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WO2024227026A1 - Composés hétérocycliques en tant qu'inhibiteurs de parp1 - Google Patents

Composés hétérocycliques en tant qu'inhibiteurs de parp1 Download PDF

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Publication number
WO2024227026A1
WO2024227026A1 PCT/US2024/026578 US2024026578W WO2024227026A1 WO 2024227026 A1 WO2024227026 A1 WO 2024227026A1 US 2024026578 W US2024026578 W US 2024026578W WO 2024227026 A1 WO2024227026 A1 WO 2024227026A1
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Prior art keywords
alkyl
cycloalkyl
membered heterocycloalkyl
membered heteroaryl
membered
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PCT/US2024/026578
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English (en)
Inventor
Jun Pan
Liangxing Wu
Wenqing Yao
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Synnovation Therapeutics, Inc.
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Publication date
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Publication of WO2024227026A1 publication Critical patent/WO2024227026A1/fr

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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 bond, 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 cycloal
  • 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
  • R 50 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, -OR a50 , - SR a50 , -NR c50 R d5 °, -NO2, -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
  • R 50 and one R 6 taken together with the atoms to which they are attached, form a Ring A which is selected from C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein the C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, and 5-6 membered heteroaryl group is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R 5 substituents;
  • the compound of Formula I is a compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein:
  • Z is C or N
  • n is 0, 1, 2, 3, 4, 5, or 6
  • 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 A is C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl, or 5-6 membered heteroaryl;
  • 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 bond, 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 cycloal
  • 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; each R 5 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
  • X is N.
  • X is C.
  • Y is C.
  • Y is N.
  • X is N and Y is C.
  • Z is N.
  • Z is C.
  • X is N
  • Y is C
  • Z is N
  • X is N
  • Y is C
  • Z is C
  • Ring A is C5-7 cycloalkyl, phenyl, 5-7 membered heterocycloalkyl, or 5-6 membered heteroaryl.
  • Ring A is 5-10 membered heterocycloalkyl.
  • Ring A is 5-7 membered heterocycloalkyl.
  • Ring A is 6-membered heterocycloalkyl. ⁇ R5) - N A
  • Ring A is selected from ,
  • Ring is asymmetric
  • Ring is asymmetric
  • n 0, 1, 2, 3, or 4.
  • n 0, 1, or 2.
  • n is 0 or 1.
  • n 0.
  • 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 5-membered heteroaryl.
  • Ring B is 6-membered heteroaryl. In some embodiments, Ring B is selected from ,
  • Ring embodiments, m is
  • n 0, 1, or 2.
  • m is 0 or 1.
  • m is 0.
  • 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 halo
  • R 1 is fluoro.
  • 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. In some embodiments, Ring C is 4-7 membered heterocycloalkyl.
  • Ring C is 6-membered heterocycloalkyl.
  • Ring C is piperazinyl
  • Ring is asymmetric
  • p is 0, 1, 2, 3, or 4.
  • p is 0, 1, or 2.
  • p is 0 or 1.
  • p is 0.
  • Ring D is 5-10 membered heteroaryl.
  • Ring D is pyridinyl
  • L is selected from bond, -O-, and -N(R L )-.
  • L is a bond
  • L is -O-.
  • L is -N(R L )-.
  • q is 0, 1, 2, 3, 4, or 5.
  • q is 1, 2, 3, 4, or 5.
  • q is 1, 2, 3, or 4.
  • q is 1, 2, or 3.
  • q is 1 or 2.
  • each R 8 is independently selected from halo, Ci-6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, Ci-6 haloalkyl, C3-10 cycloalkyl, -CN, -OR a8 , -SR a8 , - NR c8 R d8 , -NO 2 , -C(O)R a8 , -C(O)OR a8 , -C(O)NR c8 R d8 , -C(O)NR c8 (OR a8 ), -OC(O)R a8 , -OC(O)NR c8 R d8 , -OC(O)OR a8 , -OS(O) 2 R b8 , -OS(O) 2 NR c8 R d8 , -NR c8 C(O)R a8 , -NR c8 C(O)OR
  • each R 8 is independently selected from halo, C1-6 alkyl, C 2-6 alkenyl, C 2.6 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 Ci-6 alkyl, Ci-6 haloalkyl, -C(O)NR c8 R d8 , and -NR c8 C(O)R a8 .
  • each R 8 is independently selected from Ci-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 a8 , R b8 , R c8 , R d8 , R e8 , R K , and R g8 is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl.
  • each R a8 , R b8 , R c8 , R d8 , R e8 , R K , and R g8 is independently selected from H, Ci-6 alkyl, and C3-7 cycloalkyl.
  • each R c8 and R d8 is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl. In some embodiments, each R c8 and R d8 is independently selected from H, Ci-6 alkyl, and C3-7 cycloalkyl.
  • 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, and C3-7 cycloalkyl.
  • each R 8 is independently selected from methyl, methylaminocarbonyl, and cyclopropylaminocarbonyl.
  • X is C or N
  • Ring B is 5-6 membered heteroaryl
  • Ring C is 4-10 membered heterocycloalkyl
  • Ring D is 5-10 membered heteroaryl
  • R L is selected from bond, -O-, and -N(R L )-; each R L is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;
  • R 1 is selected from H, halo, and C1-3 alkyl
  • R 2 is selected from H, halo, and C1-3 alkyl
  • R 3 is selected from H, halo, and C1-3 alkyl
  • R 4 is selected from H, halo, and C1-3 alkyl
  • R 50 and one R 6 taken together with the atoms to which they are attached, form a Ring A which is selected from C5-10 cycloalkyl, phenyl, 5-10 membered heterocycloalkyl; each R 8 is independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, -CN, -OR a8 , -SR a8 , -NR c8 R d8 , -NO 2 , -C(O)R a8 , -C(O)OR a8 , - P(O)R f8 R g8 , wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl of R 8 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R 8A substituents; each R a8 , R c
  • X is C or N
  • Ring B is 5-6 membered heteroaryl
  • Ring C is 4-10 membered heterocycloalkyl
  • Ring D is 5-10 membered heteroaryl
  • R L is selected from bond, -O-, and -N(R L )-; each R L is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;
  • R 1 is selected from H, halo, and C1-3 alkyl
  • R 2 is selected from H, halo, and C1-3 alkyl
  • R 3 is selected from H, halo, and C1-3 alkyl
  • R 4 is selected from H, halo, and C1-3 alkyl; R 50 and one R 6 , taken together with the atoms to which they are attached, form a Ring A which is selected from 5-7 membered heterocycloalkyl; each R 8 is independently selected from halo, Ci-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 , and -NR c8 C(O)R a8 ; each R a8 , R c8 , and R d8 is independently selected from H, Ci-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, Ce-i
  • the compound of Formula I is a compound of Formula II, wherein:
  • X is C or N
  • Y is C or N
  • Z is C or N
  • Ring A is 5-10 membered heterocycloalkyl
  • Ring B is 5-6 membered heteroaryl
  • Ring C is 4-10 membered heterocycloalkyl
  • Ring D is 5-10 membered heteroaryl
  • R L is selected from bond, -O-, and -N(R L )-; each R L is independently selected from H, Ci-6 alkyl, and Ci-6 haloalkyl;
  • R 1 is selected from H, halo, and C1-3 alkyl
  • R 2 is selected from H, halo, and C1-3 alkyl
  • R 3 is selected from H, halo, and C1-3 alkyl
  • R 4 is selected from H, halo, and C1-3 alkyl; each R 8 is independently selected from oxo, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 haloalkyl, -CN, -OR a8 , -SR a8 , -NR c8 R d8 , -NO 2 , -C(O)R a8 , -C(O)OR a8 , - P(O)R f8 R g8 , wherein the Ci-6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, and Ci-6 haloalkyl of R 8 are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R 8A substituents; each R a8 , R c8 , and R d8 is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C 2 -6 alkeny
  • the compound of Formula I is a compound of Formula II, wherein:
  • X is C or N
  • Y is C or N
  • Z is C or N
  • Ring A is 5-10 membered heterocycloalkyl
  • Ring B is 5-6 membered heteroaryl
  • Ring C is 4-10 membered heterocycloalkyl
  • Ring D is 5-10 membered heteroaryl
  • R L is selected from bond, -O-, and -N(R L )-; each R L is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl;
  • R 1 is selected from H, halo, and C1-3 alkyl
  • R 2 is selected from H, halo, and C1-3 alkyl
  • R 3 is selected from H, halo, and C1-3 alkyl
  • R 4 is selected from H, halo, and C1-3 alkyl; 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 , and -NR c8 C(O)R a8 ; 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, 5-10 membered heteroaryl, C3-10 cycloalkyl-Ci-4 alkyl
  • 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 Illa:
  • the compound of Formula I is a compound of Formula Illb:
  • the compound of Formula I is a compound of Formula IV:
  • the compound of Formula I is a compound of Formula IVa:
  • the compound of Formula I is a compound of Formula IVb: or a pharmaceutically acceptable salt thereof.
  • the compound of Formula I is a compound of Formula V:
  • the compound of Formula I is a compound of Formula Va:
  • the compound of Formula I is a compound of Formula Vb: or a pharmaceutically acceptable salt thereof.
  • the compound provided herein is selected from:
  • the compound provided herein is selected from: 5 -(4-((3 -ethyl -9-fluoro-2-oxo-2, 3 -dihydro- 1 H-pyrimido[4, 5 , 6-de] quinazolin- 8-yl)methyl)piperazin-l-yl)-N-(2-hydroxyethyl)-6-methylpicolinamide;
  • 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.
  • 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).
  • 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.
  • 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, CCI3, CHCh, C2CI5 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 (i.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 (i.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. In some embodiments, 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-l,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”).
  • Example haloalkylene groups 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”).
  • cycloalkyl linking groups or “cycloalkylene groups” include cyclopropy-l,l,-diyl, cyclopropy-l,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 azetidin-l,2-diyl, azeti din- 1,3 -diyl, pyrrolidin- 1,2-diyl, pyrrolidin- 1,3 -diyl, pyrrolidin-2,3-diyl, piperidin-l,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.). 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.
  • 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.
  • 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.
  • 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.
  • ACN acetonitrile
  • Intermediates are prepared, for example, according to the procedures shown in Scheme I:
  • intermediate Int-3 is prepared by a process comprising reacting compounds of Formulae Int-1 and Int-2 under suitable conditions (e.g., nucleophilic aromatic substitution, Buchwald-Hartwig cross-coupling, Ullmann coupling, or Chan-Lam coupling).
  • intermediate Int-6 is prepared by a process comprising reacting compounds of Formulae Int-4 and Int-5 under suitable conditions (e.g., Suzuki, Stille, or Negishi coupling).
  • Compounds of Formula Int are prepared by treating intermediate Int-3 or Int-6 under suitable conditions (e.g., removal of PG).
  • Scheme I lnt-4 lnt-5 lnt-6
  • PG is a suitable protecting group (e.g., -Boc, -Cbz, or -SEM),
  • X lnt2 includes but is not limited to halogen, -B(OH) 2 , and -OTf
  • each of Z lnt4 and X lnts includes but is not limited to halogen, -OTf, -Bpin, -Sn(Bu) 3 , and -ZnBr,
  • Compounds of Formula I-A can be prepared, for example, according to the procedures shown in Scheme II. Reacting compound II-l and compound II-2 under reductive amination conditions in the presence of an appropriate reagent (e.g., a reducing agent such as NaBH(OAc)3 or NaBHsCN) followed by cyclization affords compound II-3, which can be converted to compound II-4 under suitable conditions (e.g., treating with triphosgene followed by NH4OH). Treating compound II-4 under suitable conditions (e.g., palladium-catalyzed cross-coupling) gives compound II-5. Compound II-6 is then prepared by treating compound II-5 under suitable conditions (e.g., Suzuki, Stille, or Negishi coupling). Finally, treating compound II-6 with Int affords compound of Formula I-A.
  • an appropriate reagent e.g., a reducing agent such as NaBH(OAc)3 or NaBHsCN
  • suitable conditions e.g., treating with triphosgene followed by
  • Compounds of Formula I-B can be prepared, for example, according to the procedures shown in Scheme III. Treating compound III-l with compound III-2 under suitable conditions (e.g., nucleophilic aromatic substitution, or Buchwald- Hartwig cross-coupling) affords compound III-3 which can be converted to compound III-4 under suitable conditions (e.g., palladium-catalyzed cross-coupling). Compound HI-4 can be subsequently converted into compound III-5 under suitable conditions (e.g., treating with NaH followed by 4-methoxybenzyl isocyanate). Compound III-6 is then prepared by treating compound III-5 under suitable conditions (e.g., Suzuki, Stille, or Negishi coupling). Finally, treating compound III-6 with Int affords compound of Formula I-B.
  • suitable conditions e.g., nucleophilic aromatic substitution, or Buchwald- Hartwig cross-coupling
  • suitable conditions e.g., palladium-catalyzed cross-coupling
  • Compound HI-4 can be subsequently converted into compound III
  • Compounds of Formula I-C can be prepared, for example, according to the procedures shown in Scheme IV.
  • Compound IV-3 is prepared by treating compound IV-2 with an appropriate reagent (e.g., 9-BBN) followed by cross-coupling with compound IV-1 under suitable conditions (e.g., PdCh(dppf)/K3PO4).
  • compound IV-3 is converted to compound IV-4 via removing Boc group followed by ring closing under suitable conditions (e.g., nucleophilic aromatic substitution, or Buchwald-Hartwig cross-coupling).
  • suitable conditions e.g., treating with NaH followed by 4-methoxybenzyl isocyanate
  • compound IV-4 can be converted into compound IV-5.
  • Compound IV-6 is then prepared by treating compound IV-5 under suitable conditions (e.g., Suzuki, Stille, or Negishi coupling). Finally, treating compound IV-6 with Int affords compound of Formula I-C.
  • 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 3 N, 6-Dimethy 1-5 -(piperazin- l-yl)picolinamide
  • Step 2 tert-Butyl 4-(6-(cyclopropylcarbamoyl)-2-methylpyridin-3-yl)piperazine-l- carboxylate Boc
  • the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 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 30% ethyl acetate in petroleum ether to give the desired product as a white solid (3.7 g, 69%).
  • Step 2 tert-Butyl 4-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)piper azine- 1- carboxylate Boc i
  • Step 2 4-Bromo-6-chloro-5-fluoro-lH-indazol-3-amine
  • 2-bromo-4-chloro-3,6-difluorobenzonitrile 7 g, 27.7 mmol
  • tert-butanol 70 mL
  • hydrazine hydrate 80% solution in water, 8.67 g, 138.7 mmol
  • the resulting mixture was stirred at 100 °C for 16 h.
  • the mixture was concentrated under reduced pressure.
  • the residue was triturated with ethyl acetate and filtered.
  • the solid was dried under vacuum to afford the desired product as a white solid (6.6 g, 91%).
  • LCMS calculated for CyHsBrClFNs (M-H)’ m/z 261.9; found 261.8.
  • Step 3 1 ()-Bromo-8-chloro-9-fluoro-l , 2, 3, 4-tetrahydropyrimido[ 1, 2-b ] indazole
  • Step 4 10-Bromo-8-chloro-9-fluoro-3, 4-dihydropyrimido[ 1, 2-b ] indazole- 1( 2H)- carboxamide
  • 10-bromo-8-chloro-9-fhioro-l,2,3,4-tetrahydropyrimido[l,2- b]indazole 400 mg, 1.31 mmol
  • A,A-dimethylpyridin-4-amine (16.05 mg, 0.13 mmol
  • triethylamine (2.66 g, 26.26 mmol
  • triphosgene (1.95 g, 6.57 mmol
  • Step 5 6-Chloro-7-fluoro-2,3-dihydro-lH-3a,4,8,9a- tetraazacyclopenta[def]phenanthren-9(8H)-one
  • Step 7 5-(4-((7-Fluoro-9-oxo-2,3,8,9-tetrahydro-lH-3a,4,8,9a- tetraazacyclopenta[def]phenanthren-6-yl)methyl)piperazin-l-yl)-N,6- dimethylpicolinamide
  • Step 4 2-((3-Bromo-5, 7-dichloro-6-fluoroquinolin-4-yl)amino)ethan-l-ol
  • Step 5 8,10-Dichloro-9-fluoro-2, 3-dihydro-lH-[ 1, 4 ]oxazino[ 2, 3-c ] quinoline
  • Step 7 6-Fluoro-7-(hydroxymethyl)-5-(4-methoxybenzyl)-2,3-dihydro-l-oxa-3a,5,9- triazapyren-4 ( 5H) -one
  • Step 8 5-( 4-(( 6-Fluoro-4-oxo-2, 3, 4, 5-tetrahydro-l-oxa-3a, 5, 9-triazapyren- 7- yl)methyl)piperazin-l-yl)-N,6-dimethylpicolinamide
  • Step 1 tert-Butyl (3-(4,5, 7-trichloro-6-fluoroquinolin-3-yl)propyl)carbamate
  • Step 3 8-Chloro-7-fluoro-6-(4-methoxybenzyl)-l,2,3, 6-tetrahydro-5H- [1,6 ] naphthyr idino[ 1, 8, 7-cde ]quinazolin-5-one
  • Step 4 7-Fluoro-8-(hydroxymethyl)-6-(4-methoxybenzyl)-l,2,3, 6-tetrahydro-5H- [1,6 ] naphthyr idino[ 1, 8, 7-cde ]quinazolin-5-one
  • Step 5 5-(4-((7-Fluoro-5-oxo-2, 3,5,6-tetrahydro-lH-[ 1 ,6]naphthyridino [ 1 ,8, 7- cde]quinazolin-8-yl)methyl)piperazin-l-yl)-N,6-dimethylpicolinamide
  • Step 1 2-Amino-4-bromo-6-fluorobenzonitrile
  • 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.
  • the reaction mixture was diluted with water (500 mL).
  • the precipitated solids were collected by filtration and washed with water (2 x 100 mL).
  • 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 7 3-Ethyl-9-fluoro-l-(4-methoxybenzyl)-8-vinyl-lH-pyrimido[4,5, 6- de ]quinazolin-2 ( 3H) -one
  • Step 8 3-Ethyl-9 -fluor o-l-(4-methoxybenzyl) -2 -oxo-2, 3-dihydro-lH-pyrimido[ 4, 5, 6- de ]quinazoline-8-carbaldehyde
  • Step 9 3-Ethyl-9-fluoro-2-oxo-2, 3-dihydro-lH-pyrimido[ 4, 5, 6-de ]quinazoline-8- carbaldehyde
  • 3 -ethyl -9-fluoro- 1 -(4-methoxybenzyl)-2-oxo-2 3 -dihydro- 1H- pyrimido[4,5,6-de]quinazoline-8-carbaldehyde (3.92 g, 10.31 mmol) was added trifluoroacetic acid (100.0 mL) at room temperature. The resulting mixture was stirred at 75 °C for 18 hours before cooling to room temperature.
  • Step 10 Methyl 5-(4-((3-ethyl-9 -fluor o-2-oxo-2, 3-dihydr o-lH-pyrimido [4,5,6- de]quinazolin-8-yl)methyl)piperazin-l-yl)-6-methylpicolinate
  • Step 11 5-( 4-(( 3-Ethyl-9-jluoro-2-oxo-2, 3-dihydr o-lH-pyrimido[ 4, 5, 6-de ]quinazolin- 8-yl)methyl)piperazin-l-yl)-6-methylpicolinic acid
  • Step 12 5-( 4-( 3-Ethyl-9-fluoro-2-oxo-2, 3-dihydro-lH-pyrimido[ 4, 5, 6-de ]quinazolin- 8-yl)methyl)piperazin-l-yl)-N-(2-hydroxyethyl)-6-methylpicolinamide
  • 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 4 8-(Bromomethyl)-3-ethyl-lH-pyrimido[ 4, 5, 6-de ]quinazolin-2(3H)-one
  • Step 5 Methyl 5-(4-((3-ethyl-2-oxo-2,3-dihydro-lH-pyrimido[4,5,6-de]quinazolin-8- yl)methyl)piperazin-l-yl)-6-methylpicolinate
  • Step 6 5-( 4-(( 3-Ethyl-2-oxo-2, 3-dihydro-lH-pyrimido[ 4, 5, 6-de ]quinazolin-8- yl)methyl)piperazin-l-yl)-6-methylpicolinic acid
  • Step 7 5-( 4-(( 3-Ethyl-2-oxo-2, 3-dihydro-lH-pyrimido[ 4, 5, 6-de ]quinazolin-8- yl)methyl)piperazin-l-yl)-N-(2-hydroxyethyl)-6-methylpicolinamide
  • Step 2 N-( 1 -(bromomethyl) cyclopropyl) -5 -( 4-( ( 3-ethyl-2-oxo-2, 3-dihydro-lH- pyrimido[ 4, 5, 6-de ]quinazolin-8-yl)methyl)piperazin-l-yl)-6-methylpicolinamide
  • Step 3 N-( I -(cyanomethyl)cyclopropyl)-5-( 4-( ( 3-ethyl-2-oxo-2, 3-dihydro-lH- pyrimido[ 4, 5, 6-de ]quinazolin-8-yl)methyl)piperazin-l-yl)-6-methylpicolinamide
  • Step 1 8-Bromo-3-cyclopropyl-l-(4-methoxybenzyl)-lH-pyrimido[4,5, 6- de ]quinazolin-2 ( 3H) -one
  • Step 2 3-Cyclopropyl-8-(hydroxymethyl)-l-(4-methoxybenzyl)-lH-pyrimido[4,5,6- de ]quinazolin-2 ( 3H) -one
  • Step 3 N-cyclopropyl-5-(4-((3-cyclopropyl-2-oxo-2,3-dihydro-lH-pyrimido[4,5, 6- de]quinazolin-8-yl)methyl)piperazin-l-yl)-6-methylpicolinamide
  • Step 2 2-( 8-Bromo-2-oxo-l , 2-dihydro-3H-pyrimido[ 4, 5, 6-de ]quinazolin-3- yl)acetonitrile
  • Step 4 2-( 8-Formyl-2-oxo-l , 2-dihydro-3H-pyrimido[ 4, 5, 6-de ]quinazolin-3- yl) acetonitrile
  • 2-(8-(J7ydroxymethyl)-2-oxo-l,2-dihydro-3JT- pyrimido[4,5,6-de]quinazolin-3-yl)acetonitrile 45 mg, 0.18 mmol
  • Dess-Martin periodinane (374 mg, 0.88 mmol)
  • sodium bicarbonate (30 mg, 0.35 mmol
  • Step 5 5-(4-((3-(Cyanomethyl)-2-oxo-2,3-dihydro-lH-pyrimido[4,5, 6-de]quinazolin- 8-yl)methyl)piperazin-l-yl)-N-cyclopropyl-6-methylpicolinamide
  • reaction mixture was purified by reversed-phase flash chromatography with the following conditions (Column: C18 silica gel; Mobile phase: acetonitrile in water (0.1% trifluoroacetic acid), Gradient: 10% to 50% in 25 min; Detector: 254 nm). Eluted fractions were collected and lyophilized to afford the TFA salt of the desired product as a white solid.
  • Example A In-Cell Western measurement of PARylation in PARP1 WT and knockout cells
  • 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.
  • 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

La présente invention concerne des composés, des compositions et des procédés utiles pour inhiber PARP1, et/ou traiter une maladie, un trouble ou un état associé à PARP1, tel que le cancer.
PCT/US2024/026578 2023-04-28 2024-04-26 Composés hétérocycliques en tant qu'inhibiteurs de parp1 WO2024227026A1 (fr)

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