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WO2024227033A1 - Heterocyclic compounds as parp1 inhibitors - Google Patents

Heterocyclic compounds as parp1 inhibitors Download PDF

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Publication number
WO2024227033A1
WO2024227033A1 PCT/US2024/026586 US2024026586W WO2024227033A1 WO 2024227033 A1 WO2024227033 A1 WO 2024227033A1 US 2024026586 W US2024026586 W US 2024026586W WO 2024227033 A1 WO2024227033 A1 WO 2024227033A1
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WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
membered heterocycloalkyl
membered heteroaryl
independently selected
Prior art date
Application number
PCT/US2024/026586
Other languages
French (fr)
Inventor
Jun Pan
Liangxing Wu
Wenqing Yao
Original Assignee
Synnovation Therapeutics, Inc.
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Publication date
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Publication of WO2024227033A1 publication Critical patent/WO2024227033A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure provides heterocyclic compounds as well as their pharmaceutical compositions that modulate the activity of PARP1 and are useful in the treatment of various diseases related to PARP1, including cancer.
  • PARPs Poly ADP -Ribose Polymerases
  • PARPs are a superfamily of enzymes that comprise at least 17 family members.
  • Some of these PARP enzymes including PARP1, PARP2, PARP5A, and PARP5B, catalyze NAD+ substrate to covalently attach poly ADP-ribose (PAR), a linear or branched, heterogeneous polymer to acceptor proteins, while other members attach mono ADP-ribose (MAR) to acceptor proteins.
  • PARP enzymes have distinct functions.
  • PARP1, PARP2 and PARP3 are DNA- dependent of which enzymatic activity is strongly stimulated by endogenous and exogenous DNA damage (van Beek, L. et al. Int. J. Mol. Sci., 2021, 22, 5112).
  • These first three PARP enzyme members are therefore important for the regulation of DNA damage repair through a mechanism called Poly ADP-ribosylation (PARylation).
  • PARylation is a dynamic, short-lived post-translational modification, which can take place in very few minutes.
  • the polymer generated by PARylation can then be degraded through another enzyme called poly ADP-ribose glycohydrolase (PARG).
  • PARG poly ADP-ribose glycohydrolase
  • PARP1 the founding member of the PARP superfamily, contributing to over 90% of PARylation, has been extensively studied for its pivotal role in DNA damage response, especially for the repair of DNA single strand breaks (SSBs) (Durkacz, B. W ., et al. Nature, 1980, 283, 593).
  • the basal level of PARylation in quiescent cells is typically below detection.
  • auto-PARylation When exposed to genotoxic stress, PARP1 is rapidly activated by self-modification (auto-PARylation), which initiates the DNA damageresponse signaling pathways.
  • This process includes a complex cascade of signaling events starting from binding of PARP proteins to the damage sites, to PARylating and recruiting of repair factors, and eventually dissociating from the damage sites (Bai, P., Mol. Cell, 2015, 58, 947).
  • PARP2 is involved in DNA damage repair as well.
  • mounting evidence suggests that PARP2 also plays crucial roles in the development and maintenance of hematopoietic cells and some other tissues.
  • PARP1 is the primary target for developing PARP inhibitors, most if not all current PARP inhibitors also suppress enzymatic activities of other PARPs, particularly PARP2, a close paralog of PARP 1 that sharing a 69% identity of its catalytic domain.
  • PARP2 catalyzes only about 10% of cellular PARylation in the presence of PARP1 (Ame, J. C., et al. Bioessays, 2004, 26, 882; Ame, J. C., et al. J. Biol. Chem., 1999, 274, 17860).
  • PARP2 Despite the functional redundancy with PARP1, PARP2 also has its own unique functions in controlling hematopoiesis, spermatogenesis, adipogenesis and transcriptional regulation.
  • pharmacologic inhibition of the PARP2 enzyme may lead to unfavorable effects in aforementioned tissues, consequently resulting in adverse effects in clinical applications (Farres, J., et al. Blood, 2013, 122, 44; Chen, Q., et al. Nat. Commun., 2018, 9, 3233; Gui, B., et al. PNAS, 2019, 116, 14573).
  • selective inhibition of PARP1 while retaining the essential functions of PARP2 and other PARP family members is expected to maximize efficacy of PARP inhibitors in treating human cancers while minimizing its unfavorable side effects.
  • the present disclosure further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure further provides methods of inhibiting PARP1 activity, comprising contacting the PARP1 with a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure further provides methods of treating a disease or a disorder associated with PARP1 in a patient by administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.
  • the present disclosure further provides use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.
  • X is C or N
  • Y is C or N
  • Ring B is C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl;
  • Ring C is 4-14 membered heterocycloalkyl
  • Ring D is C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, or 5- 10 membered heteroaryl;
  • L is selected from C1-4 alkylene, C1-4 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, -O-, -N(R L )-, -C(O)-, -C(O)N(R L )-, - N(R L )C(O)N(R L )-, -N(R L )C(O)O-, -S(O) 2 -, -N(R L )S(O) 2 -, and -N(R L )S(O) 2 N(R L )-, wherein the C1-4 alkylene, C1-4 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, C3-7 cycloalkylene
  • R 1 is selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
  • R 2 is selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
  • R 3 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl;
  • R 4 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl; or, R 3 and R 4 , together with the carbon atom to which they are attached, form a C3-7 cycloalkyl, or 4-7 membered heterocycloalkyl group, wherein the C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R G substituents;
  • R 50 is selected from H, halo, C1-6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -OR a50 , - SR a50 , -NR c50 R d5 °, -NO 2 , -C(O)R a50 , -C(O)OR a50 , -C(O)NR c50 R d5 °, - C(O)NR c50 (OR a5 °), -OC(O)R
  • each R a50 , R c50 , and R d50 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl,
  • each R b50 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7
  • X is N.
  • X is C.
  • Y is C.
  • Y is N.
  • X is N and Y is C.
  • Ring B is C5-7 cycloalkyl, phenyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl.
  • Ring B is 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl.
  • Ring B is 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl.
  • Ring B is 5-6 membered heteroaryl.
  • Ring B is 6-membered heteroaryl.
  • Ring is asymmetric
  • m is 0, 1, 2, 3, or 4.
  • n 0, 1, or 2.
  • m is 0 or 1.
  • m is 0.
  • Ring is asymmetric
  • R 1 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl;
  • R 1 is selected from H, halo, and C1-3 alkyl.
  • R 1 is H or halo.
  • R 1 is halo
  • R 1 is H or fluoro. In some embodiments, R 1 is fluoro.
  • R 1 is H.
  • R 2 is selected from H, halo, and C1-3 alkyl.
  • R 2 is selected from H and C1-3 alkyl.
  • R 2 is selected from H.
  • R 3 is selected from H, halo, and C1-3 alkyl.
  • R 3 is selected from H and C1-3 alkyl.
  • R 3 is H.
  • R 4 is selected from H, halo, and C1-3 alkyl.
  • R 4 is selected from H and C1-3 alkyl.
  • R 4 is H.
  • R 3 and R 4 are each H.
  • Ring C is 4-10 membered heterocycloalkyl.
  • Ring C is 4-7 membered heterocycloalkyl.
  • Ring C is 4-5 membered heterocycloalkyl.
  • Ring C is 4-membered heterocycloalkyl.
  • Ring is asymmetric
  • p is 0, 1, 2, 3, or 4.
  • p is 0, 1, or 2.
  • p is 0 or 1.
  • p is 1.
  • each R 7 is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, and C1-6 haloalkyl.
  • each R 7 is independently selected from C1-6 alkyl and
  • each R 7 is independently selected from C1-6 alkyl.
  • each R 7 is independently selected from C1-3 alkyl.
  • each R 7 is methyl.
  • Ring C is selected from
  • Ring is asymmetric
  • Ring is asymmetric
  • L is -O- or -N(R L )-.
  • L is -O-.
  • Ring D is 5-10 membered heteroaryl.
  • Ring D is 5-6 membered heteroaryl.
  • Ring D is 6-membered heteroaryl.
  • Ring D is pyridinyl
  • q is 1, 2, 3, or 4.
  • q is 1, 2, or 3.
  • q is 1 or 2.
  • q is 1.
  • q is 2.
  • Ring is asymmetric
  • Ring is asymmetric
  • each R 8 is independently selected from halo, C1-6 alkyl,
  • each R 8 is independently selected from halo, Ci-6 alkyl, C 2 -6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, -CN, -OR a8 , -NR c8 R d8 , -C(O)R a8 , -C(O)OR a8 , -C(O)NR c8 R d8 , and -NR c8 C(O)R a8 .
  • each R 8 is independently selected from C1-6 alkyl and - C(O)NR c8 R d8 .
  • each R 8 is independently selected from C1-3 alkyl and - C(O)NR c8 R d8 .
  • each R 8 is independently selected from -C(O)NR c8 R d8 .
  • each R a8 , R c8 , and R d8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of R c8 and R d8 are each optionally substituted with 1, 2, 3, or 4 independently selected R 8A substituents.
  • each R a8 , R c8 , and R d8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, and 5-10 membered heteroaryl.
  • each R a8 , R c8 , and R d8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of R a8 , R c8 , and R d8 are each optionally substituted with 1, 2, 3, or 4 independently selected R 8A substituents.
  • each R a8 , R c8 , and R d8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.
  • each R a8 , R c8 , and R d8 is independently selected from H, C1-6 alkyl, and C3-10 cycloalkyl.
  • each R a8 , R c8 , and R d8 is independently selected from H, C1-6 alkyl, and C3-7 cycloalkyl. In some embodiments, each R c8 and R d8 is independently selected from H, Ci-6 alkyl, and C3-10 cycloalkyl.
  • each R c8 and R d8 is independently selected from H, C1-6 alkyl, and C3-7 cycloalkyl.
  • each R c8 and R d8 is independently selected from H, methyl, and cyclopropyl
  • each R 8 is independently selected from C1-6 alkyl and - C(O)NR c8 R d8 ; and each R c8 and R d8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.
  • each R 8 is independently selected from C1-3 alkyl and - C(O)NR c8 R d8 ; and each R c8 and R d8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.
  • each R 8 is independently selected from methyl and - C(O)NR c8 R d8 ; and each R c8 and R d8 is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl.
  • each R 8 is independently selected from -C(O)NR c8 R d8 ; and each R c8 and R d8 is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl.
  • each R 8 is independently selected from methyl, methylaminocarbonyl, and cyclopropylaminocarbonyl.
  • each R 8 is independently selected from methylaminocarbonyl and cyclopropylaminocarbonyl.
  • R 50 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, and C1-6 haloalkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R 50 are each optionally substituted by 1, 2, 3, or 4 independently selected R G substituents.
  • R 50 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, and C1-6 haloalkyl. In some embodiments, R 50 is selected from H, Ci-6 alkyl, and Ci-6 haloalkyl.
  • R 50 is Ci-6 alkyl.
  • R 50 is C1-3 alkyl.
  • R 50 is ethyl
  • X is C or N
  • Y is C or N
  • Ring B is 5-6 membered heteroaryl
  • Ring C is 4-7 membered heterocycloalkyl
  • Ring D is 5-10 membered heteroaryl
  • each R L is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;
  • R 1 is selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
  • R 2 is selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
  • R 3 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl;
  • R 4 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl;
  • R 50 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R 6 is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl each R 7 is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R 8 is independently selected from each R 8 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, -CN, -OR a8 , -NR c8 R d8 , - C(O)R a8 , -C(O)OR a8 , -C(O)NR c8 R d8
  • the compound of Formula I is a compound of Formula
  • the compound of Formula I is a compound of Formula III:
  • the compound of Formula I is a compound of Formula IV: or a pharmaceutically acceptable salt thereof.
  • the compound provided herein is selected from: 5-((l-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6-de]quinazolin-)
  • each divalent linking substituent include both the forward and backward forms of the linking substituent.
  • -N(R L )C(O)- includes both -N(R L )C(O)- and -C(O)N(R L )- (e.g. -NHC(O)- includes both -NHC(O)- and -C(O)NH-).
  • n-membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazolyl is an example of a 5-membered heteroaryl ring
  • pyridyl is an example of a 6- membered heteroaryl ring
  • 1,2,3,4-tetrahydro-naphthalene is an example of a 10- membered cycloalkyl group.
  • the phrase “optionally substituted” means unsubstituted or substituted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position.
  • substituted means that a hydrogen atom is removed and replaced by a substituent.
  • a single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.
  • each ‘variable’ is independently selected from means substantially the same as wherein “at each occurrence ‘variable’ is selected from.”
  • C n -m and C m -n indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-3, C1-4, C1-6, and the like.
  • C n -m alkyl refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l- butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.
  • C n -m alkyl is understood to include deuterated analogs of saturated hydrocarbon groups as defined herein, including but not limited to, groups such as trideuteromethyl (CD3), pentadeuteroethyl (CD2CD3), and the like.
  • the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, from 2 to 6 carbon atoms, from 2 to 4 carbon atoms, from 2 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • C n -m alkenyl refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons.
  • Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec- butenyl, and the like.
  • the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • C n -m alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons.
  • Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like.
  • the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • C n -m alkoxy refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons.
  • Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tertbutoxy), and the like.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • aryl refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings).
  • C n -m aryl refers to an aryl group having from n to m ring carbon atoms.
  • Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl groups have from 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl is phenyl.
  • halo refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. In some embodiments, a halo is F or Cl. In some embodiments, a halo is F. In some embodiments, a halo is Cl.
  • C n -m haloalkoxy refers to a group of formula -O-haloalkyl having n to m carbon atoms.
  • Example haloalkoxy groups include OCF3 and OCHF2.
  • the haloalkoxy group is fluorinated only.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • C n -m haloalkyl refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms.
  • the haloalkyl group is fluorinated only.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CC1 3 , CHC1 2 , C 2 C1 5 and the like.
  • cycloalkyl refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and alkenyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2 fused rings) groups, spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O) or C(S)).
  • cycloalkyl moi eties that have one or more aromatic rings fused (z.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like.
  • a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ringforming atom of the fused aromatic ring.
  • Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (z.e., C3-10).
  • the cycloalkyl is a C3-10 monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-10 spirocycle or bridged cycloalkyl (e.g., a bridged bicycloalkyl group).
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcamyl, cubane, adamantane, bicyclo[l.l. l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • heteroaryl refers to a monocyclic or polycyclic (e.g., having 2 fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, S and B.
  • the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S and B.
  • any ring-forming N in a heteroaryl moiety can be an N-oxide.
  • the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B.
  • the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S.
  • the heteroaryl is a 5-6 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group contains 5 to 10, 5 to 7, 3 to 7, or 5 to 6 ringforming atoms.
  • the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms or 1 ring-forming heteroatom.
  • the heteroatoms may be the same or different.
  • Example heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl (or furanyl), pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4- thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and l,2-dihydro-l,2-azaborine, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azolyl, triazolyl, thiadiazolyl, quinolinyl, isoquinoliny
  • heterocycloalkyl refers to monocyclic or polycyclic heterocycles having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl is replaced by a heteroatom selected from N, O, S, and B, and wherein the ringforming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)2, etc.).
  • oxo or sulfido e.g., C(O), S(O), C(S), or S(O)2, etc.
  • a ring-forming carbon atom or heteroatom of a heterocycloalkyl group is optionally substituted by one or more oxo or sulfide
  • the O or S of said group is in addition to the number of ring-forming atoms specified herein (e.g., a l-methyl-6- oxo-l,6-dihydropyridazin-3-yl is a 6-membered heterocycloalkyl group, wherein a ring-forming carbon atom is substituted with an oxo group, and wherein the 6- membered heterocycloalkyl group is further substituted with a methyl group).
  • Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3 to 10, 4 to 10, 5 to 10, 4 to 7, 5 to 7, or 5 to 6 membered heterocycloalkyl groups.
  • Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., a 5 to 10 membered bridged biheterocycloalkyl ring having one or more of the ring-forming carbon atoms replaced by a heteroatom independently selected from N, O, S, and B).
  • the heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom.
  • the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.
  • heterocycloalkyl moi eties that have one or more aromatic rings fused (z.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • the heterocycloalkyl group contains 3 to 10 ringforming atoms, 4 to 10 ring-forming atoms, 4 to 8 ring-forming atoms, 3 to 7 ringforming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S and B and having one or more oxidized ring members.
  • the heterocycloalkyl is a monocyclic or bicyclic 5-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5 to 10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic 5 to 6 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members.
  • Example heterocycloalkyl groups include pyrrolidin-2-one (or 2- oxopyrrolidinyl), l,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, 1, 2,3,4- tetrahydroisoquinoline, tetrahydrothiopheneyl, tetrahydrothiopheneyl 1,1 -di oxide, benzazapene, azabicyclo[3.1.0]hexanyl
  • C o-P cycloalkyl-C n -m alkyl- refers to a group of formula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.
  • C 0.p aryl-C n -m alkyl- refers to a group of formula arylalkylene-, wherein the aryl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.
  • heteroaryl-C n -m alkyl- refers to a group of formula heteroaryl-alkylene-, wherein alkylene linking group has n to m carbon atoms.
  • heterocycloalkyl -C n -m alkyl- refers to a group of formula heterocycloalkyl-alkylene-, wherein alkylene linking group has n to m carbon atoms.
  • an “alkyl linking group” or “alkylene linking group” is a bivalent straight chain or branched alkyl linking group (“alkylene group”).
  • alkylene group a bivalent straight chain or branched alkyl linking group.
  • alkyl linking groups or “alkylene groups” include methylene, ethan- 1,1 -diyl, ethan- 1,2-diyl, propan-1, 3-dilyl, propan- 1,2-diyl, propan- 1,1 -diyl and the like.
  • haloalkyl linking group or “haloalkylene linking group” is a bivalent straight chain or branched haloalkyl linking group (“haloalkylene group”).
  • haloalkylene group include -CF2-, -C2F4-, -CHF-, -CCI2-, -CHC1-, -C2CI4-, and the like.
  • a “cycloalkyl linking group” or “cycloalkylene linking group” is a bivalent straight chain or branched cycloalkyl linking group (“cycloalkylene group”).
  • Examples of “cycloalkyl linking groups” or “cycloalkylene groups” include cyclopropy-l,l,-diyl, cy cl opropy- 1,2-diyl, cyclobut-l,3,-diyl, cyclopent-1, 3, -diyl, cyclopent- 1,4, -diyl, cyclohex- 1,2, -diyl, cyclohex-1, 3, -diyl, cyclohex- 1,4, -diyl, and the like.
  • heterocycloalkyl linking group or “heterocycloalkylene linking group” is a bivalent straight chain or branched heterocycloalkyl linking group (“heterocycloalkylene group”).
  • heterocycloalkylene group examples include azeti din- 1,2-diyl, azeti din- 1,3 -diyl, pyrrolidin- 1,2-diyl, pyrrolidin- 1,3 -diyl, pyrrolidin-2,3-diyl, piperi din- 1,2-diyl, piperidin-l,3-diyl, piperidin-l,4-diyl, piperi din-2, 3 -diyl, piperidin-2,4-diyl, and the like.
  • heteroaryl linking group or “heteroarylene linking group” is a bivalent straight chain or branched heteroaryl linking group (“heteroarylene group”).
  • heteroarylene group examples include pyrazol- 1,3 -diyl, imidazol-l,2,-diyl, pyri din-2, 3 -diyl, pyridin-2,4-diyl, pyridin-3,4- diyl, and the like.
  • the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.).
  • these rings can be attached to any ring member provided that the valency of the atom is not exceeded.
  • an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position.
  • each occurrence of a variable or substituent e.g., each R G
  • each R G independently selected at each occurrence from the applicable list.
  • 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.
  • Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • the compound has the (R)-configuration.
  • the compound has the (S)-configuration.
  • the Formulas e.g., Formula I, Formula II, etc. provided herein include stereoisomers of the compounds.
  • An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as P-camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- m ethylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
  • stereoisomerically pure forms of a-methylbenzylamine e.g., S and R forms, or diastereomerically pure forms
  • 2-phenylglycinol norephedrine
  • ephedrine N- m ethylephedrine
  • cyclohexylethylamine 1,2-diaminocyclohexane, and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • 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, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • preparation of compounds can involve the addition of acids or bases to affect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts.
  • the compounds provided herein, 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 provided herein.
  • 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 provided herein, 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 application also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present disclosure include the conventional non -toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
  • ACN acetonitrile
  • Compounds of Formula II-7 can be prepared, for example, according to the procedures shown in Scheme II. Reacting compound II-l (Hal 1 and Hal 2 are independently suitable halogen such as I, Br or Cl) with a suitable isocyanate can afford the urea compound II-2 (PG is a suitable protecting group such PMB). Under suitable conditions such as palladium-catalyzed cross-coupling conditions, compound II-2 can be cyclized to give compound II-3. Alkylation of the NH in compound II-3 with a suitable reagent in the presence of a suitable base can give compound II-4. Under suitable coupling conditions such as Stille or Suzuki coupling, compound II-4 can be converted to alcohol II-5.
  • 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.
  • the chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., J H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., J H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry
  • chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • ambient temperature e.g. a reaction temperature
  • room temperature e.g. a temperature that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.
  • provided compounds and compositions are for use in medicine (e.g., as therapy).
  • provided compounds and compositions are useful in treating a disease, disorder, or condition, wherein an underlying pathology is, wholly or partially, mediated by PARP1.
  • provided compounds and compositions are useful in research as, for example, analytical tools and/or control compounds in biological assays.
  • the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with PARP1. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition, wherein an underlying pathology is, wholly or partially, mediated by PARP1.
  • the compounds provided herein are useful as PARP1 inhibitors.
  • the present disclosure provides methods of inhibiting PARP1 in a subject comprising administering a provided compound or composition.
  • the present disclosure provides methods of inhibiting PARP1 in a biological sample comprising contacting the sample with a provided compound or composition.
  • the present disclosure provides methods of treating a disease, disorder or condition associated with PARP1 in a subject in need thereof, comprising administering to the subject a provided compound or composition.
  • a disease, disorder or condition is associated with overexpression of PARP1.
  • the present disclosure provides methods of treating a disease, disorder or condition, wherein an underlying pathology is, wholly or partially, mediated by PARP1, in a subject in need thereof, comprising administering to the subject a provided compound or composition.
  • the present disclosure provides methods of treating cancer, comprising administering a compound, salt, or composition provided herein to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating proliferative diseases, comprising administering a compound, salt, or composition provided herein to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating metastatic cancers, comprising administering a compound, salt, or composition provided herein to a subject in need thereof.
  • Exemplary cancers include but are not limited to breast cancer, ovarian cancer, cervical cancer, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric cancer, bladder cancer, lung cancer (e.g., adenocarcinoma, non-small-cell lung carcinoma (NSCLC) and small-cell lung carcinoma (SCLC)), bone cancer (e.g., osteosarcoma), colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma (e.g., liposarcoma), bladder cancer, uterine serous carcinoma, liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e
  • the cancer is selected from ovarian cancer, breast cancer, prostate cancer, and pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is pancreatic cancer.
  • the compounds, salts, and compositions provided herein are expected to selectively kill tumor cells characterized by homologous recombination deficiency while generating minimal impact on normal tissues.
  • the present disclosure provides methods of treating advanced cancer induced by or correlated with a dysregulated DNA repair system, comprising administering a provided compound or composition to a subject in need thereof.
  • advanced cancers include but are not limited to breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer. These malignant tumors are features of deleterious or suspected deleterious mutations of key genes involved in DNA damage repair pathways.
  • such key genes include but are not limited to ATM, ATR, BAP1, BRCA1, BRCA2, CDK12, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, PALB2, NBS1, WRN, RAD51C, RAD51D, MRE11A, CHEK1, BLM, RAD51B, and BRIPP Cancer patients with such mutations can be identified using companion diagnostics. Advanced cancer patients with a positive status of homologous recombination deficiency are expected to benefit from monotherapy with a compound, salt, or composition provided herein.
  • the compounds, salts, or compositions provided herein are useful in treating cancer featured by dysregulated DNA damage repair.
  • Exemplary cancers include but are not limited to triple-negative breast cancer, high-grade serous ovarian cancer, platinum-sensitive advanced pancreatic cancer, and castration-resistant prostate cancer. These tumors are typically sensitive to platinum-based therapies and other DNA damaging agents.
  • provided compounds and compositions of the present disclosure may reduce risks of recurrence or relapse and therefore prolong progression free survival of patients with advanced cancers.
  • a method of increasing survival or progression-free survival in a patient comprising administering a compound provided herein to the patient.
  • the patient has cancer.
  • the patient has a disease or disorder described herein.
  • progression-free survival refers to the length of time during and after the treatment of a solid tumor that a patient lives with the disease but it does not get worse.
  • Progression-free survival can refer to the length of time from first administering the compound until the earlier of death or progression of the disease.
  • Progression of the disease can be defined by RECIST v. 1.1 (Response Evaluation Criteria in Solid Tumors), as assessed by an independent centralized radiological review committee.
  • administering of the compound results in a progression free survival that is greater than about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, about 12 months, about 16 months, or about 24 months.
  • the administering of the compound results in a progression free survival that is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months.
  • the administering of the compound results in an increase of progression free survival that is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months.
  • the present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.
  • the present disclosure further provides use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.
  • 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.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting includes the administration of a compound described herein to an individual or patient, such as a human, having PARP1, as well as, for example, introducing a compound described herein into a sample containing a cellular or purified preparation containing the PARP1.
  • the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent such as an amount of any of the solid forms or salts thereof as disclosed herein 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.
  • An appropriate "effective" amount in any individual case may be determined using techniques known to a person skilled in the art.
  • phrases “pharmaceutically acceptable” is used 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, immunogenicity or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the phrase “pharmaceutically acceptable carrier or excipient” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic and neither biologically nor otherwise undesirable and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is “pharmaceutically acceptable” as defined herein.
  • treating refers to inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) or ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • Cancer cell growth and survival can be impacted by dysfunction in multiple signaling pathways. It is useful to combine compounds modulating different biological targets to treat such conditions. Targeting more than one signaling pathway or more than one biological molecule involved in a given signaling pathway also may reduce the likelihood of drug resistance.
  • a compound, salt, or composition provided herein is administered as part of a combination therapy.
  • combination therapy refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents).
  • the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
  • “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.
  • a compound, salt, or composition provided herein is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and/or therapy to address one or more side effects of such anti -cancer therapy, or otherwise to provide palliative care).
  • additional therapies e.g., an anti-cancer therapy and/or therapy to address one or more side effects of such anti -cancer therapy, or otherwise to provide palliative care.
  • Exemplary additional therapies include but are not limited to chemotherapies, radiotherapies, anti-inflammatory agents, steroids, immunosuppressants, immune- oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, phosphatase inhibitors, and targeted therapies such as kinase inhibitors.
  • a compound, salt, or composition provided herein can be combined with one or more agents targeting the following biological targets, including but not limiting to Weel, ATR, ATM, DNA-PK, CDK4/6, CHK1/2, HER2, PI3K, mTOR, EGFR, VEGFR, FGFR, PDGFR, BTK, IGF-1R, BRAF, MEK, KRAS, EZH2, BCL2, HSP90, HDAC, Topoisomerases, HIF-2a, androgen receptor, estrogen receptor, proteosome, RAD51, RAD52, POLQ, WRN, PD-1, and PD-L1.
  • agents targeting the following biological targets including but not limiting to Weel, ATR, ATM, DNA-PK, CDK4/6, CHK1/2, HER2, PI3K, mTOR, EGFR, VEGFR, FGFR, PDGFR, BTK, IGF-1R, BRAF, MEK, KRAS, EZH2, BCL2, HSP90
  • HIF-2a inhibition results in down-regulated expression of the BRCA gene, consequently making tumor cells more vulnerable to PARP1 inhibition.
  • exemplary cancers for combination of PARP1 and HIF-2a inhibitors include but not limited to clear cell renal cell carcinoma, particularly for the subgroup with the tumor suppressor von Hippel Lindau (VHL) deficiency.
  • VHL von Hippel Lindau
  • a compound, salt, or composition provided herein can be combined with chemotherapies for treatment of cancer.
  • a compound, salt, or composition provided herein can be combined with chemotherapies for treatment of high-grade serous ovarian cancer.
  • chemotherapies include but are not limited to platinum-based therapy, taxane-based therapy and some others including albumin bound paclitaxel, altretamine, capecitabine, cyclophosphamide, gemcitabine, ifosfamide, irinotecan, liposomal doxorubicin, melphalan, pemetrexed, topotecan, and vinorelbine.
  • a compound, salt, or composition provided herein can be combined with chemotherapies for treatment of advanced metastatic breast cancer.
  • chemotherapies include but are not limited to taxanes such as paclitaxel, docetaxel, and albumin-bound paclitaxel, anthracyclines, platinum agents, vinorelbine, capecitabine, gemcitabine, ixabepilone, and eribulin.
  • combination therapies can be used for malignancies derived from other histologies, including but limited to brain, lung, kidney, liver, and hematologic cancers.
  • Radiotherapies are widely used in clinic for treatment of cancers.
  • a compound, salt, or composition provided herein may improve the effectiveness of radiation therapy through its potent activity in suppressing DNA damage repair.
  • a compound, salt, or composition provided herein can be combined with radiotherapies for treatment of cancer.
  • Exemplary cancers that can be treated with radiotherapies include but are not limited to small cell lung cancer, leukemias, lymphomas, germ cell tumors, non-melanoma skin cancer, head and neck cancer, breast cancer, non-small cell lung cancer, cervical cancer, anal cancer, and prostate cancer.
  • a compound, salt, or composition provided herein may overcome the resistance of certain cancer to radiotherapy, particularly for renal cell carcinoma and melanomas.
  • a compound, salt, or composition provided herein can be combined with immunotherapies to improve the effectiveness of conventional antibody- medicated immunotherapies by promoting DNA damage, increasing mutation burden, and modulating the STING innate immune pathway.
  • a compound, salt, or composition provided herein can be combined with immunotherapies for treatment of adult and pediatric patients with unresectable or metastatic tumors.
  • a compound, salt, or composition provided herein can be combined with immunotherapies for treatment of cancer.
  • Exemplary cancers include but are not limited to non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, classical Hodgkin lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, esophageal cancer, endometrial cancer, tumor mutational burden-high cancer, cutaneous squamous cell carcinoma, microsatellite instability- high or mismatch repair deficient colorectal cancer, and triple-negative breast cancer.
  • a compound, salt, or composition provided herein can be combined with targeted therapies of well-established therapeutic targets including but not limited to PI3K inhibitors, KRAS inhibitors, CDK4/6 inhibitors, BRAF inhibitors, MEK inhibitors, androgen receptor inhibitors, selective estrogen receptor modulators, proteosome inhibitors, mTOR inhibitors, EGFR inhibitors, FGFR inhibitors, MET inhibitors, PDGFR inhibitors, VEGFR inhibitors, EZH2 inhibitors, BTK inhibitors, and BCL2 inhibitors for treatment of cancer.
  • targeted therapies of well-established therapeutic targets including but not limited to PI3K inhibitors, KRAS inhibitors, CDK4/6 inhibitors, BRAF inhibitors, MEK inhibitors, androgen receptor inhibitors, selective estrogen receptor modulators, proteosome inhibitors, mTOR inhibitors, EGFR inhibitors, FGFR inhibitors, MET inhibitors, PDGFR inhibitors, VEGFR inhibitors, EZH2 inhibitors, BTK inhibitors, and BCL2 inhibitors for treatment
  • Exemplary cancers include but are not limited to breast cancer, ovarian cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell renal cell carcinoma, melanoma, colorectal cancer, bladder cancer, prostate cancer, cholangiocarcinoma, and hematologic cancers.
  • a compound, salt, or composition provided herein can be combined with inhibitors of other DNA damage repair proteins including but not limited to CHEK1, CHEK2, ATM, ATR, DNA-PK, WEE1, RAD51, RAD52, POLQ, and WRN for treatment of cancer sensitive to DNA damage.
  • a compound, salt, or composition provided herein can be combined with a WEE1 inhibitor for treatment of uterine serous carcinoma and cancers with mutation of the TP53 genes.
  • a compound, salt, or composition provided herein can be combined with a WRN inhibitor for treatment of microsatellite instability -high cancers, such as colon cancer, gastric cancer, endometrium cancer, ovarian cancer, hepatobiliary tract cancer, urinary tract cancer, brain cancer, and skin cancers.
  • microsatellite instability -high cancers such as colon cancer, gastric cancer, endometrium cancer, ovarian cancer, hepatobiliary tract cancer, urinary tract cancer, brain cancer, and skin cancers.
  • compositions which refers to a combination of a compound of the invention, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.
  • compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.
  • Administration may be 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, oral or parenteral.
  • Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or 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.
  • 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.
  • 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 breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner
  • 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.
  • 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 pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • 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.
  • compositions of the disclosure can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are provided herein..
  • additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are provided herein.
  • Another aspect of the present invention relates to fluorescent dye, spin label, heavy metal or radio-labeled compounds of the invention that would be useful not only in imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the PARP1 protein in tissue samples, including human, and for identifying PARP1 protein ligands by inhibition binding of a labeled compound.
  • the present invention includes PARP1 biochemical assays that contain such labeled compounds.
  • the present invention further includes isotopically-labeled compounds of the invention.
  • An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), n C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 C1, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound.
  • One or more constituent atoms of the compounds presented herein can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance.
  • one or more atoms are replaced or substituted by deuterium.
  • one or more hydrogen atoms in a compound of the present disclosure can be replaced by deuterium atoms (e.g., one or more hydrogen atoms of a Ci-6 alkyl group of Formula I can be optionally substituted with deuterium atoms, such as -CD3 being substituted for -CH3).
  • alkyl groups of the disclosed Formulas e.g., the compound of any of Formulas I-IV
  • the compound provided herein e.g., the compound of any of Formulas I-IV
  • a pharmaceutically acceptable salt thereof comprises at least one deuterium atom.
  • the compound provided herein e.g., the compound of any of Formulas I-IV
  • a pharmaceutically acceptable salt thereof comprises two or more deuterium atoms.
  • the compound provided herein e.g., the compound of any of Formulas I-IV
  • a pharmaceutically acceptable salt thereof comprises three or more deuterium atoms.
  • a compound provided herein e.g., the compound of any of Formulas I-IV
  • a pharmaceutically acceptable salt thereof all of the hydrogen atoms are replaced by deuterium atoms (z.e., the compound is “perdeuterated”).
  • radio-labeled or “labeled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 1 , 35 S and 82 Br.
  • substitution with heavier isotopes may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances, (see e.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm. 2015, 58, 308-312).
  • substitution at one or more metabolism sites may afford one or more of the therapeutic advantages.
  • a radio-labeled compound of the invention can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound z.e., test compound
  • a test compound can be evaluated for its ability to reduce binding of the radio-labeled compound of the invention to the PARP1 protein. Accordingly, the ability of a test compound to compete with the radio-labeled compound for binding to the PARP1 protein directly correlates to its binding affinity.
  • kits useful, for example, in the treatment or prevention of PARP1 -associated diseases or disorders referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • Typical preparative reverse-phase high performance liquid chromatography (RP-HPLC) column conditions are as follows:
  • TFA conditions column, Waters XSelect CSH Cis 5 pm particle size, 30 x 150 mm; eluting with mobile phase A: water (0.05% trifluoroacetic acid), mobile Phase B: acetonitrile; the flow rate, 60 mL/min.
  • NH4HCO3 conditions column, waters XBridge BEH Cis 5 pm particle size, 30 x 150 mm; eluting with mobile phase A: water (10 mM ammonium bicarbonate), mobile Phase B: acetonitrile; the flow rate, 60 mL/min.
  • HCOOH conditions column, Sunfire Prep Cis OBD 5 pm particle size, 30 x 150 mm; eluting with mobile phase A: water (0.1% formic acid), mobile Phase B: acetonitrile; the flow rate, 60 mL/min.
  • the separating gradient was optimized for each compound.
  • the separated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity check under the following conditions: Instrument: Shimadzu LCMS-2020, column: Halo Cis 2 pm particle size, 3 x 30 mm; buffers: mobile phase A: 0.05% TFA in water and mobile phase B: acetonitrile; gradient: 0 to 60% of B in 1.9 min, 60% to 100% of B in 0.35 min with flow rate 1.5 mL/min.
  • LCMS liquid chromatography mass spectrometry
  • Step 2 5-((l -(Tert-butoxycarbonyl)azetidin-3-yl)oxy)picolinic acid Boc i
  • Step 3 Tert-butyl 3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-l-carboxylate
  • Step 1 Methyl 5-(((2R,3S)-l-(tert-butoxycarbonyl)-2-methylazetidin-3- yl)oxy)picolinate
  • Step 2 5-(((2R,3S)-l-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)picolinic acid
  • Step 3 Tert-butyl (2R,3S)-2-methyl-3-((6-(methylcarbamoyl)pyridin-3- yl)oxy)azetidine-l-carboxylate
  • Step 1 Tert-butyl 3-((6-(cyclopropylcarbamoyl)pyridin-3-yl)oxy)azetidine-l- carboxylate
  • Step J tert-Butyl (2R,3S)-3-((6-(cyclopropylcarbamoyl)pyridin-3-yl)oxy)-2- methylazetidine-l-carboxylate
  • Step 3 7-Br()m()-N 5 -(4-melh()xybenzyl)qiiinaz()line-4,5-diamine
  • Step 4 7-Bromo-6-fliioro-N 5 -(4-methoxybenzyl)quinazoline-4, 5-diamine
  • Step 5 8-Bromo-9-fluoro-l-(4-methoxybenzyl)-lH-pyrimido[4,5, 6-de]quinazolin- 2(3H)-one
  • Step 6 8-Bromo-3-ethyl-9-fluoro-l-(4-methoxybenzyl)-lH-pyrimido[ 4, 5, 6- de ]quinazolin-2 ( 3H) -one
  • Step 1 8-Bromo-l-(4-methoxybenzyl)-lH-pyrimido[4,5,6-de]quinazolin-2(3H)-one
  • Step 2 8-Bromo-3-ethyl-l-(4-methoxybenzyl)-lH-pyrimido[4,5, 6-de]quinazolin- 2(3H)-one
  • Step 3 3-Ethyl-8-(hydroxymethyl)-l-(4-methoxybenzyl)-lH-pyrimido[4,5, 6- de ]quinazolin-2 ( 3H) -one
  • Step 1 3-Ethyl-9-fluoro-8-(hydroxymethyl)-l-(4-methoxybenzyl)-lH-pyrimido[4,5,6- de ]quinazolin-2 ( 3H) -one
  • Step 2 5-( ( 1 -((3-Ethyl-9-fluoro-2-oxo-2, 3-dihydro-lH-pyrimido[ 4, 5, 6-de ]quinazolin- 8-yl)methyl)azetidin-3-yl)oxy)-N-methylpicolinamide
  • the residue was purified by Prep-HPLC with the following conditions (Column: Sunfire prep Cl 8 column, 30*150 mm; Mobile Phase: acetonitrile in water (0.05% trifluoroacetic acid); Flow rate: 60 mL/min; Gradient: 2% B to 20% B in 10 min; Detector: 254/220 nm). Eluted fractions were collected and lyophilized to afford the TFA salt of the desired product as a white solid.
  • the residue was purified by Prep-HPLC with the following conditions (Column: Sunfire prep Cl 8 column, 30*150 mm; Mobile Phase: acetonitrile in water (0.05% trifluoroacetic acid); Flow rate: 60 mL/min; Gradient: 2% B to 20% B in 10 min; Detector: 254/220 nm). Eluted fractions were collected and lyophilized to afford the TFA salt of the desired product as a white solid.
  • Step 1 Methyl 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-6-methylpicolinate
  • Step 2 5-((l-(Tert-butoxycarbonyl)azetidin-3-yl)oxy)-6-methylpicolinic acid
  • Step 3 Tert-butyl 3-((2-methyl-6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-l- carboxylate
  • Step 5 5-( (l-( (3-Ethyl-2-oxo-2, 3-dihydro-lH-pyrimido[ 4, 5, 6-de ]quinazolin-8- yl)methyl)azetidin-3-yl)oxy)-N,6-dimethylpicolinamide
  • Step 1 Methyl 5-(((2R,3S)-l-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)-6- methylpicolinate
  • Step 2 5-( ( (2R, 3S)-l-( tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)-6- methylpicolinic acid
  • Step 3 Tert-butyl (2R,3S)-2-methyl-3-((2-methyl-6-(methylcarbamoyl)pyridin-3- yl)oxy)azetidine-l-carboxylate
  • Step 4 N, 6-dimethyl-5-( ( 2R, 3S)-2-methylazetidin-3-yl)oxy)picolinamide
  • Step 5 5-( ( (2R, 3S)-l-((3-ethyl-2-oxo-2, 3-dihydro-lH-pyrimido[ 4, 5, 6-de ]quinazolin- 8-yl)methyl)-2-methylazetidin-3-yl)oxy)-N,6-dimethylpicolinamide
  • This cell-based assay is to measure the potency and selectivity of synthesized PARP inhibitors in suppressing hydrogen peroxide-induced PARylation in cells with and without PARP1 expression.
  • Several cell lines were used in this assay. HeLa cells (wide-type with PARP1 gene) were purchased from ATCC. The HAP1 cell line without the PARP1 gene (#HZGHC003943c006) was purchased from Horizon Discovery. Cells were cultured using complete medium containing 10% fetal bovine serum. One day before the assay, cells were seeded in 96-well plates at the density of 20,000 cells per well in 80 uL complete medium. Compounds were dissolved using DMSO and diluted to the working concentrations using complete medium.
  • Cells were pre-treated with compounds for 60 min and then stimulated with 10 mM hydrogen peroxide for 15 min. After stimulation, cells were immediately fixed using ice-cold methanol for 20 min. After fixation, cells were washed using IX PBST buffer for 3 times, 5 min each time, to eliminate residual methanol. Cells were blocked for 1 h at room temperature in blocking buffer (10% goat serum, 1% BSA, 0.1% Triton X-100 in PBST). Primary antibody was diluted in blocking buffer at 50 uL per well. Cells were incubated with the primary antibody (Adipogen, AG-20T- 0001-M001, 1 :300) at 4 °C for 18 h.
  • the primary antibody Adipogen, AG-20T- 0001-M001, 1 :300
  • IX PBST IX PBST
  • IRDye® 680RD Goat anti-Mouse IgG (H + L) secondary antibody was diluted at 1/1000 using the diluent buffer and added at 50 uL per well. Secondary antibody incubation was for 1 h at room temperature. Cells were then washed using IX PBST for 3 times, 5 min each time. The signal was detected and analyzed using LI-COR Odyssey DLx Imaging system. Data were collected and further processed using GraphPad Prism for IC50 estimation.
  • D 500 nM ⁇ IC50 ⁇ 1,000 nM
  • E 1,000 nM ⁇ IC50 ⁇ 10,000 nM.
  • Example B Cell-titer Gio measurement of cytotoxicity in BRCA2 isogenic cells
  • the purpose of this cellular assay is to measure cytotoxicity and cell killing activity of selected PARP1 inhibitors in DLD1 isogenic cells with and without the BRCA2 genes.
  • the BRCA2 knockout DLD1 cell line (#HD 105-007) and its isogenic wide-type control were purchased from Horizon Discovery. Cells were cultured using RPMI 1640 complete medium containing 10% fetal bovine serum and Penicillin- Streptomycin. One day before the assay, cells were seeded at 50-750 cells per well in 96-well plates. Compounds were dissolved and diluted in DMSO and added into complete medium to final working concentrations. The treatment was for 7 days.
  • Promega Cell-titer Gio reagents (#G7573) were added at 100 uL per well. Plates were kept on orbital shaker for 2 min. These plates were then kept in the CO2 incubator for another 10 minutes. Luminescence signal was measured using the SpectraMax i3x plate reader. Data were further analyzed using GraphPad Prism for IC50 estimation.

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Abstract

The present disclosure provides compounds, compositions, and methods useful for inhibiting PARP1, and/or treating a disease, disorder, or condition associated with PARP1, such as cancer.

Description

Heterocyclic Compounds as PARP1 Inhibitors
TECHNICAL FIELD
The present disclosure provides heterocyclic compounds as well as their pharmaceutical compositions that modulate the activity of PARP1 and are useful in the treatment of various diseases related to PARP1, including cancer.
BACKGROUND
Poly ADP -Ribose Polymerases (PARPs) are a superfamily of enzymes that comprise at least 17 family members. Some of these PARP enzymes, including PARP1, PARP2, PARP5A, and PARP5B, catalyze NAD+ substrate to covalently attach poly ADP-ribose (PAR), a linear or branched, heterogeneous polymer to acceptor proteins, while other members attach mono ADP-ribose (MAR) to acceptor proteins. Accumulating evidence suggests that PARP enzymes have distinct functions. Among those identified PARPs, PARP1, PARP2 and PARP3 are DNA- dependent of which enzymatic activity is strongly stimulated by endogenous and exogenous DNA damage (van Beek, L. et al. Int. J. Mol. Sci., 2021, 22, 5112). These first three PARP enzyme members are therefore important for the regulation of DNA damage repair through a mechanism called Poly ADP-ribosylation (PARylation).
PARylation is a dynamic, short-lived post-translational modification, which can take place in very few minutes. The polymer generated by PARylation can then be degraded through another enzyme called poly ADP-ribose glycohydrolase (PARG). These key enzymes protect cells from DNA damage-induced cell dysfunction and cell death. Because of the large size and highly charged property of PAR, PARylation dramatically alters the regulation of DNA damage response (DDR), cellular stress response and RNA transcription/processing in various biological systems (Feng, X. et al. Int. Rev. Cell Mol. BioL, 2013, 304, 227; Kraus, W. L., ol. Cell, 2015, 58, 902; Cohen, M. S., et al. Nat. Chem. Biol., 2018, 14, 236).
PARP1, the founding member of the PARP superfamily, contributing to over 90% of PARylation, has been extensively studied for its pivotal role in DNA damage response, especially for the repair of DNA single strand breaks (SSBs) (Durkacz, B. W ., et al. Nature, 1980, 283, 593). The basal level of PARylation in quiescent cells is typically below detection. When exposed to genotoxic stress, PARP1 is rapidly activated by self-modification (auto-PARylation), which initiates the DNA damageresponse signaling pathways. This process includes a complex cascade of signaling events starting from binding of PARP proteins to the damage sites, to PARylating and recruiting of repair factors, and eventually dissociating from the damage sites (Bai, P., Mol. Cell, 2015, 58, 947). PARP2 is involved in DNA damage repair as well. However, distinct from PARP1, mounting evidence suggests that PARP2 also plays crucial roles in the development and maintenance of hematopoietic cells and some other tissues.
Clinical data have clearly demonstrated the effectiveness of PARP inhibitors in treating a variety of human cancers, particularly the BRCA 1/2 -mutated, homologous recombination deficient (HRD) cancers. PARP inhibition compromises repair of SSBs by blocking PARylation. On the other hand, PARP inhibitors also trap the PARP protein onto DNA damage sites. PARP trapping leads to blockade of DNA replication, resulting in single-ended DNA double strand breaks (DSBs) due to collapse of replication forks. These breaks require homologous recombination (HR) for faithful repair. Otherwise, these cells would die due to accumulated DNA damage and genomic instability. PARP hyperactivation is frequently observed in cancer patients with HRD tumors. This correlation clearly indicates a hyper-reliance of these tumors on PARP mediated DNA repair pathways (Helleday, T., Mol. Oncol., 2011, 5, 387). These mechanistic studies provide the rationale for targeting HRD cancers with PARP inhibitors.
Although PARP1 is the primary target for developing PARP inhibitors, most if not all current PARP inhibitors also suppress enzymatic activities of other PARPs, particularly PARP2, a close paralog of PARP 1 that sharing a 69% identity of its catalytic domain. PARP2 catalyzes only about 10% of cellular PARylation in the presence of PARP1 (Ame, J. C., et al. Bioessays, 2004, 26, 882; Ame, J. C., et al. J. Biol. Chem., 1999, 274, 17860). Despite the functional redundancy with PARP1, PARP2 also has its own unique functions in controlling hematopoiesis, spermatogenesis, adipogenesis and transcriptional regulation. Therefore, pharmacologic inhibition of the PARP2 enzyme may lead to unfavorable effects in aforementioned tissues, consequently resulting in adverse effects in clinical applications (Farres, J., et al. Blood, 2013, 122, 44; Chen, Q., et al. Nat. Commun., 2018, 9, 3233; Gui, B., et al. PNAS, 2019, 116, 14573). Taken together, selective inhibition of PARP1 while retaining the essential functions of PARP2 and other PARP family members is expected to maximize efficacy of PARP inhibitors in treating human cancers while minimizing its unfavorable side effects.
SUMMARY
The present disclosure provides, inter alia, compounds of Formula I:
Figure imgf000004_0001
or pharmaceutically acceptable salts thereof, wherein constituent members are defined herein.
The present disclosure further provides a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
The present disclosure further provides methods of inhibiting PARP1 activity, comprising contacting the PARP1 with a compound described herein, or a pharmaceutically acceptable salt thereof.
The present disclosure further provides methods of treating a disease or a disorder associated with PARP1 in a patient by administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof. The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.
The present disclosure further provides use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.
DETAILED DESCRIPTION
The present application provides a compound of Formula I:
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein:
X is C or N;
Y is C or N;
= is a single or double bond; m is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, 4, 5, or 6;
Ring B is C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl;
Ring C is 4-14 membered heterocycloalkyl; Ring D is C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, or 5- 10 membered heteroaryl;
L is selected from C1-4 alkylene, C1-4 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, -O-, -N(RL)-, -C(O)-, -C(O)N(RL)-, - N(RL)C(O)N(RL)-, -N(RL)C(O)O-, -S(O)2-, -N(RL)S(O)2-, and -N(RL)S(O)2N(RL)-, wherein the C1-4 alkylene, C1-4 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, C3-7 cycloalkylene-Ci-4 alkyl, and (4-7 membered heterocycloalkylene)-Ci-4 alkyl of L are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each RL is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;
R1 is selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
R2 is selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
R3 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl;
R4 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl; or, R3 and R4, together with the carbon atom to which they are attached, form a C3-7 cycloalkyl, or 4-7 membered heterocycloalkyl group, wherein the C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents;
R50 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa50, - SRa50, -NRc50Rd5°, -NO2, -C(O)Ra50, -C(O)ORa50, -C(O)NRc50Rd5°, - C(O)NRc50(ORa5°), -OC(O)Ra50, -OC(O)NRc50Rd5°, -OC(O)ORa50, -OS(O)2Rb5°, - OS(O)2NRc50Rd5°, -NRc50C(O)Ra5°, -NRc50C(O)ORa5°, -NRc50C(O)NRc50Rd50, - NRc50S(O)2Rb5°, -NRc50S(O)2NRc50Rd5°, -NRc50ORa5°, -NRc50S(O)Rb5°, - NRc50S(O)NRc50Rd50, -S(O)Rb50, -S(O)2Rb5°, -S(O)NRc50Rd5°, -S(O)2NRc50Rd5°, - C(=NRe50)Ra5°, -C(=NRe50)NRc50Rd50, -NRc50C(=NRe50)Ra50, - NRc50C(=NRe50)NRc50Rd5°, -NRc50S(O)(=NRe50)Rb5°, -NRc50S(O)(=NRe50)NRc50Rd50, -
Figure imgf000007_0001
NRc50S(O)NRc50C(O)Rb5°, and -P(O)Rf50Rg5°, wherein the Ci-6 alkyl, C2.6 alkenyl, C2.
6 alkynyl, Ci-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R50 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Ra50, Rc50, and Rd50 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra50, Rc50, and Rd50 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; or, any Rc50 and Rd50 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4-
7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Rb50 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb50 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Re50 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each Rf50 and Rg50 are independently selected from H, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each R6 is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa6, -SRa6,
Figure imgf000008_0001
P(O)Rf6Rg6, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R6 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Ra6, Rc6, and Rd6 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra6, Rc6, and Rd6 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; or, any Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Rb6 is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb6 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Re6 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each Rf6 and Rg6 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each R7 is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa7, -SRa7, -NRc7Rd7, -NO2, -C(O)Ra7, -C(O)ORa7, -C(O)NRc7Rd7, -C(O)NRc7(ORa7), -OC(O)Ra7, -OC(O)NRc7Rd7, -OC(O)ORa7, -OS(O)2Rb7, -OS(O)2NRc7Rd7, -NRc7C(O)Ra7, - NRc7C(O)ORa7, -NRc7C(O)NRc7Rd7, -NRc7S(O)2Rb7, -NRc7S(O)2NRc7Rd7, -NRc7ORa7,
Figure imgf000010_0001
P(O)Rf7Rg7, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R7 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Ra7, Rc7, and Rd7 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra7, Rc7, and Rd7 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; or, any Rc7 and Rd7 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Rb7 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb7 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Re7 is independently selected from H, OH, CN, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each R17 and Rg7 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each R8 is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -
Figure imgf000011_0001
S(O)2NRc8C(O)Rb8, -NRc8S(O)NRc8C(O)Rb8, and -P(O)Rf8Rg8, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R8 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R8A substituents; or, a R7 and a R8, together with the atoms to which they are attached, form a C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl group, wherein the C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R8A substituents; each Ra8, Rc8, and Rd8 is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra8, Rc8, and Rd8 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R8A substituents; or, any Rc8 and Rd8 attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R8A substituents; each Rb8 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb8 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R8A substituents; each Re8 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each RK and Rg8 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R8A is independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa8A, -SRa8A, -NRc8ARd8A, -NO2, -C(O)Ra8A, -C(O)ORa8A, - 8A,
Figure imgf000013_0001
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R8A are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Ra8A, Rc8A, and Rd8A is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra8A, Rc8A, and Rd8A are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; or, any Rc8A and Rd8A attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Rb8A is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb8A are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Re8A is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each RKA and Rg8A are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; and each RG is independently selected from H, OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.
In some embodiments, X is N.
In some embodiments, X is C.
In some embodiments, Y is C.
In some embodiments, Y is N.
In some embodiments, X is N and Y is C.
In some embodiments, Ring B is C5-7 cycloalkyl, phenyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl.
In some embodiments, Ring B is 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl.
In some embodiments, Ring B is 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl.
In some embodiments, Ring B is 5-6 membered heteroaryl.
In some embodiments, Ring B is 6-membered heteroaryl.
In some embodiments, Ring
Figure imgf000015_0001
In some embodiments, m is 0, 1, 2, 3, or 4.
In some embodiments, m is 0, 1, or 2.
In some embodiments, m is 0 or 1.
In some embodiments, m is 0.
In some embodiments, Ring
Figure imgf000015_0002
In some embodiments, R1 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl;
In some embodiments, R1 is selected from H, halo, and C1-3 alkyl.
In some embodiments, R1 is H or halo.
In some embodiments, R1 is halo.
In some embodiments, R1 is H or fluoro. In some embodiments, R1 is fluoro.
In some embodiments, R1 is H.
In some embodiments, R2 is selected from H, halo, and C1-3 alkyl.
In some embodiments, R2 is selected from H and C1-3 alkyl.
In some embodiments, R2 is selected from H.
In some embodiments, R3 is selected from H, halo, and C1-3 alkyl.
In some embodiments, R3 is selected from H and C1-3 alkyl.
In some embodiments, R3 is H.
In some embodiments, R4 is selected from H, halo, and C1-3 alkyl.
In some embodiments, R4 is selected from H and C1-3 alkyl.
In some embodiments, R4 is H.
In some embodiments, R3 and R4 are each H.
In some embodiments, Ring C is 4-10 membered heterocycloalkyl.
In some embodiments, Ring C is 4-7 membered heterocycloalkyl.
In some embodiments, Ring C is 4-5 membered heterocycloalkyl.
In some embodiments, Ring C is 4-membered heterocycloalkyl.
In some embodiments, Ring
Figure imgf000016_0001
In some embodiments, p is 0, 1, 2, 3, or 4.
In some embodiments, p is 0, 1, or 2.
In some embodiments, p is 0 or 1.
In some embodiments, p is 1.
In some embodiments, each R7 is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, and C1-6 haloalkyl.
In some embodiments, each R7 is independently selected from C1-6 alkyl and
C1-6 haloalkyl.
In some embodiments, each R7 is independently selected from C1-6 alkyl.
In some embodiments, each R7 is independently selected from C1-3 alkyl.
In some embodiments, each R7 is methyl.
In some embodiments, p is 0. In some embodiments, Ring C is selected from
Figure imgf000017_0001
In some embodiments, Ring
Figure imgf000017_0002
In some embodiments, Ring
Figure imgf000017_0003
In some embodiments, L is -O- or -N(RL)-.
In some embodiments, L is -O-.
In some embodiments, Ring D is 5-10 membered heteroaryl.
In some embodiments, Ring D is 5-6 membered heteroaryl.
In some embodiments, Ring D is 6-membered heteroaryl.
In some embodiments, Ring D is pyridinyl.
In some embodiments, q is 1, 2, 3, or 4.
In some embodiments, q is 1, 2, or 3.
In some embodiments, q is 1 or 2.
In some embodiments, q is 1.
In some embodiments, q is 2.
In some embodiments, Ring
Figure imgf000017_0004
In some embodiments, Ring
Figure imgf000017_0005
In some embodiments, each R8 is independently selected from halo, C1-6 alkyl,
C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, -CN, -ORa8, -NRc8Rd8, -C(O)Ra8, -C(O)ORa8,
-C(O)NRc8Rd8, and -NRc8C(O)Ra8, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-6 haloalkyl of R8 are each optionally substituted with 1, 2, 3, or 4 independently selected R8A substituents.
In some embodiments, each R8 is independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, -CN, -ORa8, -NRc8Rd8, -C(O)Ra8, -C(O)ORa8, -C(O)NRc8Rd8, and -NRc8C(O)Ra8.
In some embodiments, each R8 is independently selected from C1-6 alkyl and - C(O)NRc8Rd8.
In some embodiments, each R8 is independently selected from C1-3 alkyl and - C(O)NRc8Rd8.
In some embodiments, each R8 is independently selected from -C(O)NRc8Rd8.
In some embodiments, each Ra8, Rc8, and Rd8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, and 5-10 membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl of Rc8 and Rd8 are each optionally substituted with 1, 2, 3, or 4 independently selected R8A substituents.
In some embodiments, each Ra8, Rc8, and Rd8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, and 5-10 membered heteroaryl.
In some embodiments, each Ra8, Rc8, and Rd8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl of Ra8, Rc8, and Rd8 are each optionally substituted with 1, 2, 3, or 4 independently selected R8A substituents.
In some embodiments, each Ra8, Rc8, and Rd8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.
In some embodiments, each Ra8, Rc8, and Rd8 is independently selected from H, C1-6 alkyl, and C3-10 cycloalkyl.
In some embodiments, each Ra8, Rc8, and Rd8 is independently selected from H, C1-6 alkyl, and C3-7 cycloalkyl. In some embodiments, each Rc8 and Rd8 is independently selected from H, Ci-6 alkyl, and C3-10 cycloalkyl.
In some embodiments, each Rc8 and Rd8 is independently selected from H, C1-6 alkyl, and C3-7 cycloalkyl.
In some embodiments, each Rc8 and Rd8 is independently selected from H, methyl, and cyclopropyl
In some embodiments, each R8 is independently selected from C1-6 alkyl and - C(O)NRc8Rd8; and each Rc8 and Rd8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.
In some embodiments, each R8 is independently selected from C1-3 alkyl and - C(O)NRc8Rd8; and each Rc8 and Rd8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.
In some embodiments, each R8 is independently selected from methyl and - C(O)NRc8Rd8; and each Rc8 and Rd8 is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl.
In some embodiments, each R8 is independently selected from -C(O)NRc8Rd8; and each Rc8 and Rd8 is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl.
In some embodiments, each R8 is independently selected from methyl, methylaminocarbonyl, and cyclopropylaminocarbonyl.
In some embodiments, each R8 is independently selected from methylaminocarbonyl and cyclopropylaminocarbonyl.
In some embodiments, R50 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, and C1-6 haloalkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R50 are each optionally substituted by 1, 2, 3, or 4 independently selected RG substituents.
In some embodiments, R50 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, and C1-6 haloalkyl. In some embodiments, R50 is selected from H, Ci-6 alkyl, and Ci-6 haloalkyl.
In some embodiments, R50 is Ci-6 alkyl.
In some embodiments, R50 is C1-3 alkyl.
In some embodiments, R50 is ethyl.
In some embodiments:
X is C or N;
Y is C or N;
= is a single or double bond; m is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, or 2;
Ring B is 5-6 membered heteroaryl;
Ring C is 4-7 membered heterocycloalkyl;
Ring D is 5-10 membered heteroaryl;
L is selected from -O- or -N(RL)-; each RL is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;
R1 is selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
R2 is selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
R3 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl;
R4 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl;
R50 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R6 is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl each R7 is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R8 is independently selected from each R8 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, -CN, -ORa8, -NRc8Rd8, - C(O)Ra8, -C(O)ORa8, -C(O)NRc8Rd8, and -NRc8C(O)Ra8; and each Ra8, Rc8, and Rd8 is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.
In some embodiments, the compound of Formula I is a compound of Formula
Figure imgf000021_0001
II or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula I is a compound of Formula III:
Figure imgf000022_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula I is a compound of Formula IV:
Figure imgf000022_0002
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound provided herein is selected from: 5-((l-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6-de]quinazolin-
8-yl)methyl)azetidin-3-yl)oxy)-N-methylpicolinamide; 5-(((2R,3S)-l-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6- de]quinazolin-8-yl)methyl)-2-methylazetidin-3-yl)oxy)-N-methylpicolinamide;
5 -(( 1 -((3 -ethyl -2-oxo-2, 3 -dihydro- 1 H-py rimido[4, 5 , 6-de] quinazolin-8- yl)methyl)azetidin-3-yl)oxy)-N-methylpicolinamide;
5 -(((2R,3 S)- 1 -((3 -ethyl-2-oxo-2, 3 -dihydro- 1 H-pyrimido[4, 5 , 6-de] quinazolin- 8-yl)methyl)-2-methylazetidin-3-yl)oxy)-N-methylpicolinamide;
N-cyclopropyl-5-((l-((3-ethyl-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6- de]quinazolin-8-yl)methyl)azetidin-3-yl)oxy)picolinamide;
N-cyclopropyl-5-(((2R,3S)-l-((3-ethyl-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6- de]quinazolin-8-yl)methyl)-2-methylazetidin-3-yl)oxy)picolinamide;
N-cyclopropyl-5-((l-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6- de]quinazolin-8-yl)methyl)azetidin-3-yl)oxy)picolinamide;
N-cyclopropyl-5-(((2R,3S)-l-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-lH- pyrimido[4,5,6-de]quinazolin-8-yl)methyl)-2-methylazetidin-3-yl)oxy)picolinamide;
5 -(( 1 -((3 -ethyl -2-oxo-2, 3 -dihydro- 1 H-py rimido[4, 5 , 6-de] quinazolin-8- yl)methyl)azetidin-3-yl)oxy)-N,6-dimethylpicolinamide; and
5-(((2A,35)-l-((3-ethyl-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6-de]quinazolin- 8-yl)methyl)-2-methylazetidin-3-yl)oxy)-N,6-dimethylpicolinamide; or a pharmaceutically acceptable salt thereof.
It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
At various places in the present specification, divalent linking substituents are described. It is specifically intended that each divalent linking substituent include both the forward and backward forms of the linking substituent. For example, -N(RL)C(O)- includes both -N(RL)C(O)- and -C(O)N(RL)- (e.g. -NHC(O)- includes both -NHC(O)- and -C(O)NH-). Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups.
The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6- membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10- membered cycloalkyl group.
As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.
As used herein, the phrase “each ‘variable’ is independently selected from” means substantially the same as wherein “at each occurrence ‘variable’ is selected from.”
Throughout the definitions, the terms “Cn-m” and “Cm-n” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-3, C1-4, C1-6, and the like.
As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l- butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. The term “Cn-m alkyl” is understood to include deuterated analogs of saturated hydrocarbon groups as defined herein, including but not limited to, groups such as trideuteromethyl (CD3), pentadeuteroethyl (CD2CD3), and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, from 2 to 6 carbon atoms, from 2 to 4 carbon atoms, from 2 to 3 carbon atoms, or 1 to 2 carbon atoms.
As used herein, “Cn-m alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec- butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
As used herein, “Cn-m alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
As used herein, the term “Cn-m alkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tertbutoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term “Cn-m aryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl groups have from 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl is phenyl.
As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. In some embodiments, a halo is F or Cl. In some embodiments, a halo is F. In some embodiments, a halo is Cl.
As used herein, “Cn-m haloalkoxy” refers to a group of formula -O-haloalkyl having n to m carbon atoms. Example haloalkoxy groups include OCF3 and OCHF2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
As used herein, the term “Cn-m haloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CH2F, CC13, CHC12, C2C15 and the like.
As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2 fused rings) groups, spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moi eties that have one or more aromatic rings fused (z.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ringforming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (z.e., C3-10). In some embodiments, the cycloalkyl is a C3-10 monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-10 spirocycle or bridged cycloalkyl (e.g., a bridged bicycloalkyl group). Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcamyl, cubane, adamantane, bicyclo[l.l. l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g., having 2 fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, S and B. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S and B. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-6 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5 membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group contains 5 to 10, 5 to 7, 3 to 7, or 5 to 6 ringforming atoms. In some embodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms or 1 ring-forming heteroatom. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. Example heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl (or furanyl), pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4- thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and l,2-dihydro-l,2-azaborine, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azolyl, triazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazofl, 2-b]thiazolyl, purinyl, triazinyl, thieno[3,2- b]pyridinyl, imidazofl, 2-a]pyridinyl, 1,5-naphthyridinyl, lH-pyrazolo[4,3- b]pyridinyl, triazolo[4,3-a]pyridinyl, lH-pyrrolo[3,2-b]pyridinyl, lH-pyrrolo[2,3- b]pyridinyl, pyrazolo[l,5-a]pyridinyl, indazolyl, and the like.
As used herein, “heterocycloalkyl” refers to monocyclic or polycyclic heterocycles having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl is replaced by a heteroatom selected from N, O, S, and B, and wherein the ringforming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)2, etc.). When a ring-forming carbon atom or heteroatom of a heterocycloalkyl group is optionally substituted by one or more oxo or sulfide, the O or S of said group is in addition to the number of ring-forming atoms specified herein (e.g., a l-methyl-6- oxo-l,6-dihydropyridazin-3-yl is a 6-membered heterocycloalkyl group, wherein a ring-forming carbon atom is substituted with an oxo group, and wherein the 6- membered heterocycloalkyl group is further substituted with a methyl group). Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3 to 10, 4 to 10, 5 to 10, 4 to 7, 5 to 7, or 5 to 6 membered heterocycloalkyl groups.
Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., a 5 to 10 membered bridged biheterocycloalkyl ring having one or more of the ring-forming carbon atoms replaced by a heteroatom independently selected from N, O, S, and B). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.
Also included in the definition of heterocycloalkyl are moi eties that have one or more aromatic rings fused (z.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
In some embodiments, the heterocycloalkyl group contains 3 to 10 ringforming atoms, 4 to 10 ring-forming atoms, 4 to 8 ring-forming atoms, 3 to 7 ringforming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5 to 10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic 5 to 6 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members.
Example heterocycloalkyl groups include pyrrolidin-2-one (or 2- oxopyrrolidinyl), l,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, 1, 2,3,4- tetrahydroisoquinoline, tetrahydrothiopheneyl, tetrahydrothiopheneyl 1,1 -di oxide, benzazapene, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, oxobicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1. l]heptanyl, diazabicyclo[3.1. l]heptanyl, azabicyclo[3.2. l]octanyl, diazabicyclo[3.2.1]octanyl, oxobicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl, oxo-adamantanyl, azaspiro[3.3]heptanyl, 2- azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, azaspiro[3.5]nonanyl, 7- azaspiro[3.5]nonanyl, oxo-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3 ,4]octanyl, oxo-azaspiro[3 ,4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxo- azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxo-diazaspiro[4.4]nonanyl, oxo-dihydropyridazinyl, oxo- 2,6-diazaspiro[3.4]octanyl, oxohexahydropyrrolo[l,2-a]pyrazinyl, 3-oxopiperazinyl, oxo-pyrrolidinyl, oxo-pyridinyl, and the like.
As used herein, “Co-P cycloalkyl-Cn-m alkyl-” refers to a group of formula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.
As used herein “C0.p aryl-Cn-m alkyl-” refers to a group of formula arylalkylene-, wherein the aryl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms. As used herein, “heteroaryl-Cn-m alkyl-” refers to a group of formula heteroaryl-alkylene-, wherein alkylene linking group has n to m carbon atoms.
As used herein “heterocycloalkyl -Cn-m alkyl-” refers to a group of formula heterocycloalkyl-alkylene-, wherein alkylene linking group has n to m carbon atoms.
As used herein, an “alkyl linking group” or “alkylene linking group” is a bivalent straight chain or branched alkyl linking group (“alkylene group”). For example, “Co-P cycloalkyl-Cn-m alkyl-”, “Co-P aryl-Cn-m alkyl-”, “phenyl-Cn-m alkyl-”, “heteroaryl-Cn-m alkyl-”, and “heterocycloalkyl -Cn-m alkyl-” contain alkyl linking groups. Examples of “alkyl linking groups” or “alkylene groups” include methylene, ethan- 1,1 -diyl, ethan- 1,2-diyl, propan-1, 3-dilyl, propan- 1,2-diyl, propan- 1,1 -diyl and the like.
As used herein, a “haloalkyl linking group” or “haloalkylene linking group” is a bivalent straight chain or branched haloalkyl linking group (“haloalkylene group”). Example haloalkylene groups include -CF2-, -C2F4-, -CHF-, -CCI2-, -CHC1-, -C2CI4-, and the like.
As used herein, a “cycloalkyl linking group” or “cycloalkylene linking group” is a bivalent straight chain or branched cycloalkyl linking group (“cycloalkylene group”). Examples of “cycloalkyl linking groups” or “cycloalkylene groups” include cyclopropy-l,l,-diyl, cy cl opropy- 1,2-diyl, cyclobut-l,3,-diyl, cyclopent-1, 3, -diyl, cyclopent- 1,4, -diyl, cyclohex- 1,2, -diyl, cyclohex-1, 3, -diyl, cyclohex- 1,4, -diyl, and the like.
As used herein, a “heterocycloalkyl linking group” or “heterocycloalkylene linking group” is a bivalent straight chain or branched heterocycloalkyl linking group (“heterocycloalkylene group”). Examples of “heterocycloalkyl linking groups” or “heterocycloalkylene groups” include azeti din- 1,2-diyl, azeti din- 1,3 -diyl, pyrrolidin- 1,2-diyl, pyrrolidin- 1,3 -diyl, pyrrolidin-2,3-diyl, piperi din- 1,2-diyl, piperidin-l,3-diyl, piperidin-l,4-diyl, piperi din-2, 3 -diyl, piperidin-2,4-diyl, and the like.
As used herein, a “heteroaryl linking group” or “heteroarylene linking group” is a bivalent straight chain or branched heteroaryl linking group (“heteroarylene group”). Examples of “heteroaryl linking groups” or “heteroarylene groups” include pyrazol- 1,3 -diyl, imidazol-l,2,-diyl, pyri din-2, 3 -diyl, pyridin-2,4-diyl, pyridin-3,4- diyl, and the like. At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position.
As used herein, the term “oxo” refers to an oxygen atom (z.e., =0) as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=0 or C(0)), or attached to a nitrogen or sulfur heteroatom forming a nitroso, sulfinyl, or sulfonyl group.
As used herein, the term “independently selected from” means that each occurrence of a variable or substituent (e.g., each RG) , are independently selected at each occurrence from the applicable list.
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 disclosure 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. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R)-configuration. In some embodiments, the compound has the (S)-configuration. The Formulas (e.g., Formula I, Formula II, etc.) provided herein include stereoisomers of the compounds.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as P-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- m ethylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
Compounds provided herein 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, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents e.g. hydrates and solvates) or can be isolated.
In some embodiments, preparation of compounds can involve the addition of acids or bases to affect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts.
In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds provided herein. 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 provided herein, or salt thereof.
The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non -toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
Synthesis Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and according to various possible synthetic routes. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below.
Intermediates of Formula Int can also be prepared according to the procedures shown in Scheme I. Reacting of compound 1-1 (wherein PG is a suitable protecting group such as Boc; LG is a suitable leaving group such as Br, OMs or OH) with compound 1-2 (wherein L1 is a suitable linking group such as OH or NH2) under suitable conditions, such as nucleophilic substitution conditions or Mitsunobu reaction conditions, can give compounds of Formula 1-3. Removal of protecting group in 1-3 can afford compounds of Formula Int.
Scheme I.
Figure imgf000034_0001
Compounds of Formula II-7 can be prepared, for example, according to the procedures shown in Scheme II. Reacting compound II-l (Hal1 and Hal2 are independently suitable halogen such as I, Br or Cl) with a suitable isocyanate can afford the urea compound II-2 (PG is a suitable protecting group such PMB). Under suitable conditions such as palladium-catalyzed cross-coupling conditions, compound II-2 can be cyclized to give compound II-3. Alkylation of the NH in compound II-3 with a suitable reagent in the presence of a suitable base can give compound II-4. Under suitable coupling conditions such as Stille or Suzuki coupling, compound II-4 can be converted to alcohol II-5. The benzylic alcohol in compound II-5 can be converted to Br under suitable conditions (such as HBr in acetic acid), followed by removal of the protecting group giving compound II-6. Reacting compound II-6 with intermediate of formula Int can give compounds of formula II-7. Scheme II.
Figure imgf000035_0001
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. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.
Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.
Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., JH or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
The expressions, “ambient temperature,” “room temperature,” and “r.t ”, as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.
Methods of Use
The present disclosure provides uses for compounds and compositions described herein. In some embodiments, provided compounds and compositions are for use in medicine (e.g., as therapy). In some embodiments, provided compounds and compositions are useful in treating a disease, disorder, or condition, wherein an underlying pathology is, wholly or partially, mediated by PARP1. In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and/or control compounds in biological assays.
In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with PARP1. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition, wherein an underlying pathology is, wholly or partially, mediated by PARP1.
In some embodiments, the compounds provided herein (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof) are useful as PARP1 inhibitors. In some embodiments, the present disclosure provides methods of inhibiting PARP1 in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods of inhibiting PARP1 in a biological sample comprising contacting the sample with a provided compound or composition. In some embodiments, the present disclosure provides methods of treating a disease, disorder or condition associated with PARP1 in a subject in need thereof, comprising administering to the subject a provided compound or composition. In some embodiments, a disease, disorder or condition is associated with overexpression of PARP1. In some embodiments, the present disclosure provides methods of treating a disease, disorder or condition, wherein an underlying pathology is, wholly or partially, mediated by PARP1, in a subject in need thereof, comprising administering to the subject a provided compound or composition.
In some embodiments, the present disclosure provides methods of treating cancer, comprising administering a compound, salt, or composition provided herein to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating proliferative diseases, comprising administering a compound, salt, or composition provided herein to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating metastatic cancers, comprising administering a compound, salt, or composition provided herein to a subject in need thereof. Exemplary cancers include but are not limited to breast cancer, ovarian cancer, cervical cancer, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, prostate cancer, testicular cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric cancer, bladder cancer, lung cancer (e.g., adenocarcinoma, non-small-cell lung carcinoma (NSCLC) and small-cell lung carcinoma (SCLC)), bone cancer (e.g., osteosarcoma), colon cancer, rectal cancer, thyroid cancer, brain and central nervous system cancers, glioblastoma, neuroblastoma, neuroendocrine cancer, rhabdoid cancer, keratoacanthoma, epidermoid carcinoma, seminoma, melanoma, sarcoma (e.g., liposarcoma), bladder cancer, uterine serous carcinoma, liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma), myeloid disorders (e.g., acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome and promyelocytic leukemia), and lymphoid disorders (e.g., leukemia, multiple myeloma, mantle cell lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma, hairy cell lymphoma). In some embodiments, the cancer is selected from ovarian cancer, breast cancer, prostate cancer, and pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is pancreatic cancer.
When used as a single agent for monotherapy, the compounds, salts, and compositions provided herein are expected to selectively kill tumor cells characterized by homologous recombination deficiency while generating minimal impact on normal tissues. In some embodiments, the present disclosure provides methods of treating advanced cancer induced by or correlated with a dysregulated DNA repair system, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, such advanced cancers include but are not limited to breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer. These malignant tumors are features of deleterious or suspected deleterious mutations of key genes involved in DNA damage repair pathways. In some embodiments, such key genes include but are not limited to ATM, ATR, BAP1, BRCA1, BRCA2, CDK12, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, PALB2, NBS1, WRN, RAD51C, RAD51D, MRE11A, CHEK1, BLM, RAD51B, and BRIPP Cancer patients with such mutations can be identified using companion diagnostics. Advanced cancer patients with a positive status of homologous recombination deficiency are expected to benefit from monotherapy with a compound, salt, or composition provided herein.
When used as a frontline maintenance therapy, the compounds, salts, or compositions provided herein are useful in treating cancer featured by dysregulated DNA damage repair. Exemplary cancers include but are not limited to triple-negative breast cancer, high-grade serous ovarian cancer, platinum-sensitive advanced pancreatic cancer, and castration-resistant prostate cancer. These tumors are typically sensitive to platinum-based therapies and other DNA damaging agents. As a maintenance therapy, provided compounds and compositions of the present disclosure may reduce risks of recurrence or relapse and therefore prolong progression free survival of patients with advanced cancers.
In some embodiments, provided herein is a method of increasing survival or progression-free survival in a patient, comprising administering a compound provided herein to the patient. In some embodiments, the patient has cancer. In some embodiments, the patient has a disease or disorder described herein. As used herein, progression-free survival refers to the length of time during and after the treatment of a solid tumor that a patient lives with the disease but it does not get worse. Progression-free survival can refer to the length of time from first administering the compound until the earlier of death or progression of the disease. Progression of the disease can be defined by RECIST v. 1.1 (Response Evaluation Criteria in Solid Tumors), as assessed by an independent centralized radiological review committee. In some embodiments, administering of the compound results in a progression free survival that is greater than about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, about 12 months, about 16 months, or about 24 months. In some embodiments, the administering of the compound results in a progression free survival that is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months. In some embodiments, the administering of the compound results in an increase of progression free survival that is at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months.
The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.
The present disclosure further provides use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.
As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.
As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” PARP1 with a compound described herein includes the administration of a compound described herein to an individual or patient, such as a human, having PARP1, as well as, for example, introducing a compound described herein into a sample containing a cellular or purified preparation containing the PARP1.
As used herein, the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent such as an amount of any of the solid forms or salts thereof as disclosed herein 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. An appropriate "effective" amount in any individual case may be determined using techniques known to a person skilled in the art.
The phrase “pharmaceutically acceptable” is used 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, immunogenicity or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, the phrase “pharmaceutically acceptable carrier or excipient” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic and neither biologically nor otherwise undesirable and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is “pharmaceutically acceptable” as defined herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.
As used herein, the term “treating” or “treatment” refers to inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) or ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
Combination Therapy
Cancer cell growth and survival can be impacted by dysfunction in multiple signaling pathways. It is useful to combine compounds modulating different biological targets to treat such conditions. Targeting more than one signaling pathway or more than one biological molecule involved in a given signaling pathway also may reduce the likelihood of drug resistance.
In some embodiments, a compound, salt, or composition provided herein is administered as part of a combination therapy. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.
For example, in some embodiments, a compound, salt, or composition provided herein is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and/or therapy to address one or more side effects of such anti -cancer therapy, or otherwise to provide palliative care).
Exemplary additional therapies include but are not limited to chemotherapies, radiotherapies, anti-inflammatory agents, steroids, immunosuppressants, immune- oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, phosphatase inhibitors, and targeted therapies such as kinase inhibitors.
In some embodiments, a compound, salt, or composition provided herein can be combined with one or more agents targeting the following biological targets, including but not limiting to Weel, ATR, ATM, DNA-PK, CDK4/6, CHK1/2, HER2, PI3K, mTOR, EGFR, VEGFR, FGFR, PDGFR, BTK, IGF-1R, BRAF, MEK, KRAS, EZH2, BCL2, HSP90, HDAC, Topoisomerases, HIF-2a, androgen receptor, estrogen receptor, proteosome, RAD51, RAD52, POLQ, WRN, PD-1, and PD-L1. Hypoxia induced by HIF-2a inhibition results in down-regulated expression of the BRCA gene, consequently making tumor cells more vulnerable to PARP1 inhibition. Exemplary cancers for combination of PARP1 and HIF-2a inhibitors include but not limited to clear cell renal cell carcinoma, particularly for the subgroup with the tumor suppressor von Hippel Lindau (VHL) deficiency.
In some embodiments, a compound, salt, or composition provided herein can be combined with chemotherapies for treatment of cancer. In some embodiments, a compound, salt, or composition provided herein can be combined with chemotherapies for treatment of high-grade serous ovarian cancer. Exemplary chemotherapies include but are not limited to platinum-based therapy, taxane-based therapy and some others including albumin bound paclitaxel, altretamine, capecitabine, cyclophosphamide, gemcitabine, ifosfamide, irinotecan, liposomal doxorubicin, melphalan, pemetrexed, topotecan, and vinorelbine.
In some embodiments, a compound, salt, or composition provided herein can be combined with chemotherapies for treatment of advanced metastatic breast cancer. Exemplary chemotherapies include but are not limited to taxanes such as paclitaxel, docetaxel, and albumin-bound paclitaxel, anthracyclines, platinum agents, vinorelbine, capecitabine, gemcitabine, ixabepilone, and eribulin. In some embodiments, such combination therapies can be used for malignancies derived from other histologies, including but limited to brain, lung, kidney, liver, and hematologic cancers.
Radiotherapies are widely used in clinic for treatment of cancers. A compound, salt, or composition provided herein may improve the effectiveness of radiation therapy through its potent activity in suppressing DNA damage repair. In some embodiments, a compound, salt, or composition provided herein can be combined with radiotherapies for treatment of cancer. Exemplary cancers that can be treated with radiotherapies include but are not limited to small cell lung cancer, leukemias, lymphomas, germ cell tumors, non-melanoma skin cancer, head and neck cancer, breast cancer, non-small cell lung cancer, cervical cancer, anal cancer, and prostate cancer. In some embodiments, a compound, salt, or composition provided herein may overcome the resistance of certain cancer to radiotherapy, particularly for renal cell carcinoma and melanomas.
Immunotherapies including antibodies of PD1, PD-L1, and CTLA4 have been successfully used for treatment of cancer. Despite this huge success, resistance and relapse remain a challenge for the vast majority of cancer patients. In some embodiments, a compound, salt, or composition provided herein can be combined with immunotherapies to improve the effectiveness of conventional antibody- medicated immunotherapies by promoting DNA damage, increasing mutation burden, and modulating the STING innate immune pathway. In some embodiments, a compound, salt, or composition provided herein can be combined with immunotherapies for treatment of adult and pediatric patients with unresectable or metastatic tumors. In some embodiments, a compound, salt, or composition provided herein can be combined with immunotherapies for treatment of cancer. Exemplary cancers include but are not limited to non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, classical Hodgkin lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, esophageal cancer, endometrial cancer, tumor mutational burden-high cancer, cutaneous squamous cell carcinoma, microsatellite instability- high or mismatch repair deficient colorectal cancer, and triple-negative breast cancer.
In some embodiments, a compound, salt, or composition provided herein can be combined with targeted therapies of well-established therapeutic targets including but not limited to PI3K inhibitors, KRAS inhibitors, CDK4/6 inhibitors, BRAF inhibitors, MEK inhibitors, androgen receptor inhibitors, selective estrogen receptor modulators, proteosome inhibitors, mTOR inhibitors, EGFR inhibitors, FGFR inhibitors, MET inhibitors, PDGFR inhibitors, VEGFR inhibitors, EZH2 inhibitors, BTK inhibitors, and BCL2 inhibitors for treatment of cancer. Exemplary cancers include but are not limited to breast cancer, ovarian cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell renal cell carcinoma, melanoma, colorectal cancer, bladder cancer, prostate cancer, cholangiocarcinoma, and hematologic cancers.
In some embodiments, a compound, salt, or composition provided herein can be combined with inhibitors of other DNA damage repair proteins including but not limited to CHEK1, CHEK2, ATM, ATR, DNA-PK, WEE1, RAD51, RAD52, POLQ, and WRN for treatment of cancer sensitive to DNA damage. In some embodiments, a compound, salt, or composition provided herein can be combined with a WEE1 inhibitor for treatment of uterine serous carcinoma and cancers with mutation of the TP53 genes. In some embodiments, a compound, salt, or composition provided herein can be combined with a WRN inhibitor for treatment of microsatellite instability -high cancers, such as colon cancer, gastric cancer, endometrium cancer, ovarian cancer, hepatobiliary tract cancer, urinary tract cancer, brain cancer, and skin cancers.
Pharmaceutical Formulations and Dosage Forms When employed as pharmaceuticals, the compounds and salts provided herein can be administered in the form of pharmaceutical compositions which 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 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, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these pre-formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above.
The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or 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.
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.
The compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner
The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
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 compositions of the disclosure can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are provided herein..
Labeled Compounds and Assay Methods
Another aspect of the present invention relates to fluorescent dye, spin label, heavy metal or radio-labeled compounds of the invention that would be useful not only in imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the PARP1 protein in tissue samples, including human, and for identifying PARP1 protein ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes PARP1 biochemical assays that contain such labeled compounds.
The present invention further includes isotopically-labeled compounds of the invention. An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), nC, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36C1, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and 131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro PARP1 labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, 1251 , 131I, or 35S will generally be most useful. For radio-imaging applications nC, 18F, 125I, 123I, 124I, 13 JI, 75Br, 76Br or 77Br will generally be most useful.
One or more constituent atoms of the compounds presented herein can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, one or more atoms are replaced or substituted by deuterium. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced by deuterium atoms (e.g., one or more hydrogen atoms of a Ci-6 alkyl group of Formula I can be optionally substituted with deuterium atoms, such as -CD3 being substituted for -CH3). In some embodiments, alkyl groups of the disclosed Formulas (e.g., the compound of any of Formulas I-IV) can be perdeuterated.
In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-IV), or a pharmaceutically acceptable salt thereof, comprises at least one deuterium atom.
In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-IV), or a pharmaceutically acceptable salt thereof, comprises two or more deuterium atoms.
In some embodiments, the compound provided herein (e.g., the compound of any of Formulas I-IV), or a pharmaceutically acceptable salt thereof, comprises three or more deuterium atoms.
In some embodiments, for a compound provided herein (e.g., the compound of any of Formulas I-IV), or a pharmaceutically acceptable salt thereof, all of the hydrogen atoms are replaced by deuterium atoms (z.e., the compound is “perdeuterated”).
It is understood that a “radio-labeled ” or “labeled compound” is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of 3H, 14C, 1251 , 35S and 82Br.
Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in various studies such as NMR spectroscopy, metabolism experiments, and/or assays.
Substitution with heavier isotopes, such as deuterium, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances, (see e.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitution at one or more metabolism sites may afford one or more of the therapeutic advantages.
A radio-labeled compound of the invention can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (z.e., test compound) can be evaluated for its ability to reduce binding of the radio-labeled compound of the invention to the PARP1 protein. Accordingly, the ability of a test compound to compete with the radio-labeled compound for binding to the PARP1 protein directly correlates to its binding affinity.
Kits
The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of PARP1 -associated diseases or disorders referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (while the embodiments are intended to be combined as if written in multiply dependent form). Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be inhibitors of PARP1 as described below.
EXAMPLES
As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
The final compounds were purified on a preparative scale reverse-phase high performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) as indicated in the Examples. Typical preparative reverse-phase high performance liquid chromatography (RP-HPLC) column conditions are as follows:
TFA conditions: column, Waters XSelect CSH Cis 5 pm particle size, 30 x 150 mm; eluting with mobile phase A: water (0.05% trifluoroacetic acid), mobile Phase B: acetonitrile; the flow rate, 60 mL/min.
NH4HCO3 conditions: column, waters XBridge BEH Cis 5 pm particle size, 30 x 150 mm; eluting with mobile phase A: water (10 mM ammonium bicarbonate), mobile Phase B: acetonitrile; the flow rate, 60 mL/min.
HCOOH conditions: column, Sunfire Prep Cis OBD 5 pm particle size, 30 x 150 mm; eluting with mobile phase A: water (0.1% formic acid), mobile Phase B: acetonitrile; the flow rate, 60 mL/min.
The separating gradient was optimized for each compound. The separated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity check under the following conditions: Instrument: Shimadzu LCMS-2020, column: Halo Cis 2 pm particle size, 3 x 30 mm; buffers: mobile phase A: 0.05% TFA in water and mobile phase B: acetonitrile; gradient: 0 to 60% of B in 1.9 min, 60% to 100% of B in 0.35 min with flow rate 1.5 mL/min.
Intermediate 1. 5-(Azetidin-3-yloxy)-N-methylpicolinamide
Figure imgf000052_0001
Step 1: Methyl 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)picolinate
Boc i
Figure imgf000052_0002
To the mixture of methyl 5-hydroxypyridine-2-carboxylate (200 mg, 1.3 mmol), tert-butyl 3 -hydroxyazetidine-1 -carboxylate (249 mg, 1.4 mmol) and triphenylphosphine (685 mg, 2.6 mmol) in tetrahydrofuran (10 mL) were added diisopropyl azodicarboxylate (528 mg, 2.6 mmol) in tetrahydrofuran (3 mL) dropwise at 0 °C. The reaction mixture was stirred for 3 h at 60 °C. Upon cooling to room temperature, the mixture was diluted with water (20 mL). The aqueous solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 75% ethyl acetate in petroleum ether to afford the desired product as a yellow solid (350 mg, 87%). LCMS calculated for C15H21N2O5 (M+H)+ m/z = 309.1; found 308.9.
Step 2: 5-((l -(Tert-butoxycarbonyl)azetidin-3-yl)oxy)picolinic acid Boc i
Figure imgf000053_0001
The mixture of methyl 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)picolinate (350 mg, 1.1 mmol) in tetrahydrofuran (10 mL) and water (3 mL) was added lithium hydroxide (109 mg, 4.5 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The mixture was then neutralized to pH 5 with hydrochloric acid (1 M). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product as a yellow solid (320 mg) which was used in the next step directly without further purification. LCMS calculated for C14H19N2O5 (M+H)+ m/z = 295.1; found 295.2.
Step 3: Tert-butyl 3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-l-carboxylate
Boc
Figure imgf000053_0002
The mixture of 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)picolinic acid (350 mg, 1.12 mmol) and 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (678 mg, 1.8 mmol) in
Figure imgf000053_0003
-di methyl form am ide (5 mL) was stirred for 15 min at room temperature. To the above mixture was added methylamine hydrochloride (120 mg, 1.8 mmol) and 7V,7V-diisopropylethylamine (461 mg, 3.6 mmol). The reaction mixture was stirred for 1 h. The mixture was then purified by reversed-phase flash chromatography with the following conditions (Column: C18 silica gel; Mobile phase: acetonitrile in water (10 mmol/L ammonium bicarbonate); Gradient: 5% to 95% gradient in 30 min; Detector: 254 nm). Eluted fractions were collected and concentrated to afford the desired product as a white solid (250 mg, 68%). LCMS calculated for C15H22N3O4 (M+H)+ m/z = 308.2; found 308.1.
Step 4: 5-(Azetidin-3-yloxy)-N-methylpicolinamide
To the mixture of tert-butyl 3-((6-(methylcarbamoyl)pyridin-3- yl)oxy)azetidine-l -carboxylate (250 mg, 0.8 mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (0.5 mL) at room temperature. The reaction was stirred for 1 h. The resulting mixture was concentrated under reduced pressure to give the TFA salt of the crude product which was used in the next step directly without further purification. LCMS calculated for C10H14N3O2 (M+H)+ m/z = 208.1; found 208.2.
Intermediate 2. N-methyl-5-(((2R,3S)-2-methylazetidin-3-yl)oxy)picolinamide
Figure imgf000054_0001
Step 1: Methyl 5-(((2R,3S)-l-(tert-butoxycarbonyl)-2-methylazetidin-3- yl)oxy)picolinate
Boc 1
Figure imgf000054_0002
To the mixture of methyl 5-hydroxypyridine-2-carboxylate (180 mg, 1.17 mmol), tert-butyl (2A,3A)-3-hydroxy-2-methylazetidine-l-carboxylate (200 mg, 1.07 mmol) and triphenylphosphine (560 mg, 2.14 mmol) in tetrahydrofuran (10 mL) were added dibenzyl azodicarboxylate (492 mg, 2.14 mmol) in tetrahydrofuran (3 mL) dropwise at 0 °C. The reaction mixture was stirred for 2 h at 60 °C. Upon cooling to room temperature, the mixture was diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 75% ethyl acetate in petroleum ether to afford the desired product as a yellow solid (300 mg, 87%). LCMS calculated for C16H23N2O5 (M+H)+ m/z = 323.2; found 323.2.
Step 2: 5-(((2R,3S)-l-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)picolinic acid
Figure imgf000055_0001
To the mixture of methyl 5-(((2A,35 -l-(tert-butoxycarbonyl)-2- methylazetidin-3-yl)oxy)picolinate (300 mg, 0.93 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added lithium hydroxide monohydrate (156 mg, 3.72 mmol) at room temperature. The reaction was stirred for 1 h. The mixture was neutralized to pH 5 with hydrochloric acid (1 M). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product as a yellow solid (300 mg) which was used in the next step directly without further purification. LCMS calculated for C15H21N2O5 (M+H)+ m/z = 309.1; found 309.1.
Step 3: Tert-butyl (2R,3S)-2-methyl-3-((6-(methylcarbamoyl)pyridin-3- yl)oxy)azetidine-l-carboxylate
Figure imgf000055_0002
The mixture of 5-(((2A,35)-l-(tert-butoxycarbonyl)-2-methylazetidin-3- yl)oxy)picolinic acid (300 mg, 0.97 mmol) and 2-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (555 mg, 1.46 mmol) in N,N- dimethylformamide (5 mL) was stirred for 15 min at room temperature. To the above mixture was added methylamine hydrochloride (98 mg, 1.46 mmol) and N,N- diisopropylethylamine (377 mg, 2.92 mmol). The resulting mixture was stirred for 16 h. The mixture was then purified by reversed-phase flash chromatography with the following conditions (Column: C18 silica gel; Mobile phase: acetonitrile in water (10 mmol/L ammonium bicarbonate); Gradient: 5% to 95% gradient in 30 min; Detector: 254 nm). Eluted fractions were collected and concentrated to afford the desired product as a white solid (200 mg, 64%). LCMS calculated for CieH24N3O4 (M+H)+ m/z = 322.2; found 322.2.
Step 4: N-methyl-5-( ( (2R, 3S)-2-methylazetidin-3-yl)oxy)picolinamide
To the mixture of tert-butyl (2A,35)-2-methyl-3-((6- (methylcarbamoyl)pyridin-3-yl)oxy)azetidine-l-carboxylate (200 mg, 0.62 mmol) in di chloromethane (5 mL) was added trifluoroacetic acid (1 mL) at room temperature. The reaction was stirred for 1 h. The resulting mixture was concentrated under reduced pressure to give the TFA salt of the crude product which was used in the next step directly without further purification. LCMS calculated for C11H16N3O2 (M+H)+ m/z = 222.1; found 222.0.
Intermediate 3. 5-(Azetidin-3-yloxy)-N-cyclopropylpicolinamide
Figure imgf000056_0001
Step 1: Tert-butyl 3-((6-(cyclopropylcarbamoyl)pyridin-3-yl)oxy)azetidine-l- carboxylate
Boc
Figure imgf000056_0002
The mixture of 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)picolinic acid (Intermediate 1, Step 2: 500 mg, 1.7 mmol) and 2-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (969 mg, 2.55 mmol) in N,N- dimethylformamide (5 mL) was stirred at room temperature for 20 min. To the above mixture was added 7V,7V-diisopropylethylamine (439 mg, 3.4 mmol) and cyclopropanamine (145 mg, 2.55 mmol). After stirring at room temperature for additional 2 h, the resulting mixture was purified by reversed-phase flash chromatography with the following conditions (Column: C18 silica gel; Mobile phase: acetonitrile in water (0.1% formic acid), Gradient: 30% to 95% in 30 min; Detector: 254 nm). Eluted fractions were collected and concentrated to afford the desired product as a white solid (380 mg, 67%). LCMS calculated for C17H24N3O4 (M+H)+ m/z = 334.2; found 334.2.
Step 2: 5-(Azetidin-3-yloxy)-N-cyclopropylpicolinamide
The mixture of tert-butyl 3-((6-(cyclopropylcarbamoyl)pyridin-3- yl)oxy)azetidine-l -carboxylate (380 mg, 1.14 mmol) in hydrogen chloride (4 M in 1,4-di oxane, 5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford the HC1 salt of the crude product as a white solid (300 mg) which was used in the next step directly without further purification. LCMS calculated for C12H16N3O2 (M+H)+ m/z = 234.1; found 234.0.
Intermediate 4. N-cyclopropyl-5-(((2R,3S)-2-methylazetidin-3- yl)oxy)picolinamide
Figure imgf000057_0001
Step J: tert-Butyl (2R,3S)-3-((6-(cyclopropylcarbamoyl)pyridin-3-yl)oxy)-2- methylazetidine-l-carboxylate
Figure imgf000058_0001
The mixture of 5-(((2A,35)-l-(tert-butoxycarbonyl)-2-methylazetidin-3- yl)oxy)picolinic acid (Intermediate 2, Step 2: 500 mg, 1.62 mmol) and 2-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (925 mg, 2.43 mmol) in
Figure imgf000058_0002
-di methyl form am ide (5 mL) was stirred at room temperature for 20 min. To the above mixture was added A,7V-diisopropylethylamine (419 mg, 3.2 mmol) and cyclopropanamine (139 mg, 2.43 mmol). After stirring at room temperature for additional 2 h, the resulting mixture was purified by reversed-phase flash chromatography with the following conditions (Column: C18 silica gel; Mobile phase: acetonitrile in water (0.1% formic acid), Gradient: 30% to 80% in 30 min; Detector: 254 nm). Eluted fractions were collected and concentrated to afford the desired product as a brown solid (350 mg, 62%). LCMS calculated for C18H26N3O4 (M+H)+ m/z = 348.2; found 348.2.
Step 2: N-cyclopropyl-5-(((2R,3S)-2-methylazetidin-3-yl)oxy)picolinamide
The mixture of tert-butyl (2A,35)-3-((6-(cyclopropylcarbamoyl)pyridin-3- yl)oxy)-2-methylazetidine-l -carboxylate (350 mg, 1.01 mmol) in hydrogen chloride (4 M in 1,4-di oxane, 5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford the HC1 salt of the crude product as a white solid (280 mg) which was used in the next step directly without further purification. LCMS calculated for C13H18N3O2 (M+H)+ m/z = 248.1; found 248.0.
Intermediate 5. 8-Bromo-3-ethyl-9-fluoro-l-(4-methoxybenzyl)-lH- pyrimido [4,5,6-de] quinazolin-2(3H)-one
Figure imgf000059_0001
Step 1: 2-Amino-4-bromo-6-fluorobenzonitrile
Figure imgf000059_0002
A mixture of 4-bromo-2,6-difluorobenzonitrile (10 g, 45.87 mmol) and ammonium hydroxide (16.08 g, 458.7 mmol) in propan-2-ol (25 mL) was stirred at 80 °C for 16 h. Upon cooling to room temperature, the reaction mixture was diluted with water (500 mL). The precipitated solids were collected by filtration and washed with water (2 x 100 mL). The residue was purified by silica gel column chromatography, eluted with 20% ethyl acetate in petroleum ether to provide the desired product as a white solid (5.8 g, 59%). LCMS calculated for CyHsBrFN? (M-H)’ m/z = 212.9; found 212.9.
Step 2: 7-Bromo-5-fluoroquinazolin-4-amine
Figure imgf000059_0003
A mixture of 2-amino-4-bromo-6-fluorobenzonitrile (3.9 g, 18.14 mmol), ammonium acetate (21 g, 272.1 mmol) and triethyl orthoformate (40.32 g, 272.1 mmol) in ethanol (40 mL) was stirred at 110 °C for 16 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% ethyl acetate in petroleum ether to provide the desired product as a yellow solid (3.3 g, 75%). LCMS calculated for C8H6BrFN3 (M+H)+ m/z = 242.0; found 242.0.
Step 3: 7-Br()m()-N5-(4-melh()xybenzyl)qiiinaz()line-4,5-diamine
Figure imgf000060_0001
A mixture of 7-bromo-5-fluoroquinazolin-4-amine (1 g, 4.13 mmol) and (4- methoxyphenyl)methanamine (763.2 mg, 6.2 mmol) in dimethyl sulfoxide (10 mL) was stirred for 5 h at 80 °C. Upon cooling to room temperature, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (3 x 100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 80% ethyl acetate in di chloromethane to afford a yellow solid (1 g, 67%). LCMS calculated for Ci6Hi6BrN4O (M+H)+ m/z = 359.1; found 359.0.
Step 4: 7-Bromo-6-fliioro-N5 -(4-methoxybenzyl)quinazoline-4, 5-diamine
Figure imgf000060_0002
A mixture of 7-bromo-N5-(4-methoxybenzyl)quinazoline-4, 5-diamine (1 g, 2.78 mmol) in PS-750-M (3% in water, 12 mL) was stirred at room temperature for 2 min under nitrogen atmosphere, followed by the addition of N- fluorobenzenesulfonimide (2.19 g, 6.96 mmol) in THF (12 mL) in portions over 5 min at room temperature. The resulting mixture was stirred at 60 °C for 16 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 7% methanol in dichloromethane to afford the desired product (450 mg, 43%) as a yellow solid. LCMS calculated for CieHisBrFN^ (M+H)+ m/z = 377.0; found 377.0; 'H NMR (300 MHz, CDC13) 8 8.49 (s, 1H), 7.91 (d, J = 6.6 Hz, 1H), 7.59 (s, 2H), 7.26-7.19 (m, 2H), 6.96-6.88 (m, 2H), 4.10 (d, J = 6.3 Hz, 2H), 3.85 (s, 3H).
Step 5: 8-Bromo-9-fluoro-l-(4-methoxybenzyl)-lH-pyrimido[4,5, 6-de]quinazolin- 2(3H)-one
Figure imgf000061_0001
A mixture of 7-bromo-6-fluoro-N5-[(4-methoxyphenyl)methyl]quinazoline- 4,5-diamine (710 mg, 1.88 mmol), triphosgene (1117 mg, 3.76 mmol) and N,N- diisopropylethylamine (486.5 mg, 3.76 mmol) in tetrahydrofuran (10 mL) was stirred for 1 h at room temperature under nitrogen atmosphere; and then quenched with sat. ammonium chloride (aq.) at 0 °C. The precipitated solids were collected by filtration and washed with water (3 x 100 mL). The residue was purified by trituration with ethyl acetate (100 mL). The resulting product was a yellow solid (400 mg, 53%) which was used in the next step without further purification. LCMS calculated for Ci7Hi3BrFN4O2 (M+H)+ m/z = 403.0; found 403.1.
Step 6: 8-Bromo-3-ethyl-9-fluoro-l-(4-methoxybenzyl)-lH-pyrimido[ 4, 5, 6- de ]quinazolin-2 ( 3H) -one
A mixture of 8-bromo-9-fluoro-l-(4-methoxybenzyl)-lH-pyrimido[4,5,6- de]quinazolin-2(3H)-one (170 mg, 0.42 mmol) and potassium carbonate (116.5 mg, 0.84 mmol) in N,N-dimethylformamide (3 mL) was treated with ethyl iodide (131.5 mg, 0.84 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h, and then diluted with water (30 mL), extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluted with 10% methanol in di chloromethane to afford a yellow solid (145 mg, 80%). LCMS calculated for Ci9Hi7BrFN4O2 (M+H)+ m/z = 431.1 ; found 431.0.
Intermediate 6. 3-ethyl-8-(hydroxymethyl)-l-(4-methoxybenzyl)-l//- pyrimido [4,5,6-de] quinazolin-2(3ZZ)-one
Figure imgf000062_0001
Step 1: 8-Bromo-l-(4-methoxybenzyl)-lH-pyrimido[4,5,6-de]quinazolin-2(3H)-one
Figure imgf000062_0002
To the mixture of 7-bromo-7V5-[(4-methoxyphenyl)methyl]quinazoline-4,5- diamine (Intermediate 5, Step 3: 18 g, 50.1 mmol) and 7V,7V-diisopropylethylamine (19.4 g, 150.3 mmol) in THF (300 mL) were added triphosgene (15.6 g, 52.6 mmol) in tetrahydrofuran (100 mL) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred for 3 h. The resulting mixture was treated with saturated aqueous sodium bicarbonate (500 mL). The precipitated solids were collected by filtration and washed with water (3 x 100 mL). The solid was dried under reduced pressure to afford the desired product as a yellow solid (12 g, 62%). LCMS calculated for Ci7Hi4BrN4O2 (M+H)+ m/z = 385.0; found 385.0.
Step 2: 8-Bromo-3-ethyl-l-(4-methoxybenzyl)-lH-pyrimido[4,5, 6-de]quinazolin- 2(3H)-one
Figure imgf000062_0003
To the mixture of 8-bromo-l-(4-methoxybenzyl)-lJ/-pyrimido[4,5,6- de]quinazolin-2(3J7)-one (2 g, 5.2 mmol) and potassium carbonate (1.44 g, 10.4 mmol) in 7V,7V-dimethylformamide (20 mL) was added iodoethane (1.6 g, 10.4 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred for 16 h. The resulting mixture was diluted with water (100 mL). The aqueous solution was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 75% ethyl acetate in petroleum ether to afford the desired product as a light-yellow solid (1.5 g, 70%). LCMS calculated for C^HisBrlS Ch (M+H)+ m/z = 413.1; found 413.1.
Step 3: 3-Ethyl-8-(hydroxymethyl)-l-(4-methoxybenzyl)-lH-pyrimido[4,5, 6- de ]quinazolin-2 ( 3H) -one
To a screw-cap vial equipped with a magnetic stir bar were placed 8-bromo-3- ethyl-l-(4-methoxybenzyl)-U/-pyrimido[4,5,6-de]quinazolin-2(3J7)-one (1.5 g, 3.6 mmol) and XPhos Pd G3 (307 mg, 0.36 mmol). The vial was sealed with a Teflon- lined septum, evacuated and backfilled with nitrogen (this process was repeated a total of three times). A solution of (tributyl stannyl)methanol (1.748 g, 5.45 mmol) in 1,4-di oxane (20 mL) was added via syringe. The reaction was stirred at 80 °C for 3 h. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% methanol in di chloromethane to afford the desired product as a light-yellow solid (1.2 g, 91%). LCMS calculated for C20H21N4O3 (M+H)+ m/z = 365.2; found 365.1.
Example 1. 5-((l-((3-Ethyl-9-fluoro-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6- de]quinazolin-8-yl)methyl)azetidin-3-yl)oxy)-N-methylpicolinamide
Figure imgf000063_0001
Step 1: 3-Ethyl-9-fluoro-8-(hydroxymethyl)-l-(4-methoxybenzyl)-lH-pyrimido[4,5,6- de ]quinazolin-2 ( 3H) -one
Figure imgf000063_0002
A mixture of 8-bromo-3-ethyl-9-fluoro-l-(4-methoxybenzyl)-lH- pyrimido[4,5,6-de]quinazolin-2(3H)-one (Intermediate 5: 126 mg, 0.29 mmol), XPhos Pd G3 (50 mg, 0.06 mmol) and (tributyl stannyl)methanol (141 mg, 0.44 mmol) in dioxane (2 mL) was stirred for 2 h at 100 °C under nitrogen atmosphere. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% methanol in di chloromethane to provide the desired product (80 mg, 72%) as a white solid. LCMS calculated for C20H20FN4O3 (M+H)+ m/z = 383.2; found 383.0.
Step 2: 5-( ( 1 -((3-Ethyl-9-fluoro-2-oxo-2, 3-dihydro-lH-pyrimido[ 4, 5, 6-de ]quinazolin- 8-yl)methyl)azetidin-3-yl)oxy)-N-methylpicolinamide
The mixture of 3-ethyl-9-fluoro-8-(hydroxymethyl)-l-(4-methoxybenzyl)-lH- pyrimido[4,5,6-de]quinazolin-2(3H)-one (58 mg, 0.15 mmol) was combined with hydrogen bromide (33 wt.% solution in glacial acid, 2 mL) at room temperature. The reaction mixture was then heated at 80 °C for 2 h. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was taken in acetonitrile (3 mL), followed by the addition of 5-(azetidin-3-yloxy)-7V- methylpicolinamide (Intermediate 1 : 33 mg, 0.16 mmol) and MA- diisopropylethylamine (189 mg, 1.5 mmol). The resulting mixture was stirred at room temperature for 16 h, and then concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Sunfire prep Cl 8 column, 30*150 mm; Mobile Phase: acetonitrile in water (0.05% trifluoroacetic acid); Flow rate: 60 mL/min; Gradient: 2% B to 20% B in 10 min; Detector: 254/220 nm). Eluted fractions were collected and lyophilized to afford the TFA salt of the desired product as a white solid. LCMS calculated for C22H23FN7O3 (M+H)+ m/z = 452.2; found 452.2; 'H NMR (400 MHz, DMSO-t/6) 8 11.77 (s, 1H), 8.73 (s, 1H), 8.56 (q, J = 4.8 Hz, 1H), 8.27 (d, J= 2.8 Hz, 1H), 7.99 (d, J= 8.8 Hz, 1H), 7.53-7.43 (m, 2H), 5.30-5.18 (m, 1H), 4.73-4.60 (m, 4H), 4.27 (s, 2H), 4.14 (q, J= 7.2 Hz, 2H), 2.80 (d, J= 4.8 Hz, 3H), 1.22 (t, J= 7.2 Hz, 3H). Example 2. 5-(((2R,3S)-l-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-lH- pyrimido[4,5,6-de]quinazolin-8-yl)methyl)-2-methylazetidin-3-yl)oxy)-N- methylpicolinamide
Figure imgf000065_0001
The title compound was prepared according to the procedure described in Example 1, using N-methyl-5-(((2R,3S)-2-methylazetidin-3-yl)oxy)picolinamide (Intermediate 2) instead of 5-(azetidin-3-yloxy)-7V-methylpicolinamide in Step 2. LCMS calculated for C23H25FN7O3 (M+H)+ m/z = 466.2; found 466.2; 1 H NMR (400 MHz, DMSO-tfc) 8 11.81 (s, 1H), 8.74 (s, 1H), 8.58 (q, J= 4.8 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.00 (d, J= 8.8 Hz, 1H), 7.59 (d, J= 4.4 Hz, 1H), 7.50 (dd, J= 8.8, 2.8 Hz, 1H), 5.05-4.95 (m, 1H), 4.90-4.50 (m, 4H), 4.27-4.06 (m, 3H), 2.80 (d, J= 4.8 Hz, 3H), 1.49 (d, J= 6.8 Hz, 3H), 1.23 (t, J= 7.2 Hz, 3H).
Example 3. 5-((l-((3-Ethyl-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6-de]quinazolin- 8-yl)methyl)azetidin-3-yl)oxy)-N-methylpicolinamide
Figure imgf000065_0002
The mixture of 3 -ethyl-8-(hydroxymethyl)- l-(4-m ethoxybenzyl)- 1H- pyrimido[4,5,6-de]quinazolin-2(3J7)-one (Intermediate 6: 40 mg, 0.1 mmol) was combined with hydrogen bromide (33 wt.% solution in glacial acid, 2 mL) at room temperature. The reaction mixture was then heated at 80 °C for 2 h. Upon cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was taken in acetonitrile (3 mL), followed by the addition of 5-(azetidin-3-yloxy)-7V- methylpicolinamide (Intermediate 1 : 22 mg, 0.11 mmol) and 7V,7V- diisopropylethylamine (126 mg, 1.0 mmol). The resulting mixture was stirred at room temperature for 16 h, and then was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Sunfire prep Cl 8 column, 30*150 mm; Mobile Phase: acetonitrile in water (0.05% trifluoroacetic acid); Flow rate: 60 mL/min; Gradient: 2% B to 20% B in 10 min; Detector: 254/220 nm). Eluted fractions were collected and lyophilized to afford the TFA salt of the desired product as a white solid. LCMS calculated for C22H24N7O3 (M+H)+ m/z = 434.2; found 434.2; 'H NMR (400 MHz, DMSO-t/6) 5 11.70 (s, 1H), 8.74 (s, 1H), 8.56 (q, J = 4.8 Hz, 1H), 8.27 (d, J= 2.8 Hz, 1H), 7.99 (d, J= 8.8 Hz, 1H), 7.50-7.43 (m, 2H), 6.94 (s, 1H), 5.36-5.14 (m, 1H), 4.69-4.54 (m, 4H), 4.27 (s, 2H), 4.13 (q, J= 7.2 Hz, 2H), 2.80 (d, J= 4.8 Hz, 3H), 1.22 (t, J= 7.2 Hz, 3H).
Example 4. 5-(((2R,3S)-l-((3-ethyl-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6- de]quinazolin-8-yl)methyl)-2-methylazetidin-3-yl)oxy)-N-methylpicolinamide
Figure imgf000066_0001
The title compound was prepared according to the procedure described in Example 3, using N-methyl-5-(((2R,3S)-2-methylazetidin-3-yl)oxy)picolinamide (Intermediate 2) instead of 5-(azetidin-3-yloxy)-7V-methylpicolinamide. LCMS calculated for C23H26N7O3 (M+H)+ m/z = 448.2; found 448.2; 1 H NMR (400 MHz, DMSO-t/,) 8 11.72 (s, 1H), 8.75 (s, 1H), 8.58 (q, J= 4.8 Hz, 1H), 8.29 (d, J= 2.8 Hz, 1H), 8.00 (d, J= 8.8 Hz, 1H), 7.53-7.46 (m, 2H), 6.98 (s, 1H), 5.06-4.97 (m, 1H), 4.82-4.47 (m, 4H), 4.24-4.09 (m, 3H), 2.80 (d, J= 4.8 Hz, 3H), 1.45 (d, J= 6.8 Hz, 3H), 1.22 (t, 7= 7.2 Hz, 3H).
Example 5. N-cyclopropyl-5-((l-((3-ethyl-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6- de]quinazolin-8-yl)methyl)azetidin-3-yl)oxy)picolinamide
Figure imgf000067_0001
The title compound was prepared according to the procedure described in Example 3, using 5-(azetidin-3-yloxy)-N-cyclopropylpicolinamide (Intermediate 3) instead of 5-(azetidin-3-yloxy)-7V-methylpicolinamide. LCMS calculated for C24H26N7O3 (M+H)+ m/z = 460.2; found 460.3; 'H NMR (300 MHz, Methanol-^) 6 8.87 (s, 1H), 8.28 (d, J= 2.8 Hz, 1H), 8.07 (d, J= 8.8 Hz, 1H), 7.47 (d, J= 1.2 Hz, 1H), 7.41 (dd, J= 8.8, 2.8 Hz, 1H), 7.13 (d, J= 1.2 Hz, 1H), 5.41-5.29 (m, 1H), 4.84- 4.74 (m, 2H), 4.71 (s, 2H), 4.49-4.27 (m, 4H), 2.94-2.80 (m, 1H), 1.35 (t, J= 7.2 Hz, 3H), 0.89-0.79 (m, 2H), 0.71-0.62 (m, 2H).
Example 6. N-cyclopropyl-5-(((2R,3S)-l-((3-ethyl-2-oxo-2,3-dihydro-lH- pyrimido [4,5,6-de] quinazolin-8-yl)methyl)-2-methylazetidin-3- yl)oxy)picolinamide
Figure imgf000067_0002
The title compound was prepared according to the procedure described in Example 3, using N-cyclopropyl-5-(((2R,3S)-2-methylazetidin-3-yl)oxy)picolinamide (Intermediate 4) instead of 5-(azetidin-3-yloxy)-7V-methylpicolinamide. LCMS calculated for C25H28N7O3 (M+H)+ m/z = 474.2; found 474.3; 1 H NMR (300 MHz, Methanol-t/4) 8 8.89 (s, 1H), 8.30 (d, J= 2.8 Hz, 1H), 8.08 (d, J= 8.8 Hz, 1H), 7.53 (d, J= 1.2 Hz, 1H), 7.44 (dd, J= 8.8, 2.8 Hz, 1H), 7.19 (d, J= 1.2 Hz, 1H), 5.14-5.04 (m, 1H), 4.92-4.82 (m, 1H), 4.80-4.65 (m, 3H), 4.35 (q, J= 7.2 Hz, 2H), 4.29-4.19 (m, 1H), 2.92-2.82 (m, 1H), 1.61 (d, J= 6.8 Hz, 3H), 1.35 (t, J= 7.2 Hz, 3H), 0.89- 0.79 (m, 2H), 0.72-0.62 (m, 2H). Example 7. N-cyclopropyl-5-((l-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-lH- pyrimido[4,5,6-de]quinazolin-8-yl)methyl)azetidin-3-yl)oxy)picolinamide
Figure imgf000068_0001
The title compound was prepared according to the procedure described in Example 1, using 5-(azetidin-3-yloxy)-N-cyclopropylpicolinamide (Intermediate 3) instead of 5-(azetidin-3-yloxy)-7V-methylpicolinamide in Step 2. LCMS calculated for C24H25FN7O3 (M+H)+ m/z = 478.2; found 478.3; 'H NMR (300 MHz, Methanol-^) 6 8.76 (s, 1H), 8.29 (d, J= 2.8 Hz, 1H), 8.08 (d, J= 8.8 Hz, 1H), 7.49 (d, J= 5.2 Hz, 1H), 7.42 (dd, J= 8.8, 2.8 Hz, 1H), 5.39-5.27 (m, 1H), 4.89-4.76 (m, 4H), 4.52-4.41 (m, 2H), 4.31 (q, J= 7.2 Hz, 2H), 2.92-2.82 (m, 1H), 1.34 (t, J= 7.2 Hz, 3H), 0.92- 0.79 (m, 2H), 0.71-0.63 (m, 2H).
Example 8. N-cyclopropyl-5-(((2R,3S)-l-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-lH- pyrimido [4,5,6-de] quinazolin-8-yl)methyl)-2-methylazetidin-3- yl)oxy)picolinamide
Figure imgf000068_0002
The title compound was prepared according to the procedure described in Example 1, using N-cyclopropyl-5-(((2R,3S)-2-methylazetidin-3-yl)oxy)picolinamide (Intermediate 4) instead of 5-(azetidin-3-yloxy)-7V-methylpicolinamide in Step 2. LCMS calculated for C25H27FN7O3 (M+H)+ m/z = 492.2; found 492.3; 1 H NMR (300 MHz, Methanol-^) 8 8.82 (s, 1H), 8.30 (d, J= 2.8 Hz, 1H), 8.08 (d, J= 8.8 Hz, 1H), 7.56 (d, J= 5.2 Hz, 1H), 7.44 (dd, J= 8.8, 2.8 Hz, 1H), 5.14-5.02 (m, 1H), 4.93-4.69 (m, 4H), 4.41-4.22 (m, 3H), 2.93-2.81 (m, 1H), 1.66 (d, J= 6.8 Hz, 3H), 1.36 (t, J =
7.2 Hz, 3H), 0.92-0.78 (m, 2H), 0.72-0.61 (m, 2H).
Example 9. 5-((l-((3-Ethyl-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6-de]quinazolin- 8-yl)methyl)azetidin-3-yl)oxy)-N,6-dimethylpicolinamide
Figure imgf000069_0001
Step 1: Methyl 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-6-methylpicolinate
Boc i
Figure imgf000069_0002
To a stirred mixture of tert-butyl 3 -hydroxyazetidine-1 -carboxylate (1.13 g, 6.5 mmol) in tetrahydrofuran (15 mL) was added potassium Zc/V-butoxide (1 M in tetrahydrofuran, 7.8 mL, 7.8 mmol) dropwise at 0 °C. The mixture was stirred for 30 min at the same temperature. Then methyl 5-fluoro-6-methylpyridine-2-carboxylate (1 g, 5.91 mmol) was added. After stirring at room temperature for 2 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% ethyl acetate in petroleum ether to afford the desired product as a yellow solid (1.5 g, 79%). LCMS calculated for C16H23N2O5 (M+H)+ m/z = 323.2; found 323.1.
Step 2: 5-((l-(Tert-butoxycarbonyl)azetidin-3-yl)oxy)-6-methylpicolinic acid
Boc i
Figure imgf000069_0003
To a mixture of methyl 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-6- methylpicolinate (1.5 g, 4.65 mmol) in water (10 mL) and tetrahydrofuran (10 mL) was added lithium hydroxide monohydrate (0.78 g, 18.61 mmol) at room temperature. After stirring at the same temperature for 2 h, tetrahydrofuran was removed under reduced pressure. The mixture was neutralized to pH 5 with hydrochloric acid (1 M). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product as a yellow solid (1.1 g) which was used directly in the next step without further purification. LCMS calculated for C15H21N2O5 (M+H)+ m/z = 309.1; found 309.2.
Step 3: Tert-butyl 3-((2-methyl-6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-l- carboxylate
Boc 1
Figure imgf000070_0001
The mixture of 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-6- methylpicolinic acid (400 mg, 1.3 mmol) and HATU (592 mg, 1.56 mmol) in N,N- dimethylformamide (5 mL) was stirred at room temperature for 15 min. Then methylamine hydrochloride (131 mg, 1.9 mmol) was added, followed by N,N- diisopropylethylamine (503 mg, 3.89 mmol). After stirring at room temperature for 16 h, the mixture was diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% ethyl acetate in petroleum ether to afford the desired product as a yellow solid (150 mg, 36%). LCMS calculated for C16H24N3O4 (M+H)+ m/z = 322.2; found 322.3.
Step 4: 5-(Azetidin-3-yloxy)-N, 6-dimethylpicolinamide
Figure imgf000071_0001
The mixture of tert-butyl 3-((2-methyl-6-(methylcarbamoyl)pyridin-3- yl)oxy)azetidine-l -carboxylate (150 mg, 0.47 mmol) in hydrochloride (4 M in 1,4- dioxane, 5 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to afford HC1 salt of the desired product as a yellow solid (120 mg). LCMS calculated for C11H16N3O2 (M+H)+ m/z = 222.1; found 222.0.
Step 5: 5-( (l-( (3-Ethyl-2-oxo-2, 3-dihydro-lH-pyrimido[ 4, 5, 6-de ]quinazolin-8- yl)methyl)azetidin-3-yl)oxy)-N,6-dimethylpicolinamide
To 3-ethyl-8-(hydroxymethyl)-l-(4-methoxybenzyl)-lH-pyrimido[4,5,6- de]quinazolin-2(3H)-one (150 mg, 0.41 mmol) was added hydrogen bromide (33 wt.% solution in glacial acid, 5 mL) at room temperature. The reaction mixture was heated at 80 °C under nitrogen atmosphere for 2 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added acetonitrile (5 mL); followed by 5-(azetidin-3-yloxy)-N,6- dimethylpicolinamide hydrochloride (105 mg, 0.41 mmol) and 7V-ethyl-7V- isopropylpropan-2-amine (529 mg, 4.1 mmol). The resulting mixture was stirred at room temperature for 16 h; and then was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography, Cl 8 silica gel; mobile phase, acetonitrile in water (0.1% trifluoroacetic acid), 5% to 50% gradient over 20 min; detector, UV 254 nm. The collected fractions were lyophilized to provide the TFA salt of the desired product as a white solid (61 mg). LCMS calculated for C23H26N7O3 (M+H)+ m/z = 448.2; found 448.2. 1 H NMR (400 MHz, Methanol-^) 8 8.83 (d, J= 1.2 Hz, 1H), 7.89 (d, .7= 8.8 Hz, 1H), 7.45 (s, 1H), 7.16 (d, J= 8.8 Hz, 1H), 7.10-7.08 (m, 1H), 5.27 (t, J= 6.0 Hz, 1H), 4.79-4.74 (m, 2H), 4.69 (s, 2H), 4.43-4.39 (m, 2H), 4.35-4.30 (m, 2H), 2.94 (s, 3H), 2.55 (s, 3H), 1.33 (t, J= 6.8 Hz, 3H). Example 10. 5-(((21?,3‘ )-l-((3-ethyl-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6- de]quinazolin-8-yl)methyl)-2-methylazetidin-3-yl)oxy)-N,6-dimethylpicolinamide
Figure imgf000072_0001
Step 1: Methyl 5-(((2R,3S)-l-(tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)-6- methylpicolinate
Boc i
Figure imgf000072_0002
To a stirred mixture of tert-butyl (2A,35)-3-hydroxy-2-methylazetidine-l- carboxylate (996 mg, 5.32 mmol) in tetrahydrofuran (15 mL) was added potassium /c/7-butoxide (1 M in tetrahydrofuran, 5.86 mL, 5.86 mmol) dropwise at 0 °C. The mixture was stirred for 30 min at the same temperature. Then methyl 5-fluoro-6- methylpyridine-2-carboxylate (1 g, 5.91 mmol) was added. After stirring at room temperature for 2 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% ethyl acetate in petroleum ether to afford the desired product as a yellow solid (1.5 g, 75%). LCMS calculated for C17H25N2O5 (M+H)+ m/z = 337.2; found 337.2.
Step 2: 5-( ( (2R, 3S)-l-( tert-butoxycarbonyl)-2-methylazetidin-3-yl)oxy)-6- methylpicolinic acid
Boc i
Figure imgf000072_0003
To a mixture of methyl 5-(((2A,35)-l-(tert-butoxycarbonyl)-2-methylazetidin- 3-yl)oxy)-6-methylpicolinate (740 mg, 2.2 mmol) in water (8 mL) and tetrahydrofuran (8 mL) was added lithium hydroxide monohydrate (369 mg, 8.8 mmol) at room temperature. After stirring at the same temperature for 2 h, tetrahydrofuran was removed under reduced pressure. The mixture was neutralized to pH 6 with hydrochloric acid (1 M). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product as a yellow solid (650 mg) which was used directly in the next step without further purification. LCMS calculated for C16H23N2O5 (M+H)+ m/z = 323.2; found 323.1.
Step 3: Tert-butyl (2R,3S)-2-methyl-3-((2-methyl-6-(methylcarbamoyl)pyridin-3- yl)oxy)azetidine-l-carboxylate
Boc 1
Figure imgf000073_0001
The mixture of 5-(((2R,3S)-l-(tert-butoxycarbonyl)-2-methylazetidin-3- yl)oxy)-6-methylpicolinic acid (400 mg, 1.3 mmol) and HATU (566 mg, 1.49 mmol) in AA-dimethylformamide (5 mL) was stirred at room temperature for 15 min. Then methylamine hydrochloride (126 mg, 1.9 mmol) was added, followed by N,N- diisopropylethylamine (481 mg, 3.72 mmol). After stirring at room temperature for 16 h, the mixture was diluted with water (50 mL). The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% ethyl acetate in petroleum ether to afford the desired product as a yellow solid (200 mg, 36%). LCMS calculated for C17H26N3O4 (M+H)+ m/z = 336.2; found 336.3.
Step 4: N, 6-dimethyl-5-( ( 2R, 3S)-2-methylazetidin-3-yl)oxy)picolinamide
Figure imgf000074_0001
The mixture of tert-butyl (2R,3S)-2-methyl-3-((2-methyl-6- (methylcarbamoyl)pyridin-3-yl)oxy)azetidine-l-carboxylate (200 mg, 0.6 mmol) in hydrochloride (4 M in 1,4-di oxane, 5 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to afford HC1 salt of the desired product as a yellow solid (180 mg). LCMS calculated for C12H18N3O2 (M+H)+ m/z = 236.1; found 236.3.
Step 5: 5-( ( (2R, 3S)-l-((3-ethyl-2-oxo-2, 3-dihydro-lH-pyrimido[ 4, 5, 6-de ]quinazolin- 8-yl)methyl)-2-methylazetidin-3-yl)oxy)-N,6-dimethylpicolinamide
To 3-ethyl-8-(hydroxymethyl)-l-(4-methoxybenzyl)-lH-pyrimido[4,5,6- de]quinazolin-2(3H)-one (134 mg, 0.37 mmol) was added hydrogen bromide (33 wt.% solution in glacial acid, 5 mL) at room temperature. The reaction mixture was heated at 80 °C under nitrogen atmosphere for 2 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added acetonitrile (5 mL); followed by N,6-dimethyl-5-(((27?,35)-2- methylazetidin-3-yl)oxy)picolinamide hydrochloride (100 mg, 0.37 mmol) and A- ethyl-7V-isopropylpropan-2-amine (477 mg, 3.7 mmol). The resulting mixture was stirred at room temperature for 16 h; and then was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography, Cl 8 silica gel; mobile phase, acetonitrile in water (0.1% trifluoroacetic acid), 5% to 50% gradient over 20 min; detector, UV 254 nm. The collected fractions were lyophilized to provide the TFA salt of the desired product as a white solid (52.9 mg). LCMS calculated for C24H28N7O3 (M+H)+ m/z = 462.2; found 462.2. 1 H NMR (400 MHz, Methanol-^) 8 8.88-8.82 (m, 1H), 7.90 (d, J= 8.8 Hz, 1H), 7.52-7.48 (m, 1H), 7.23-7.09 (m, 2H), 5.00 (t, J= 6.0 Hz, 1H), 4.73-4.66 (m, 4H), 4.35-4.31 (m, 2H), 4.24-4.20 (m, 1H), 2.94 (s, 3H), 2.55 (s, 3H), 1.62 (d, J= 2.1 Hz, 3H), 1.33 (t, J= 6.8 Hz, 3H). Example A. In-Cell Western measurement of PARylation in PARP1 WT and knockout cells
The purpose of this cell-based assay is to measure the potency and selectivity of synthesized PARP inhibitors in suppressing hydrogen peroxide-induced PARylation in cells with and without PARP1 expression. Several cell lines were used in this assay. HeLa cells (wide-type with PARP1 gene) were purchased from ATCC. The HAP1 cell line without the PARP1 gene (#HZGHC003943c006) was purchased from Horizon Discovery. Cells were cultured using complete medium containing 10% fetal bovine serum. One day before the assay, cells were seeded in 96-well plates at the density of 20,000 cells per well in 80 uL complete medium. Compounds were dissolved using DMSO and diluted to the working concentrations using complete medium. Cells were pre-treated with compounds for 60 min and then stimulated with 10 mM hydrogen peroxide for 15 min. After stimulation, cells were immediately fixed using ice-cold methanol for 20 min. After fixation, cells were washed using IX PBST buffer for 3 times, 5 min each time, to eliminate residual methanol. Cells were blocked for 1 h at room temperature in blocking buffer (10% goat serum, 1% BSA, 0.1% Triton X-100 in PBST). Primary antibody was diluted in blocking buffer at 50 uL per well. Cells were incubated with the primary antibody (Adipogen, AG-20T- 0001-M001, 1 :300) at 4 °C for 18 h. The wells were then washed using IX PBST for 3 times, 5 min each time. IRDye® 680RD Goat anti-Mouse IgG (H + L) secondary antibody was diluted at 1/1000 using the diluent buffer and added at 50 uL per well. Secondary antibody incubation was for 1 h at room temperature. Cells were then washed using IX PBST for 3 times, 5 min each time. The signal was detected and analyzed using LI-COR Odyssey DLx Imaging system. Data were collected and further processed using GraphPad Prism for IC50 estimation.
Results of the assay described above for HeLa WT are presented in Table 1. Compounds denoted of the present disclosure showed IC50 values in the following ranges:
A: IC50 < 10 nM;
B: 10 nM < IC50 < 100 nM;
C: 100 nM < IC50 < 500 nM;
D: 500 nM < IC50 < 1,000 nM; E: 1,000 nM < IC50 < 10,000 nM.
Table 1.
Figure imgf000076_0001
Example B. Cell-titer Gio measurement of cytotoxicity in BRCA2 isogenic cells
The purpose of this cellular assay is to measure cytotoxicity and cell killing activity of selected PARP1 inhibitors in DLD1 isogenic cells with and without the BRCA2 genes. The BRCA2 knockout DLD1 cell line (#HD 105-007) and its isogenic wide-type control were purchased from Horizon Discovery. Cells were cultured using RPMI 1640 complete medium containing 10% fetal bovine serum and Penicillin- Streptomycin. One day before the assay, cells were seeded at 50-750 cells per well in 96-well plates. Compounds were dissolved and diluted in DMSO and added into complete medium to final working concentrations. The treatment was for 7 days. At the end of this assay, Promega Cell-titer Gio reagents (#G7573) were added at 100 uL per well. Plates were kept on orbital shaker for 2 min. These plates were then kept in the CO2 incubator for another 10 minutes. Luminescence signal was measured using the SpectraMax i3x plate reader. Data were further analyzed using GraphPad Prism for IC50 estimation.
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I:
Figure imgf000077_0001
or a pharmaceutically acceptable salt thereof, wherein:
X is C or N;
Y is C or N;
= is a single or double bond; m is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, 3, 4, 5, or 6;
Ring B is C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl;
Ring C is 4-14 membered heterocycloalkyl;
Ring D is C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, or 5- 10 membered heteroaryl;
L is selected from C1-4 alkylene, C1-4 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, -C3-7 cycloalkylene-Ci-4 alkyl-, -(4-7 membered heterocycloalkylene)-Ci-4 alkyl-, -O-, -N(RL)-, -C(O)-, -C(O)N(RL)-, - N(RL)C(O)N(RL)-, -N(RL)C(O)O-, -S(O)2-, -N(RL)S(O)2-, and -N(RL)S(O)2N(RL)-, wherein the C1-4 alkylene, C1-4 haloalkylene, C3-7 cycloalkylene, 4-7 membered heterocycloalkylene, C3-7 cycloalkylene-Ci-4 alkyl, and (4-7 membered heterocycloalkylene)-Ci-4 alkyl of L are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each RL is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;
R1 is selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
R2 is selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
R3 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl;
R4 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl; or, R3 and R4, together with the carbon atom to which they are attached, form a C3-7 cycloalkyl, or 4-7 membered heterocycloalkyl group, wherein the C3-7 cycloalkyl, and 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents;
R50 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa50, - SRa50, -NRc50Rd5°, -NO2, -C(O)Ra50, -C(O)ORa50, -C(O)NRc50Rd5°, - C(O)NRc50(ORa5°), -OC(O)Ra50, -OC(O)NRc50Rd5°, -OC(O)ORa50, -OS(O)2Rb5°, - OS(O)2NRc50Rd5°, -NRc50C(O)Ra5°, -NRc50C(O)ORa5°, -NRc50C(O)NRc50Rd50, - NRc50S(O)2Rb5°, -NRc50S(O)2NRc50Rd50, -NRc50ORa5°, -NRc50S(O)Rb5°, - NRc50S(O)NRc50Rd50, -S(O)Rb50, -S(O)2Rb5°, -S(O)NRc50Rd5°, -S(O)2NRc50Rd5°, - C(=NRe50)Ra5°, -C(=NRe50)NRc50Rd50, -NRc50C(=NRe50)Ra50, - NRc50C(=NRe50)NRc50Rd5°, -NRc50S(O)(=NRe50)Rb5°, -NRc50S(O)(=NRe50)NRc50Rd50, - OS(O)(=NRe50)Rb5°, -S(O)(=NRe50)Rb5°, -S(O)(=NRe50)NRc50Rd50, - C(O)NRc50S(O)2Rb5°, -C(O)NRc50S(O)2NRc50Rd5°, -S(O)2NRc50C(O)Rb5°, - NRc50S(O)NRc50C(O)Rb5°, and -P(O)Rf50Rg5°, wherein the Ci-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R50 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Ra50, Rc50, and Rd50 is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra50, Rc50, and Rd50 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; or, any Rc50 and Rd50 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Rb50 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb50 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Re50 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each Rf50 and Rg50 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each R6 is independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa6, -SRa6,
Figure imgf000080_0001
P(O)Rf6Rg6, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R6 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Ra6, Rc6, and Rd6 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra6, Rc6, and Rd6 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; or, any Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Rb6 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb6 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Re6 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each Rf6 and Rg6 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each R7 is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, (5-6 membered heteroaryl)-Ci-4 alkyl, -CN, -ORa7, -SRa7,
Figure imgf000081_0001
P(O)Rf7Rg7, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of R7 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Ra7, Rc7, and Rd7 is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci- 4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Ra7, Rc7, and Rd7 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; or, any Rc7 and Rd7 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4- 7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Rb7 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl of Rb7 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Re7 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each R17 and Rg7 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-Ci-4 alkyl, phenyl-Ci-4 alkyl, (4-7 membered heterocycloalkyl)-Ci-4 alkyl, and (5-6 membered heteroaryl)-Ci-4 alkyl; each R8 is independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci-4 alkyl, -CN, -
Figure imgf000083_0001
S(O)2NRc8C(O)Rb8, -NRc8S(O)NRc8C(O)Rb8, and -P(O)Rf8Rg8, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R8 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R8A substituents; or, a R7 and a R8, together with the atoms to which they are attached, form a C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl group, wherein the C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R8A substituents; each Ra8, Rc8, and Rd8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra8, Rc8, and Rd8 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R8A substituents; or, any Rc8 and Rd8 attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R8A substituents; each Rb8 is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb8 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R8A substituents; each Re8 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each RK and Rg8 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, Ci- 6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each R8A is independently selected from oxo, H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, (5-10 membered heteroaryl)-Ci- 4 alkyl, -CN, -ORa8A, -SRa8A, -NRc8ARd8A, -NO2, -C(O)Ra8A, -C(O)ORa8A, - C(O)NRc8ARd8A, -C(O)NRc8A(ORa8A), -OC(O)Ra8A, -OC(O)NRc8ARd8A, -OC(O)ORa8A, -OS(O)2Rb8A, -OS(O)2NRc8ARd8A, -NRc8AC(O)Ra8A, -NRc8AC(O)ORa8A, - NRc8AC(O)NRc8ARd8A, -NRc8AS(O)2Rb8A, -NRc8AS(O)2NRc8ARd8A, -NRc8AORa8A, - NRc8AS(O)Rb8A, -NRc8AS(O)NRc8ARd8A, -S(O)Rb8A, -S(O)2Rb8A, -S(O)NRc8ARd8A, - S(O)2NRc8ARd8A, -C(=NRe8A)Ra8A, -C(=NRe8A)NRc8ARd8A, -NRc8AC(=NRe8A)Ra8A, - NRc8AC(=NRe8A)NRc8ARd8A, -NRc8AS(O)(=NRe8A)Rb8A, - NRc8AS(O)(=NRe8A)NRc8ARd8A, -OS(O)(=NRe8A)Rb8A, -S(O)(=NRe8A)Rb8A, - S(O)(=NRe8A)NRc8ARd8A, -C(O)NRc8AS(O)2Rb8A, -C(O)NRc8AS(O)2NRc8ARd8A, - S(O)2NRc8AC(O)Rb8A, -NRc8AS(O)NRc8AC(O)Rb8A, and -P(O)Rf8ARg8A, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of R8A are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Ra8A, Rc8A, and Rd8A is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci- 4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl of Ra8A, Rc8A, and Rd8A are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; or, any Rc8A and Rd8A attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Rb8A is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl- C1-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5- 10 membered heteroaryl)-Ci-4 alkyl of Rb8A are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected RG substituents; each Re8A is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; each RKA and Rg8A are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-io aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl, Ce-io aryl-Ci-4 alkyl, (4-10 membered heterocycloalkyl)-Ci-4 alkyl, and (5-10 membered heteroaryl)-Ci-4 alkyl; and each RG is independently selected from H, OH, CN, halo, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, cyano-Ci-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-Ci-4 alkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-3 alkylamino, di(Ci-3 alkyl)amino, thio, C1-3 alkylthio, C1-3 alkylsulfinyl, Ci- 3 alkyl sulfonyl, carbamyl, C1-3 alkylcarbamyl, di(Ci-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxy carbonylamino, aminocarbonyloxy, C1-3 alkylaminocarbonyloxy, di (C 1-3 alkyl)aminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(Ci-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di (C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(Ci-3 alkyl)aminocarbonylamino.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is C.
4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Ring B is 5-6 membered heteroaryl.
5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Ring
Figure imgf000087_0001
6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.
7. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein m is 0.
8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, halo, and C1-3 alkyl.
9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R1 is H or halo.
10. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R1 is H or fluoro.
11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, halo, and C1-3 alkyl.
12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H.
13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from H, halo, and C1-3 alkyl.
14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R3 is H.
15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from H, halo, and C1-3 alkyl.
16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R4 is H.
17. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are each H.
18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Ring C is 4-7 membered heterocycloalkyl.
19. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Ring
Figure imgf000088_0001
20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1.
21. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein p is 1.
22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each R7 is independently selected from C1-6 alkyl.
23. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein each R7 is methyl.
24. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein p is 0.
25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from,
Figure imgf000089_0001
26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein L is -O-.
27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Ring D is 5-10 membered heteroaryl.
28. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Ring D is pyridinyl.
29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.
30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, -CN, -ORa8, -NRc8Rd8, -C(O)Ra8, -C(O)ORa8, - C(O)NRc8Rd8, and -NRc8C(O)Ra8.
31. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from -C(O)NRc8Rd8.
32. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from C1-6 alkyl and - C(O)NRc8Rd8; and each Rc8 and Rd8 is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.
33. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from C1-3 alkyl and - C(O)NRc8Rd8; and each Rc8 and Rd8 is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl.
34. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from methyl, methylaminocarbonyl and cyclopropylaminocarbonyl.
35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R50 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R50 are each optionally substituted by 1, 2, 3, or 4 independently selected RG substituents.
36. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R50 is selected from H, C1-6 alkyl, and C1-6 haloalkyl.
37. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R50 is C1-6 alkyl.
38. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R50 is ethyl.
39. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
X is C or N;
Y is C or N; = is a single or double bond; m is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, or 2;
Ring B is 5-6 membered heteroaryl;
Ring C is 4-7 membered heterocycloalkyl;
Ring D is 5-10 membered heteroaryl;
L is selected from -O- or -N(RL)-; each RL is independently selected from H, Ci-6 alkyl, and Ci-6 haloalkyl;
R1 is selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
R2 is selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
R3 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl;
R4 is selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl;
R50 is selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R6 is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl each R7 is independently selected from oxo, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl; each R8 is independently selected from each R8 is independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, -CN, -ORa8, -NRc8Rd8, - C(O)Ra8, -C(O)ORa8, -C(O)NRc8Rd8, and -NRc8C(O)Ra8; and each Ra8, Rc8, and Rd8 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.
40. The compound of claim 1, wherein the compound of Formula I is a compound of Formula II:
Figure imgf000092_0001
II or a pharmaceutically acceptable salt thereof.
41. The compound of claim 1, wherein the compound of Formula I is a compound of Formula III:
Figure imgf000092_0002
III or a pharmaceutically acceptable salt thereof.
42. The compound of claim 1, wherein the compound of Formula I is a compound of Formula IV:
Figure imgf000093_0001
or a pharmaceutically acceptable salt thereof.
43. The compound of claim 1, which is selected from:
5-((l-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6-de]quinazolin- 8-yl)methyl)azetidin-3-yl)oxy)-N-methylpicolinamide;
5-(((2R,3S)-l-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6- de]quinazolin-8-yl)methyl)-2-methylazetidin-3-yl)oxy)-N-methylpicolinamide;
5 -(( 1 -((3 -ethyl -2-oxo-2, 3 -dihydro- 1 H-py rimido[4, 5 , 6-de] quinazolin-8- yl)methyl)azetidin-3-yl)oxy)-N-methylpicolinamide;
5 -(((2R,3 S)- 1 -((3 -ethyl-2-oxo-2, 3 -dihydro- 1 H-pyrimido[4, 5 , 6-de] quinazolin- 8-yl)methyl)-2-methylazetidin-3-yl)oxy)-N-methylpicolinamide;
N-cyclopropyl-5-((l-((3-ethyl-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6- de]quinazolin-8-yl)methyl)azetidin-3-yl)oxy)picolinamide;
N-cyclopropyl-5-(((2R,3S)-l-((3-ethyl-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6- de]quinazolin-8-yl)methyl)-2-methylazetidin-3-yl)oxy)picolinamide;
N-cyclopropyl-5-((l-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6- de]quinazolin-8-yl)methyl)azetidin-3-yl)oxy)picolinamide; and N-cyclopropyl-5-(((2R,3S)-l-((3-ethyl-9-fluoro-2-oxo-2,3-dihydro-lH- pyrimido[4,5,6-de]quinazolin-8-yl)methyl)-2-methylazetidin-3-yl)oxy)picolinamide; or a pharmaceutically acceptable salt thereof.
44. The compound of claim 1, which is selected from:
5 -(( 1 -((3 -ethyl -2-oxo-2, 3 -dihydro- 1 H-py rimido[4, 5 , 6-de] quinazolin-8- yl)methyl)azetidin-3-yl)oxy)-N,6-dimethylpicolinamide; and
5-(((2A,35 -l-((3-ethyl-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6-de]quinazolin- 8-yl)methyl)-2-methylazetidin-3-yl)oxy)-N,6-dimethylpicolinamide; or a pharmaceutically acceptable salt thereof.
45. A pharmaceutical composition comprising a compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
46. A method of inhibiting PARP1, comprising administering to a subject the compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof.
47. A method of treating a disease, disorder, or condition associated with PARP1, comprising administering to a subject in need thereof the compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof.
48. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof.
49. The method of claim 48, wherein the cancer is selected from ovarian cancer, breast cancer, prostate cancer, and pancreatic cancer.
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