3-dihydro- 1,3-benzimidazol-5-ylsulfonyl ⁇ [3-(fluoromethyl)-3-oxetanyl]amine; ⁇ 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-6-fluoro-2-oxo-1
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof selected from: 4-[(R)-4-isobutyryl-3-methyl-1-piperazinyl]-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2- yl]-6-[3-(fluoromethyl)-3-oxetanylaminosulfonyl]-1,3-dihydro-1,3-benzimidazol-2-one; 4-[(R)-4-isobutyryl-3-methyl-1-piperazinyl]-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2- yl]-6-(3-methyl-3-oxetanylaminosulfonyl)-1,3-dihydro-1,3-benzimidazol-2-one; ⁇ 7-[(R)-3-methyl-1-piperazinyl]-3-[5-(difluoromethyl)-1,3,
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof selected from: 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-N-(3-(fluoromethyl)oxetan-3-yl)- 7-(1-(1-(2-hydroxyethoxy)cyclopropane-1-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-oxo- 2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide; Attorney Docket No.: 53238-0005WO1 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(1-ethoxycyclopropane-1- carbonyl)piperazin-1-yl)-1-ethyl-N-(3-(fluoromethyl)oxetan-3
  • aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency.
  • pyridinyl may refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.
  • n-membered 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.
  • Attorney Docket No.: 53238-0005WO1 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.
  • 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 include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like.
  • the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.
  • 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.
  • Attorney Docket No.: 53238-0005WO1 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.
  • amino employed alone or in combination with other terms, refers to NH2.
  • 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 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.
  • heterocycloalkyl Attorney Docket No.: 53238-0005WO1 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).
  • 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 C2-7 monocyclic heterocycloalkyl group.
  • the heterocycloalkyl group is a morpholine ring, pyrrolidine ring, piperazine ring, piperidine ring, tetrahydropyran ring, tetrahydropyridine, 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 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 Attorney Docket No.: 53238-0005WO1 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. 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.
  • 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 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: .
  • 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 Attorney Docket No.: 53238-0005WO1 number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • the compounds of the invention include at least one deuterium atom.
  • the term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, 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 Attorney Docket No.: 53238-0005WO1 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.
  • 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 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., 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.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry Attorney Docket No.: 53238-0005WO1 (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 Attorney Docket No.: 53238-0005WO1 (e.g., UV-visible), or mass spectrometry
  • chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • the compound of Formula (1-6) is cyclized in the presence of sodium nitrite and acid to form triazole compound of Formula (1-7).
  • the compound of Formula (1-7) is reacted with a palladium catalyst like palladium acetate, K 2 SO 5 and then N-fluorobenzenesulfonimide to form sulfonyl fluoride compound of Formula (1-8).
  • the compound of Formula (1-8) is substituted with amine compound of Formula (1-9) to form sulfonamide compound of Formula (1-9).
  • Ring C is an N-containing 5-10 membered heteroaryl or N-containing 4-10 membered heterocycloalkyl, wherein said 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl 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 1-4 alkyl, C3-7 cycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 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
  • an appropriately substituted, aryl fluoride- containing compound of Formula (2-1) is substituted with amine compound (2-2) in the presence of a base to form the aryl compound of Formula (2-3).
  • the compound of Formula Attorney Docket No.: 53238-0005WO1 (2-3) is reduced to form amine compound of Formula (2-4).
  • the compound of Formula (2-4) is cyclized with 1,1'-carbonyldiimidazole to form benzimidazole compound of Formula (2-5).
  • the compound of Formula (2-5) is substituted with a compound of Formula (2-6) in the presence of base and heat to form the compound of Formula (2-7).
  • the compound of Formula (2-7) is substituted with chlorosulfonic acid to form sulfonyl chloride compound of Formula (2-8).
  • the compound of Formula (2-8) is substituted with a compound of Formula (2-9) in the presense of base to form sulfonamide compound of Formula (2-10).
  • Scheme 2 Ring D is 5-membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 R’; and LG is a leaving group, such as halo.
  • an appropriately substituted, aryl fluoride- containing compound of Formula (3-1) is substituted with an appropriately substituted heterocycloalkyl (3-2, e.g., piperidinyl) in the presence of a base to form the aryl compound of Formula (3-3).
  • the aryl fluoride containing-compound of Formula (3-3) is substituted with Attorney Docket No.: 53238-0005WO1 amine compound (3-4) to form aryl compound of Formula (3-5).
  • the compound of Formula (3-5) is reduced and cyclized to form the compound of Formula (3-6).
  • the compound of Formula (3-6) is substituted with a compound of Formula (3-7) in the presence of a base to form compound of Formula (3-8).
  • the compound of Formula (3-8) is reacted with a palladium catalyst like palladium acetate, K2SO5 and then N-fluorobenzenesulfonimide to form sulfonyl fluoride compound of Formula (3-9).
  • the compound of Formula (3-9) is substituted with amine compound of Formula (3-10) to form sulfonamide compound of Formula (3-11).
  • the compound of Formula (4-7) is substituted with amine compound of Formula (4-8) to form sulfonamide compound of Formula (4-9).
  • the compound of Formula (4-9) is substituted with borate compound of Formula (4-10, e.g., a tetrahydropyridinyl substituted with a borate moiety) in the presence of a palladium catalyst and base to form sulfonamide compound of Formula (4-11).
  • the 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 and diseases and disorders sensitive to the accumulation of ADP-ribose that results from treatment with PARG inhibitors.
  • the compounds of the invention are useful in the treatment of cancer.
  • the cancer is a cellular stress-dependent cancer.
  • the cancer exhibits cancer dependent transcriptional gene misregulation.
  • the cancer is selected from lung cancer, colon cancer, breast cancer, ovarian cancer, gastric 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 Attorney Docket No.: 53238-0005WO1 “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 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 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.
  • 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 Attorney Docket No.: 53238-0005WO1 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).
  • anti-estrogen agents including but not limited to tamoxifen and Attorney Docket No.: 53238-0005WO1 toremifene
  • aromatase inhibitors including but not limited to letrozole
  • 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.
  • 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,
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfon
  • Additional anti-cancer agent(s) for use in combination with the compounds of the present invention include DNA damage or cell cycle check point inhibitors, including ATR, ATM, Wee1, CHK1, CHK2, Pol Theta inhibitors.
  • 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- ⁇ , 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.
  • Attorney Docket No.: 53238-0005WO1 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.
  • compositions 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 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.
  • 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 when it 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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 Attorney Docket No.: 53238-0005WO1 breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions 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.
  • 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.
  • 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.
  • Example 1 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-7-[4-(2- methylpropanoyl)piperazin-1-yl]-1,2,3-benzotriazole-5-sulfonamide
  • Step 1 N-(5-bromo-3-fluoro-2-nitrophenyl)-5-(difluoromethyl)-1,3,4- thiadiazol-2-amine.
  • the reaction was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The resulting mixture was diluted with H2O (30 mL). The resulting mixture was extracted with EA (3 ⁇ 20 mL). The combined organic layers were washed with brine (30 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, 5 ⁇ m; Mobile Phase A: Water(10mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 32%B to 62%B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.22) to afford 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-7-[4-(2- methylpropanoyl)piperazin-1-yl]-1,2,3-benzotriazole-5-sulfonamide (45.3 mg, 39.26%) as a yellow solid.
  • Example 2 3-[5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-7-(4- propanoylpiperazin-1-yl)-1,2,3-benzotriazole-5-sulfonamide
  • Step 1 1-[4-(5-bromo-3-fluoro-2-nitrophenyl)piperazin-1-yl]-2-methylpropan-1-one.
  • Step 2 ethyl 5-( ⁇ 5-bromo-3-[4-(2-methylpropanoyl)piperazin-1-yl]-2-nitrophenyl ⁇ amino)- 1,3,4-thiadiazole-2-carboxylate.
  • Step 3 ethyl 5-( ⁇ 2-amino-5-bromo-3-[4-(2-methylpropanoyl)piperazin-1-yl] phenyl ⁇ amino)- 1,3,4-thiadiazole-2-carboxylate.
  • Step 4 ethyl 5- ⁇ 6-bromo-4-[4-(2-methylpropanoyl)piperazin-1-yl]-1,2,3-benzotriazol-1-yl ⁇ - 1,3,4-thiadiazole-2-carboxylate.
  • Step 5 1-(4- ⁇ 6-bromo-1-[5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl]-1,2,3-benzotriazol-4- yl ⁇ piperazin-1-yl)-2-methylpropan-1-one.
  • the reaction was quenched by the addition of potassium sodium tartrate (aq., 50 mL) at 0 °C.
  • the resulting mixture was extracted with DCM (3 x 80 mL).
  • the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step 6 1- ⁇ 4-[6-bromo-1-(5- ⁇ [(tert-butyldimethylsilyl)oxy]methyl ⁇ -1,3,4-thiadiazol-2-yl)- 1,2,3-benzotriazol-4-yl]piperazin-1-yl ⁇ -2-methylpropan-1-one.
  • Step 7 3-(5- ⁇ [(tert-butyldimethylsilyl)oxy]methyl ⁇ -1,3,4-thiadiazol-2-yl)-N-(3-methyloxetan- 3-yl)-7-[4-(2-methylpropanoyl) piperazin-1-yl]-1,2,3-benzotriazole-5-sulfonamide.
  • Step 8 3-[5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-7-(4- propanoylpiperazin-1-yl)-1,2,3-benzotriazole-5-sulfonamide.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP 18 OBD Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10mmol/L NH4HCO3 + 0.1% NH3-H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 23% B to 53% B in7min; Wave Length: 254nm nm; RT1(min): 6.33) to afford 3- [5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl]-N-(3-methyloxetan-3-yl)-7-(4-propanoylpiperazin- 1-yl)-1,2,3-benzotriazole-5-sulfonamide (2.6 mg, 8.08%) as a light-green solid.
  • Example 3 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-6-fluoro-2-oxo-1,3- benzodiazole-5-sulfonyl chloride
  • Step 1 N-ethyl-5-fluoro-2-nitroaniline. To a stirred mixture of 2,4-difluoro-1-nitro-benzene (3.
  • the mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(10 mmol/L NH 4 HCO 3 + 0.1% NH3-H2O), 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; to afford 3-[5-(difluoromethyl)-1,3,4- thiadiazol-2-yl]-1-ethyl-6-fluoro-N-(3-methyloxetan-3-yl)-2-oxo-1,3-benzodiazole-5- sulfonamide (3.7 mg, 13.18%) as a white solid.
  • Example 4 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-(3-methyloxetan-3- yl)-2-oxo-1-(prop-2-yn-1-yl)-1,3-benzodiazole-5-sulfonamide
  • Step 1 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-(3-methyloxetan-3-yl)-2-oxo- 1H-1,3-benzodiazole-5-sulfonamide.
  • Step 2 N- ⁇ 1-acetyl-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-2-oxo-1,3- benzodiazol-5-ylsulfonyl ⁇ -N-(3-methyloxetan-3-yl)acetamide.
  • Step 3 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-(3-methyloxetan-3-yl)-2-oxo- 1-(prop-2-yn-1-yl)-1,3-benzodiazole-5-sulfonamide.
  • Example 5 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-6-fluoro-N-[3- (fluoromethyl)oxetan-3-yl]-2-oxo-1,3-benzodiazole-5-sulfonamide
  • 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-6-fluoro-2-oxo- 1,3-benzodiazole-5-sulfonyl chloride (30 mg, 0.073 mmol, 1 equiv) in DMF (1 mL) was added 3-(fluoromethyl)oxetan-3-amine hydrochloride (15.43 mg, 0.109 mmol, 1.5 equiv) and TEA (14.71 mg, 0.146 mmol, 2 equiv).
  • the mixture was stirred at room temperature for 2 h. Desired product could be detected by LCMS.
  • the mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water(10 mmol/L NH 4 HCO 3 + 0.1% NH 3 -H 2 O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 35% B to 60% B in 10 min, 60% B; Wave Length: 254 nm; RT1(min): 8; to afford 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl- 6-fluoro-N-[3-(fluoromethyl)oxetan-3-yl]-2-oxo-1,3-benzodiazole-5-sulfonamide (3.2 mg, 9.08%) as a white solid.
  • Example 6 N-(3-cyanooxetan-3-yl)-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl- 6-fluoro-2-oxo-1,3-benzodiazole-5-sulfonamide Attorney Docket No.: 53238-0005WO1 To the mixture of 3-[5- - thiadiazol-2-yl]-1-ethyl-6-fluoro-2-oxo- 1,3-benzodiazole-5-sulfonyl chloride (30 mg, 0.073 mmol, 1 equiv) in pyridine (2 mL) was added 3-aminooxetane-3-carbonitrile hydrochloride (14.67 mg, 0.109 mmol, 1.5 equiv).
  • Example 7 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[3- (fluoromethyl)oxetan-3-yl]-2-oxo-1-(prop-2-yn-1-yl)-1,3-benzodiazole-5-sulfonamide
  • Step 1 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-2-oxo-1H-1,3-benzodiazole-5- sulfonyl chloride.
  • Step 2 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[3-(fluoromethyl)oxetan-3- yl]-2-oxo-1H-1,3-benzodiazole-5-sulfonamide.
  • Step 3 1-acetyl-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[3- (fluoromethyl)oxetan-3-yl]-2-oxo-1,3-benzodiazole-5-sulfonamide.
  • Step 4 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[3-(fluoromethyl)oxetan-3- yl]-2-oxo-1-(prop-2-yn-1-yl)-1,3-benzodiazole-5-sulfonamide.
  • the mixture was allowed to cool down to room temperature.
  • the reaction mixture was purified by prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 -H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 58% B in 7 min; Wave Length: 254 nm; RT1(min): 5.48) to afford 3-[5- (difluoromethyl)-1,3,4-thiadiazol-2-yl]-6-fluoro-N-[3-(fluoromethyl)oxetan-3-yl]-2-oxo-1- (prop-2-yn-1-yl)-1,3-benzodiazole-5-sulfonamide (11.8 mg, 18.96%) as a white solid.
  • Example 8 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-N-(3- methyloxetan-3-yl)-2-oxo-1,3-benzodiazole-5-sulfonamide
  • a solution of 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-2-oxo- 1,3-benzodiazole-5-sulfonyl chloride (50 mg, 0.118 mmol, 1 equiv) in DMF (2 mL) was added 3-methyloxetan-3-amine (20.51 mg, 0.236 mmol, 2 equiv) and DIEA (66.33 mg, 0.513 mmol, 3 equiv) dropwise at 0 °C.
  • the resulting mixture was stirred for 2 h at room temperature. Desired product could be detected by LCMS.
  • the resulting mixture was quenched with water (30 mL).
  • the aqueous layer was extracted with EA (3 ⁇ 20 mL).
  • the combined organic layers were washed by brine (30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Example 9 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N- (3-(fluoromethyl)oxetan-3- yl)-1-(2-methoxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide
  • a solution of 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-(2-methoxyethyl)-2-oxo- 1,3-benzodiazole-5-sulfonyl chloride (30 mg, 0.071 mmol, 1 equiv) in DMF (1 mL) was added 3-(fluoromethyl)oxetan-3-amine hydrochloride (20.16 mg, 0.142 mmol, 2 equiv) and DIEA (27.38 mg, 0.213 mmol, 3 equiv) dropwise at 0 °C.
  • Example 10 7-bromo-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl] -1-ethyl-N-[3- (fluoromethyl)oxetan-3-yl]-2- oxo-1,3-benzodiazole-5-sulfonamide
  • Step 1 7-bromo-3-[5- - 2-yl]-1-ethyl-2-oxo-1,3-benzodiazole- 5-sulfonyl chloride.
  • the resulting mixture was diluted with H 2 O (30 mL).
  • the resulting mixture was extracted with EA (3 ⁇ 20 mL).
  • the combined organic layers were washed with saturation brine (2 ⁇ 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Example 11 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-N-[3- (fluoromethyl)oxetan-3-yl]-7-[4-(2-methylpropanoyl)piperazin-1-yl]-2-oxo-1,3- benzodiazole-5-sulfonamide
  • 7-bromo-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1- Ethyl- N-[3-(fluoromethyl) oxetan-3-yl]-2-oxo-1,3-benzodiazole-5-sulfonamide 450 mg, 0.830 mmol, 1 equiv
  • 2-methyl-1-(piperazin-1-yl) propan-1-one (259.25 mg, 1.660 mmol, 2 equiv) in 1,4-dioxane (5 mL)
  • the resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H 2 O (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).
  • the crude product was purified by Prep-HPLC with the following conditions: (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 43% B to 73% B in 7 min, 73% B; Wave Length: 254 nm; RT1(min): 6.78; Injection Volume: 0.8 mL; to afford 3-[5-(difluoromethyl)-1,3,4-thiadiazol- 2-yl]-1-ethyl-N-[3-(fluoromethyl)oxetan-3-yl]-7-[4-(2-methylpropanoyl)piperazin-1-yl]-2- oxo-1,3-benzodiazole-5-sulfonamide (44.4 mg, 8.59%) as a white solid.
  • Example 12 7-bromo-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-N-(3- methyloxetan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide
  • Step 1 7-bromo-3-[5- - 2-yl]-1-ethyl-2-oxo-1,3-benzodiazole- 5-sulfonyl chloride.
  • the resulting mixture was quenched with water (30 mL).
  • the aqueous layer was Attorney Docket No.: 53238-0005WO1 extracted with EA (3 ⁇ 20 mL).
  • the combined organic layers were washed by brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Example 13 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-N-(3-methyloxetan-3- yl)-7-[4-(2-methylpropanoyl) piperazin-1-yl]-2-oxo-1,3-benzodiazole-5-sulfonamide
  • 7-bromo-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl- N-(3-methyloxetan-3-yl)-2-oxo-1,3-benzodiazole-5-sulfonamide 500 mg, 0.954 mmol, 1 equiv) in dioxane (5 mL) was added Pd-PEPPSI-IPentCl (160.22 mg, 0.191 mmol, 0.2 equiv), Cs2CO3 (932.05 mg, 2.862 mmol,
  • the resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with H2O (50 mL). The filtrate 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 crude product was purified by Prep-HPLC with the following conditions: (Column: C18; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 50 Attorney Docket No.: 53238-0005WO1 mL/min; Gradient: 45% B to 65% B in 10 min, 65% B; Wave Length: 254 nm; RT1(min): 6.35 to afford 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-N-(3-methyloxetan-3-yl)- 7-[4-(2-methylpropanoyl) piperazin-1-yl]-2-oxo-1,3-benzodiazole-5-sulfonamide (50.9 mg, 8.64%) as a white solid.
  • Example 14 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-N-[3-(methyl)oxetan-3- yl]-7-[(3R)-3-methyl-4-(2-methylpropanoyl)piperazin-1-yl]-2-oxo-1,3-benzodiazole-5- sulfonamide
  • Step 1 tert-butyl (2R)-4-(5-bromo-3-fluoro-2-nitrophenyl)-2-methylpiperazine-1- carboxylate.
  • Step 4 1-[(2R)-4-(5-bromo-3- ⁇ [5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]amino ⁇ -2- nitrophenyl)-2-methylpiperazin-1-yl]-2-methylpropan-1-one.
  • the reaction was monitored by LCMS.
  • the resulting mixture was diluted with water (1 L).
  • the resulting mixture was washed with EA (3 x 600 mL).
  • the combined organic layers were brine (2 x 800 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Step 6 6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-[(3R)-3-methyl-4-(2- methylpropanoyl)piperazin-1-yl]-3H-1,3-benzodiazol-2-one.
  • Step 7 6-bromo-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-3-ethyl-4-[(3R)-3-methyl-4-(2- methylpropanoyl)piperazin-1-yl]-1,3-benzodiazol-2-one.
  • the mixture was allowed to cool down to room temperature.
  • the resulting mixture was diluted with water (100 mL).
  • the resulting mixture was washed with EA (3 x 80 mL).
  • the combined organic layers were washed with brine (2 x 120 mL) dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Step 8 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-7-[(3R)-3-methyl-4-(2- methylpropanoyl)piperazin-1-yl]-2-oxo-1,3-benzodiazole-5-sulfonyl fluoride.
  • Step 9 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-7-[(3R)-3-methyl-4-(2- methylpropanoyl)piperazin-1-yl]-N-(3-methyloxetan-3-yl)-2-oxo-1,3-benzodiazole-5- sulfonamide.
  • the reaction was monitored by LCMS.
  • the resulting mixture was diluted with e water (60 mL).
  • the resulting mixture was washed with EA (3 x 50 mL).
  • the combined organic layers were washed with brine (2 x 80 mL) dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge BEH Shield RP18 Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water(10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min mL/min; Gradient: 41%B to 71%B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.53) to afford 3-[5- (difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-7-[(3R)-3-methyl-4-(2- methylpropanoyl)piperazin-1-yl]-N-(3-methyloxetan-3-yl)-2-oxo-1,3-benzodiazole-5- sulfonamide (32.7 mg, 28.98%) as a white solid.
  • Example 15 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-N-[3- (fluoromethyl)oxetan-3-yl]-7-[(3R)-3-methyl-4-(2-methylpropanoyl)piperazin-1-yl]-2- oxo-1,3-benzodiazole-5-sulfonamide
  • the reaction was monitored by LCMS.
  • the resulting mixture was diluted with ethyl acetate (60 mL).
  • the residue was washed with water (4 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge BEH Shield RP18 Column, 19*250 mm, 5 ⁇ m; Mobile Phase A: Water(10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min mL/min; Gradient: 45%B to 75%B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.55) to afford 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-N-[3-(fluoromethyl)oxetan-3-yl]- 7-[(3R)-3-methyl-4-(2-methylpropanoyl)piperazin-1-yl]-2-oxo-1,3-benzodiazole-5- sulfonamide (30.7 mg, 26.52%) as a white solid.
  • Example 17 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5- dimethylpiperazin-1-yl)-N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Step 1 (5-bromo-3-chloropyridin-2-yl)methanamine.
  • 5-bromo-3-chloropicolinonitrile (20.00 g, 91.97 mmol) and DCE (200 mL) at r. t.
  • Step 2 ethyl 2-(((5-bromo-3-chloropyridin-2-yl)methyl)amino)-2-oxoacetate
  • 5-bromo-3-chloropyridin-2-yl)methanamine 13.50 g, 60.95 mmol
  • DIPEA 15.76 g, 121.91 mmol, 21.23 mL
  • ethyl 2-chloro- 2-oxoacetate 3 9.99 g, 73.14 mmol
  • Step3 ethyl 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carboxylate
  • POCl3 60 mL
  • P2O5 15.36 g, 108.22 mmol
  • Step 4 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carbohydrazide
  • ethyl 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carboxylate 10.70 g, 35.25 mmol
  • ethanol 120 mL
  • NH2NH2 11.30 g, 352.51 mmol
  • LC-MS analysis showed the completion of reaction.
  • the reaction mixture was cooled to 0 °C and filtered.
  • Step 5 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,5-a]pyridine-3-carbohydrazide
  • 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carbohydrazide 8.00 g, 27.63 mmol
  • ethanol 120 mL
  • ethyl 2,2-difluoroacetate 7 34.29 g, 276.32 mmol
  • DBU 8.40 g, 55.26 mmol
  • Step 6 2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole
  • 6-bromo-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,5-a]pyridine-3- carbohydrazide (10.00 g, 27.21 mmol) in toluene (110 mL) was added the Lawesson's reagent (12.11 g, 29.93 mmol) at r. t, and the resulting mixture was stirred at 120 °C for 2 hours under N 2 till reaction completed (detected by LC-MS).
  • Step 7 2-(6-(benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4- thiadiazole
  • 2-(6-bromo-8-chloroimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)- 1,3,4-thiadiazole 7.10 g, 19.42 mmol
  • phenylmethanethiol (2.65 g, 21.36 mmol) in dioxane (120 mL) was added the Pd2(dba)3 (888.51 mg, 971.05 ⁇ mol), XantPhos (1.12 g, 1.94 mmol) and DIPEA (7.53 g, 58.26 mmol, 10.15 mL).
  • Step 8 2-(6-(benzylthio)-8-chloro-1-iodoimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)- 1,3,4-thiadiazole
  • 2-(6-(benzylthio)-8-chloroimidazo[1,5-a]pyridin-3-yl)-5- (difluoromethyl)-1,3,4-thiadiazole 7.60 g, 18.59 mmol) in MeCN (60 mL) was added AcOH (2.5 mL) at r. t.
  • the NIS (8.36 g, 37.18 mmol
  • Step 9 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodoimidazo[1,5-a]pyridine- 6-sulfonyl chloride
  • acetic acid 30 mL
  • water 6 mL
  • NCS 2.72 g, 20.38 mmol
  • 2 drops of HCl 2 drops of HCl in ice bath.
  • the resulting mixture was stirred at r. t. for 30 minutes.
  • the reaction mixture was clear first and then a precipitate appeared.
  • LC-MS analysis showed the reaction was completed.
  • the mixture was added ice cold water (70 mL) and filtered.
  • Step 10 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-iodo-N-(3-methyloxetan-3- yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • 3-methyloxetan-3-amine (245.97 mg, 2.82 mmol)
  • THF 4 mL
  • water 2 mL
  • the NaHCO 3 (395.27 mg, 4.71 mmol) was added at r. t.
  • Step 11 2-(8-chloro-6-hydrosulfonylimidazo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4- thiadiazole
  • DIPEA 350.63 mg, 2.71 mmol, 472.55 ⁇ L
  • Pd/C 100 mg
  • Step 12 tert-butyl (2S,6S)-4-(3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3- methyloxetan-3-yl)sulfamoyl)imidazo[1,5-a]pyridin-8-yl)-2,6-dimethylpiperazine-1- carboxylate
  • tert-butyl (2S,6S)-2,6- dimethylpiperazine-1-carboxylate 147.51 mg, 688.30 ⁇ mol
  • dioxane 8 mL
  • Step 13 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)- N-(3-methyloxetan-3-yl)imidazo[1,5-a]pyridine-6-sulfonamide
  • Example 27 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3- (fluoromethyl)oxetan-3-yl)sulfamoyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol- 4-yl)-N,N-dimethyl-5,6-dihydropyridine-1(2H)-carboxamide Step 1: N-(5-bromo-3-chloro-2-nitrophenyl)-5-(difluoromethyl)-1,3,4-thiadiazol -2-amine.
  • Step 7 7-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3- yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide.
  • Step 8 tert-butyl 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3- (fluoromethyl)oxetan-3-yl)sulfamoyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)-5,6-dihydropyridine-1(2H)-carboxylate.
  • Step 9 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-1- methyl-2-oxo-7-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5- sulfonamide.
  • Step 10 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3-(fluoromethyl)oxetan-3- yl)sulfamoyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-N,N-dimethyl-5,6- dihydropyridine-1(2H)-carboxamide.
  • Example 31 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3- yl)-7-(1-(1-methoxycyclopropanecarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide
  • HATU 75.21 mg, 197.91 ⁇ mol
  • DIPEA 85.26 mg, 659.70 ⁇ mol, 114.91 ⁇ L
  • Step 2 (R)-tert-butyl 4-(5-bromo-3-((5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)amino)-2- nitrophenyl)-2-methylpiperazine-1-carboxylate.
  • Step 3 (R)-tert-butyl 4-(2-amino-5-bromo-3-((5-(difluoromethyl)-1,3,4-thiadiazol-2- yl)amino)phenyl)-2-methylpiperazine-1-carboxylate.
  • Step 4 (R)-tert-butyl 4-(6-bromo-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)-2-methylpiperazine-1-carboxylate.
  • Step 5 (R)-tert-butyl 4-(6-bromo-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2-methylpiperazine-1-carboxylate.
  • Step 6 7-((R)-4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-3-(5-(difluoromethyl)-1,3,4- thiadiazol-2-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfinic acid.
  • step 6 To a solution of step 6 in DMSO (80) and DMF (40 mL) was added NFSI (4.16 g, 21.46 mmol) at 0 °C, the reaction mixture was stirred at 0 °C for 0.5 h. Monitored by LCMS.
  • Step 8 (R)-tert-butyl 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(3- (fluoromethyl)oxetan-3-yl)sulfamoyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)-2-methylpiperazine-1-carboxylate.
  • Step 9 (R)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-1- methyl-7-(3-methylpiperazin-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide.
  • Step 10 (R)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-7- (4-isobutyryl-3-methylpiperazin-1-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5- sulfonamide.
  • Step 1 tert-butyl (S)-4-(5- -2-methylpiperazine-1-carboxylate.
  • reaction mixture was purified by Prep-HPLC and dried by hyophilization to give tert-butyl rac-(2S)-4-[2-amino-5-bromo-3-[[5-(difluoromethyl)-1,3,4-thiadiazol-2- yl]amino]phenyl]-2-methyl-piperazine-1-carboxylate (6.26 g, crude) as yellow solid.
  • LCMS 519 [M+H] + .
  • Step 4 tert-butyl (S)-4-(6-bromo-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)-2-methylpiperazine-1-carboxylate.
  • Step 5 tert-butyl (S)-4-(6-bromo-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2-methylpiperazine-1-carboxylate.
  • Step 6 7-((S)-4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-3-(5-(difluoromethyl)-1,3,4- thiadiazol-2-yl)-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfinic acid.
  • Step 7 tert-butyl (S)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-6- (fluorosulfonyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2-methylpiperazine-1- carboxylate.
  • Step 8 tert-butyl (S)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(N-(3- (fluoromethyl)oxetan-3-yl)sulfamoyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2- methylpiperazine-1-carboxylate.
  • Step 9 (S)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-N-(3-(fluoromethyl)oxetan-3- yl)-7-(3-methylpiperazin-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide.
  • Step 10 (S)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-N-(3-(fluoromethyl)oxetan- 3-yl)-7-(4-isobutyryl-3-methylpiperazin-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5- sulfonamide.
  • reaction mixture was purified by Prep-HPLC and dried by hyophilization to give 3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1-ethyl-N-[3- (fluoromethyl)oxetan-3-yl]-2-oxo-7-[(3S)-3-methyl-4-(2-methylpropanoyl)piperazin-1- yl]benzimidazole-5-sulfonamide (211 mg, 331.02 ⁇ mol, 44.80% yield, 99.1% purity) as a white solid.
  • LCMS 632.5[M+H] + .
  • Example 55 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-N-(3- (fluoromethyl)oxetan-3-yl)-7-(1-(1-methoxycyclopropanecarbonyl)-1,2,3,6- tetrahydropyridin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide.
  • Step 1 6-bromo-4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-1H- benzo[d]imidazol-2(3H)-one.
  • 5-bromo-7-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H- benzimidazol-2-one (4 g, 10.48 mmol) and Cs2CO3 (6.83 g, 20.97 mmol) in DMF (30 mL) was added EtI (1.96 g, 12.58 mmol), the reaction mixture was stirred at 25 °C for 3 h.
  • Step 2 7-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-sulfinic acid.
  • Step 3 7-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-sulfonyl fluoride.
  • DMF 10 mL
  • DMSO DMSO
  • NFSI 3.93 g, 12.46 mmol
  • Step 4 7-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-N-(3- (fluoromethyl)oxetan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide.
  • Step 5 tert-butyl 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(N-(3- (fluoromethyl) oxetan-3-yl)sulfamoyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-5,6- dihydropyridine-1(2H)-carboxylate.
  • Step 6 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-N-(3-(fluoromethyl)oxetan-3-yl)- 2-oxo-7-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide.
  • Step 7 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-N-(3-(fluoromethyl)oxetan-3-yl)- 7-(1-(1-methoxycyclopropanecarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-oxo-2,3-dihydro- 1H-benzo[d]imidazole-5-sulfonamide.
  • Example 57 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-N-(3- (fluoromethyl)oxetan-3-yl)-7-(4-(1-methoxycyclopropane-1-carbonyl)piperazin-1-yl)-2- oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide
  • Step 1 tert-butyl 4-(5-bromo-3-fluoro-2-nitrophenyl)piperazine-1-carboxylate.
  • Step 6 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2- yl)-1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-sulfinic acid.
  • Step 7 tert-butyl 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(fluorosulfonyl)-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazine-1-carboxylate.
  • Step 8 tert-butyl 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(N-(3- (fluoromethyl)oxetan-3-yl)sulfamoyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)piperazine-1-carboxylate.
  • Step 9 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-N-(3-(fluoromethyl)oxetan-3-yl)- 2-oxo-7-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide.
  • Step 10 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-ethyl-N-(3-(fluoromethyl)oxetan-3-yl)- 7-(4-(1-methoxycyclopropane-1-carbonyl)piperazin-1-yl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-sulfonamide.
  • Example 60 rel-(R)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(N-(3- (fluoromethyl)oxetan-3-yl)sulfamoyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)- N,N,6-trimethyl-5,6-dihydropyridine-1(2H)-carboxamide; Attorney Docket No.: 53238-0005WO1
  • Example 61 rel-(R)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(N-(3- (fluoromethyl)oxetan-3-yl)sulfamoyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl
  • Step 1 tert-butyl 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(N-(3- (fluoromethyl)oxetan-3-yl)sulfamoyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-6- methyl-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl 4-(1-(5-(difluoromethyl)-1,3,4- thiadiazol-2-yl)-3-ethyl-6-(N-(3-(fluoromethyl)oxetan-3-yl)sulfamoyl)-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-2-methyl-3,
  • Step 3 rel-(R)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(N-(3- (fluoromethyl)oxetan-3-yl)sulfamoyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-N,N,6- trimethyl-5,6-dihydropyridine-1(2H)-carboxamide; rel-(R)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(N-(3-(fluoromethyl)oxetan- 3-yl)sulfamoyl)-2-oxo-2,3
  • Example 60 rel-(R)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(N-(3- (fluoromethyl)oxetan-3-yl)sulfamoyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-N,N,2- trimethyl-3,6-dihydropyridine-1(2H)-carboxamide (9.5 mg, 15.07 ⁇ mol, 34.24% yield, 99.9% purity) as a white solid.
  • Second lowest retention compound (Example 61): rel-(R)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(N-(3- (fluoromethyl)oxetan-3-yl)sulfamoyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-N,N,2- trimethyl-5,6-dihydropyridine-1(2H)-carboxamide (33.2 mg, 52.67 ⁇ mol, 29.91% yield, 99.9% purity) as a white solid.
  • Example 65 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3- yl)-7-(1-isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-sulfonamide
  • Step 1 tert-butyl 4-(1-(5- - 2-yl)-6-(N-(3- (fluoromethyl)oxetan-3-yl)sulfamoyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)-5,6-dihydropyridine-1(
  • Step 2 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-1- methyl-2-oxo-7-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5- sulfonamide.
  • Step 3 3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-7-(1- isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazole-5-sulfonamide.
  • TFMU 4- (trifluoromethyl)umbelliferone
  • HCC1806 cells were seeded onto plates (day 0) and the following day (day 1) media was replaced with media containing inhibitors at three concentrations (100 nM, 500 nM, and 1000 nM) or DMSO alone as a control. Cells were incubated at 37 °C for 24 h in a CO 2 incubator. The following day (day 2), cells were washed with PBS, lysed with lysis buffer containing 50 mM TrisHCl, 100 mM NaCl, 1% Tritonx-100, 5 mM MgCl2, 1 mM DTT, protease inhibitors, and olaparib.
  • Cell Seeding 1.1 The cells were passaged as per ATCC guidelines. The cells were split in log growth into 384 well plates the night before performing the assay. Three experimental replicates were performed for each assay. 2. Compound preparation and treatment 2.1 The compound dilutions were prepared in fresh tissue culture media to achieve 10 doses with 1:2 fold dilution steps. These dilutions were made at 2X the final dilution. 2.2 The media was removed from the 384 well plate and 30 ⁇ l fresh media was dispensed per well into the plate. 2.330 ⁇ l of the 2X dilutions made in step 2.1 were dispensed. The doses were transferred for each experimental replicate at the same time.
  • Example D Data obtained for the Example compounds using the cell viability assay described in Example D is provided in Table D.
  • Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

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Abstract

La présente invention concerne des sulfonamides de formule (I) qui sont des inhibiteurs de PARG et sont utiles dans le traitement du cancer.
PCT/US2024/041747 2023-08-10 2024-08-09 Inhibiteurs de parg Pending WO2025035108A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025133396A1 (fr) * 2023-12-22 2025-06-26 Forx Therapeutics Ag Nouveaux inhibiteurs de parg bicyclo hétéroaryles
WO2026026739A1 (fr) * 2024-07-29 2026-02-05 海思科医药集团股份有限公司 Composé sulfonamide et son utilisation pharmaceutique

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MA41179A (fr) * 2014-12-19 2017-10-24 Cancer Research Tech Ltd Composés inhibiteurs de parg
CN106800538B (zh) * 2015-12-03 2019-12-17 四川省人民医院 一种苯并咪唑衍生物及其合成方法
JP7032724B2 (ja) * 2017-09-12 2022-03-09 学校法人兵庫医科大学 新規ベンズイミダゾール誘導体及びその用途
WO2020097408A1 (fr) * 2018-11-09 2020-05-14 Nimbus Artemis, Inc. Inhibiteurs d'acly et leurs utilisations
AU2020368368B2 (en) * 2019-10-14 2026-03-19 The Regents Of The University Of California Broad spectrum anti-cancer compounds
KR102885432B1 (ko) * 2020-07-03 2025-11-14 난징 이뮤노파지 바이오테크 코., 엘티디. CCR8 억제제로 Tregs를 표적화하는 방법 및 조성물
CA3225500A1 (fr) * 2021-10-04 2023-04-13 Ulrich Luecking Composes inhibiteurs de parg
US20250002491A1 (en) * 2021-10-04 2025-01-02 Forx Therapeutics Ag N,n-dimethyl-4-(7-(n-(1-methylcyclopropyl)sulfamoyl)-imidazo[1,5-a]pyridin-5-yl)piperazine-1-carboxamide derivatives and the corresponding pyrazolo[1,5-a]pyridine derivatives as parg inhibitors for the treatment of cancer
WO2024173524A1 (fr) * 2023-02-14 2024-08-22 Ideaya Biosciences, Inc. Composés benzimidazoles à substitution hétéroaryle

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
"Physicians' Desk Reference", 1996, MEDICAL ECONOMICS COMPANY
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY, pages: 1418
BOCK FJTODOROVA TTCHANG P., MOL CELL, 2015
CAIAFA. GUASTAFIERRO ET AL., FASEB J, 2009
CHANGMITCHISON, NATURE, 2004
COHEN MSCHANG P., NAT CHEM BIOL., 2018
CURTINSZABO, MOL ASPECTS MED., 2013
DAHL, MATURI ET AL., PLOS ONE, 2014
GUASTAFIERRO, CATIZONE ET AL., BIOCHEM J, 2013
JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, no. 2, 1977
LE MAY, LITIS ET AL., MOL CELL, 2012
LEUNG, CHANG ET AL., MOL CELL, 2011
MORTUSEWICZ, FOUQUEREL ET AL., NUCLEIC ACID RES., 2011
T.W. GREENEP.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY & SONS, INC.

Cited By (2)

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WO2025133396A1 (fr) * 2023-12-22 2025-06-26 Forx Therapeutics Ag Nouveaux inhibiteurs de parg bicyclo hétéroaryles
WO2026026739A1 (fr) * 2024-07-29 2026-02-05 海思科医药集团股份有限公司 Composé sulfonamide et son utilisation pharmaceutique

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