WO2023205914A1 - Dérivés hétérocycliques tricycliques, compositions et utilisations de ceux-ci - Google Patents

Dérivés hétérocycliques tricycliques, compositions et utilisations de ceux-ci Download PDF

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Publication number
WO2023205914A1
WO2023205914A1 PCT/CN2022/000075 CN2022000075W WO2023205914A1 WO 2023205914 A1 WO2023205914 A1 WO 2023205914A1 CN 2022000075 W CN2022000075 W CN 2022000075W WO 2023205914 A1 WO2023205914 A1 WO 2023205914A1
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alkyl
compound
cycloalkyl
independently selected
optionally substituted
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PCT/CN2022/000075
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English (en)
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Zhangqi YU
Dan YAN
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Danatlas Pharmaceuticals Co., Ltd.
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Priority to PCT/CN2022/000075 priority Critical patent/WO2023205914A1/fr
Priority to PCT/CN2023/091076 priority patent/WO2023208092A1/fr
Priority to CN202380010595.6A priority patent/CN117157299B/zh
Priority to TW112115875A priority patent/TW202400597A/zh
Priority to US18/499,097 priority patent/US20240140954A1/en
Publication of WO2023205914A1 publication Critical patent/WO2023205914A1/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
    • C07D487/04—Ortho-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 relates to tricyclic heterocyclic derivatives as inhibitor of PARG.
  • the present disclosure also relates to methods for preparing the tricyclic heterocyclic derivatives, pharmaceutical compositions, and their uses in the treatment of diseases related to the activity of PARG including, e.g., cancers and other diseases.
  • DNA damage repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. But once a cancer has formed, DNA repair pathways become a double-edged sword because they promote the repair and survival of cancer cells in response to chemotherapies and radiotherapies. As a result, cancers with compromised DNA repair are susceptible to DNA damage and depend on complementary repair pathways which can be exploited therapeutically.
  • An aberrant DDR often can sensitize cancer cells to specific types of DNA damage, thus defective DDR can be developed into targeted cancer therapies.
  • Targeting DNA repair deficiencies has become a proven and effective strategy in cancer treatment. For example, the success of poly (ADP-ribose) polymerase (PARP) inhibitors in treating BRCA-deficient breast, ovarian, prostate and pancreatic cancers (Audeh MW et al., 2010) .
  • PARP poly (ADP-ribose) polymerase
  • Poly (ADP-ribosyl) ation is a unique posttranslational modification for maintaining genome stability through different molecular pathways, especially DNA repair (Kraus WL et al., 2015) .
  • the binding of PARP to the break and the rapid synthesis of poly ADP-ribose (PAR) on PARP itself is one of the earliest events during single strand DNA repair.
  • Current PARP inhibitors primarily suppress PARP1 and PARP2 enzymatic activities, which inhibits PARP1/2-dependent DNA repair. Recently, clinical resistance to PARP inhibitors has been described (Drost and Jonkers, 2014) (Barber LJ et al., 2013) (Tobalina L et al., 2021) and therefore alternative inhibitors targeting the DNA damage repair machinery are required.
  • PARylation is a transient posttranslational modification and is rapidly degraded by the enzyme PAR glycohydrolase (PARG) (Barkauskaite E et al., 2015) .
  • PARG PAR glycohydrolase
  • PARP When PARP is bound to PAR, its catalytic activity is reduced and therefore PARG activity helps to restore PARP to its catalytically active form (Curtin and Szabo, 2013) .
  • PARG Similar to PARPs, PARG also facilitates both DNA double-strand break (DSB) and single-strand break (SSB) repair (Mortusewicz O et al., 2011) .
  • DSB DNA double-strand break
  • SSB single-strand break
  • PARG impacts PAR signaling in RNA splicing, transcriptional and epigenetic regulation (Ji and Tulin 2009) (Le May N et al., 2012) (Dahl M et al. 2014) (Guastafierro T et al., 2013) (Caiafa P et al., 2009) .
  • Some evidence suggests that PARG depletion inhibits SSB repair and reduces survival of BRCA2-deficient cells (Fathers C et al., 2012) .
  • BRCA-ness may also cause sensitizing tumor cells to PARG inhibition.
  • PARG knock-down or depletion can sensitize lung, cervical and pancreatic cancer cells to irradiation or experimental DNA damaging agents (e.g. hydrogen peroxide, Methylmethanesulfonate) (Ame JC et al., 2009) (Nakadate Y et al., 2013) (Shirai H et al., 2013) .
  • agents e.g. gemcitabine, camptothecin
  • Cell permeable PARG inhibitors have been limited to compounds such as Tannic acid or Gallotannin or PDD00017273 which have low specificity for PARG and limited bioavailability (Sun Y et al., 2012) (Fathers C et al., 2012) (Blenn C et al., 2011) (James DI et al., 2016) .
  • An object of this invention is to provide cell permeable inhibitors of PARG.
  • the present disclosure relates to, inter alia, compounds of Formula (I) ,
  • a pharmaceutical composition comprising a compound of formula (I) , or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof and at least one pharmaceutically acceptable carrier.
  • a method of inhibiting PARG comprising:
  • a method of treating cancers and other diseases comprising administering to a patient a therapeutically effective amount of a compound of formula (I) , or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof.
  • compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect.
  • the present disclosure provides, inter alia, a compound of formula (I) :
  • X is O or NR 5 ;
  • Y 1 is N or CR 6 ;
  • Y 2 is N, or CR 7 , and only one of Y 1 or Y 2 is N;
  • Y 3 is N, or CR 8 ;
  • n 0, 1 or 2;
  • Cy 1 is a 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 R 9 ;
  • Cy 2 is independently selected from C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein, the C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl optionally substituted by 1, 2, 3, 4, or 5 R 10 ;
  • R 1 , R 2 and R 3 are each independently selected from H, D, CN, C (O) R B , C (O) NR C R D , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 7 cycloalkyl, or 4-7 membered heterocycloalkyl, wherein the C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 7 cycloalkyl, or 4-7 membered heterocycloalkyl is optionally substituted by 1-5 substituents independently selected from D, halo, CN, OH, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl;
  • R 2 and R 3 together with the carbon atom to which they are attached form a C 3 -C 7 cycloalkyl, or 4-7 membered heterocycloalkyl, wherein, the C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO 2 , oxo, OH, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl;
  • R 4 is selected from H, D, halo, OH, CN, NO 2 , SF 5 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, -O-C 1 -C 3 alkyl, or NR C R D ; wherein, the C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl is optionally substituted with halogen or CN;
  • R 5 is selected from H, D, CN, OR B , or C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with at least one of D, F, Cl, CN, NH 2 , OH, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted 4-7 membered heterocycloalkyl;
  • R 1 and R 5 together with the atoms to which they are attached is form a 5-7 membered partially saturated heterocycloalkyl, wherein, the 5-7 membered partially saturated heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halogen, CN, CF 3 , NO 2 , oxo, OH, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl;
  • R 8 is selected from H, D, CN, halo, OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, -O-C 1 -C 3 alkyl, -OC 1 -C 3 haloalkyl, C 1 -C 3 cyanoalkyl, or SF 5 ;
  • R 10 wherein two adjacent R 10 , together with the atoms to which they are attached, optionally form a C 3 -C 10 cycloalkyl or a 4-10 membered heterocycloalkyl, wherein, the C 3 -C 10 cycloalkyl or 4-10 membered heterocycloalkyl optionally substituted by l, 2, or 3 substituents independently selected from D, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 -cyanoalkyl, CN, NO 2 , oxo, OR a , SR a , SF 5 , NHOR a , C (O) R b , C (O) NR c R d , C (O) OR a , OC (O) R b , OC (O) NR c R d
  • Cy 3 is independently selected from optionally substituted C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl;
  • C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, of any of the R 6 , R 7 , R 9 and R 10 can be unsubstituted or substituted with 1, 2, or 3 R 11 ;
  • each R 11 is independently selected from H, D, halo, CN, NO 2 , N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, OC 1 -C 6 alkylOH, OC 1 -C 6 alkyl-O-C 1 -C 6 alkyl, CN, OR a1 , SR a1 , SF 5 , NHOR a1 , C (O) R b1 , C (O) NR c1 R d1 , C (O) OR a1 , OC (O) OR a1 , OC (O) R b1 , OC (O) NR c1 R d1 , NR c1 R d1 , NR c1 C (O) R b1 , NR c1 C (O) NR c1 R d1
  • C 3 -C 7 cycloalkyl of R 9 can be unsubstituted or substituted with 1, 2, 3 or 4 R 12 ;
  • each R 12 is independently selected from D, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, CN, NO 2 , N 3 , OR a1 , SR a1 , SF 5 , NHOR a1 , C (O) R b1 , C (O) NR c1 R d1 , C (O) OR a1 , OC (O) R b1 , OC (O) NR c1 R d1 , NR c1 R d1 , NR c1 C (O) R b1 , NR c1 C (O) NR c1 C (O) R b1 , NR c1 C (O) NR c
  • R A is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D,
  • R B is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D,
  • R C and R D are each independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN,
  • R C and R D together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, oxo, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , halo, or C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, or OC 1 -C 4 haloalkyl;
  • R a and R a1 are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1
  • R b and R b1 are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D,
  • R c and R d are each independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl; wherein the C 1 -4 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, C 6 -C 10 aryl, 5-10 membered hetero
  • R c and R d together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 cyanoalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C (O) OR a1 , C (O) R b1 , S (O) 2 R b1 , C 1 -C 4 alkoxy-C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-C 1 -
  • R c1 and R d1 are each independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; wherein the C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalky
  • R c1 and R d1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, and C 1 -4 haloalkoxy;
  • R E , R e and R e1 are each independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, (C 1 -C 4 alkoxy) -C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 alkyl;
  • R F , R f and R f1 are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, or 4-10 membered heterocycloalkyl.
  • X is O or NR 5 . In some embodiments, X is O. In other embodiments, X is NR 5 .
  • Y 1 is N or CR 6 . In some embodiments, Y 1 is N; In other embodiments, Y 1 is CR 6 .
  • Y 2 is N or CR 6 . In some embodiments, Y 2 is N; In other embodiments, Y 2 is CR 7 ;
  • only one Y 1 or Y 2 is N. In some embodiments, Y 1 is N, and Y 2 is CR 7 . In other embodiments, Y 1 is CR 6 , and Y 2 is N. In yet other embodiments, Y 1 is CR 6 , and Y 2 is CR 7 .
  • Y 3 is N or CR 8 . In some embodiments, Y 3 is N. In other embodiments, Y 3 is CR 8 .
  • n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
  • each R 1 , R 2 and R 3 is independently selected from H, D, CN, C (O) R B , C (O) NR C R D , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 7 cycloalkyl, or 4-7 membered heterocycloalkyl, wherein the C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl is optionally substituted by 1-5 substituents independently selected from D, halo, CN, OH, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.
  • each R 1 , R 2 and R 3 is independently selected from H, D, CN, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 7 cycloalkyl, or 4-7 membered heterocycloalkyl, wherein the C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 7 cycloalkyl, or 4-7 membered heterocycloalkyl is optionally substituted by 1-5 substituents independently selected from D, halo, CN, OH, OMe, OCF 3 , OEt.
  • R 1 is C (O) R B . In embodiments, R 1 is PrC (O) -. In embodiments, R 1 is C (O) Et. In embodiments, R 1 is C (O) Me.
  • R 1 is C (O) NR C R D . In embodiments, R 1 is C (O) NMe 2 .
  • R 1 is independently selected from H, D, CN, CH 3 , CH 2 CH 3 , CH 2 F or CH 2 CH 2 F.
  • R 1 is independently selected from CN, CH 3 , CH 2 CH 3 , CH 2 F or CH 2 CH 2 F. In embodiments, R 1 is CH 2 F. In embodiments, R 1 is CH 3 . In embodiments, R 1 is CN.
  • R 2 and R 3 are each independently selected from C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 7 cycloalkyl, or 4-7 membered heterocycloalkyl, wherein the C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl is optionally substituted by 1-5 substituents independently selected from D, halo, CN, OH, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.
  • R 2 and R 3 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl, or 4-7 membered heterocycloalkyl, wherein, the C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO 2 , oxo, OH, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.
  • R 2 and R 3 together with the carbon atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO 2 , oxo, OH, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.
  • R 2 and R 3 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO 2 , oxo, OH, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.
  • R 2 and R 3 together with the carbon atom to which they are attached form a cyclobutyl. In embodiments, R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl.
  • each R 4 is independently selected from H, D, halo, OH, CN, NO 2 , SF 5 , C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, -OC 1 -C 3 alkyl, or NR C R D ; wherein, the C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl is optionally substituted with halogen or CN.
  • each R 4 is independently selected from H, D, OH, CN, NO 2 , SF 5 , halo, C 1 -C 3 alkyl optionally substituted with halogen or CN.
  • each R 4 is independently selected from H, D, halo, C 1 -C 3 alkyl.
  • each R 4 is independently selected from H, D, halo. In embodiments, each R 4 is independently selected from H, D, F, or Cl.
  • each R 5 is H, D, CN, OR B , or C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with at least one of D, F, Cl, CN, NH 2 , OH, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted 4-7 membered heterocycloalkyl.
  • R 5 is H. In embodiments, R 5 is D. In embodiments, R 5 is CN. In embodiments, R 5 is OR B . In embodiments, R 5 is C 1 -C4 alkyl, wherein said that C 1 -C 4 alkyl is optionally substituted with at least one of D, F, Cl, CN, NH 2 , OH, OMe, OCF 3 . In embodiments, R 5 is optionally substituted C 3 -C 7 cycloalkyl. In embodiments, R 5 is optionally substituted 4-7 membered heterocycloalkyl.
  • R 1 and R 5 together with the atoms to which they are attached form a 5-to 7-membered partially saturated heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halogen, CN, CF 3 , NO 2 , oxo, OH, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.
  • R 1 and R 5 together with the atoms to which they are attached form a 5-to 7-membered partially saturated heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halogen, CN, CF 3 , oxo, OH, OMe, OCF 3 , OEt.
  • each R 6 is independently H, D. F, Cl, OH, CN, NO 2 , or SF 5 .
  • R 6 is F.
  • R 6 is D.
  • R 6 is H.
  • R 6 is OR A .
  • R 6 is SR A .
  • R 6 is C 1 -C 6 alkyl, for example, -CH 3 .
  • R 6 is C 1 -C 6 haloalkyl, for example, -CF 3 .
  • R 6 is C 2 -C 6 alkenyl.
  • R 6 is C 2 -C 6 alkynyl.
  • R 6 is B (OR C ) (OR D ) , for example, B (OH) 2 .
  • R 6 is NHOR A .
  • R 6 is NR C R D .
  • each R 7 is independently H, D. F, Cl, OH, CN, NO 2 , or SF 5 .
  • R 7 is F.
  • R 7 is D.
  • R 7 is H.
  • R 7 is OR A .
  • R 7 is SR A .
  • R 7 is C 1 -C 6 alkyl, for example, -CH 3 .
  • R 7 is C 1 -C 6 haloalkyl, for example, -CF 3 .
  • R 7 is C 2 -C 6 alkenyl.
  • R 7 is C 2 -C 6 alkynyl.
  • R 7 is B (OR C ) (OR D ) , for example, B (OH) 2 .
  • R 7 is NHOR A .
  • R 7 is NR C R D .
  • each R 8 is selected from H, D, CN, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl, or SF 5 .
  • R 8 is selected from H, D, F, Cl, OH, CN, CF 3 , OMe, OCF 3 , or SF 5 .
  • R 8 is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl -O-C 1 -C 6 alkyl, or -OC 1 -C 6 haloalkyl.
  • R 8 is H. In some embodiments, R 8 is D. In some embodiments, R 8 is F. In some embodiments, R 8 is Cl. In some embodiments, R 8 is OH. In some embodiments, R 8 is CN. In some embodiments, R 8 is CF 3 . In some embodiments, R 8 is OMe. In some embodiments, R 8 is OCF 3 . In some embodiments, R 8 is SF 5 .
  • Cy 1 is a 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 R 9 ;
  • Cy 1 is 6 membered heteroaryl optionally substituted by 1, 2, 3, or 4 R 9 ,
  • Cy 1 is 5 membered heteroaryl optionally substituted by 1, 2, or 3 R 9 , wherein, the 5 membered heteroaryl is independently selected from:
  • Cy 1 is 5 membered heteroaryl optionally substituted by 1 or 2 R 9 , wherein, the 5 membered heteroaryl is independently selected from:
  • Cy 1 is 5 membered heteroaryl optionally substituted by 1 or 2 R 9 , wherein, the 5 membered heteroaryl is
  • Cy 1 is 5 membered heteroaryl optionally substituted by 1 or 2 R 9 , wherein, the 5 membered heteroaryl is
  • R 9 is independently H. In some embodiments, R 9 is independently D. In some embodiments, R 9 is independently halo. In some embodiments, R 9 is independently CN. In some embodiments, R 9 is independently NO 2 . In some embodiments, R 9 is independently N 3 . In some embodiments, R 9 is independently OR A . In some embodiments, R 9 is independently SR A . In some embodiments, R 9 is independently SF 5 . In some embodiments, R 9 is independently NHOR A . In some embodiments, R 9 is independently C (O) R B . In some embodiments, R 9 is independently C (O) NR C R D . In some embodiments, R 9 is independently C (O) OR A .
  • each R 9 is independently C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl. In some embodiments, each R 9 is C 1 -C 6 alkyl. In other embodiments, each R 9 is C 2 -C 6 alkenyl. In yet other embodiments, each R 9 is independently C 2 -C 6 alkynyl. In yet other embodiments, each R 9 is independently C 1 -C 6 haloalkyl.
  • each R 9 is independently optionally substituted C 3 -C 7 cycloalkyl.
  • Cy 2 is independently selected from C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, wherein, the C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 R 10 .
  • Cy 2 is C 6 -C 10 aryl optionally substituted by 1, 2, or 3 R 10 .
  • Cy 2 is 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 R 10 .
  • Cy 2 is C 3 -C 10 cycloalkyl optionally substituted by 1, 2, or 3 R 10 .
  • Cy 2 is 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 R 10 .
  • each R 10 is independently C 1 -C 6 alkyl. In yet other embodiments, each R 10 is independently C 2 -C 6 alkenyl. In yet other embodiments, each R 10 is independently C 2 -C 6 alkynyl. In yet other embodiments, each R 10 is independently C 1 -C 6 haloalkyl. In yet other embodiments, each R 10 is independently C 1 -C 6 cyanoalkyl. In yet other embodiments, each R 10 is independently Cy 3 . In yet other embodiments, each R 10 is independently C 1 -C 6 alkyl-Cy 3 . In yet other embodiments, each R 10 is independently OCy 3 . In yet other embodiments, each R 10 is independently O-C 1 -C 6 alkyl-Cy 3 .
  • two adjacent R 10 together with the atoms to which they are attached form a C 3 -C 10 membered cycloalkyl or a 4-10 membered heterocycloalkyl, wherein, the C 3 -C 10 membered cycloalkyl or 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 substituents independently selected from D, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 -cyanoalkyl, CN, NO 2 , oxo, OR a , SR a , SF 5 , NHOR a , C (O) R b , C (O) NR c R d , C (O) OR a , OC (O) R b , OC (O) NR c R d ,
  • two adjacent R 10 together with the atoms to which they are attached form a C 3 -C 10 membered cycloalkyl optionally substituted by 1, 2, or 3 substituents independently selected from D, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 -cyanoalkyl, CN, NO 2 , oxo, OR a , SR a , SF 5 , NHOR a , C (O) R b , C (O) NR c R d , C (O) OR a , OC (O) R b , OC (O) NR c R d , NR c R d , NR c C (O) R b , NR c C (O) NR c R d , NR c C (O) R b
  • two adjacent R 10 together with the atoms to which they are attached form a 4-10 membered heterocycloalkyl optionally substituted by 1, 2, or 3 substituents independently selected from D, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 -cyanoalkyl, CN, NO 2 , oxo, OR a , SR a , SF 5 , NHOR a , C (O) R b , C (O) NR c R d , C (O) OR a , OC (O) R b , OC (O) NR c R d , NR c R d , NR c C (O) R b , NR c C (O) NR c R d , NR c C (O) OR , NR c
  • each Cy 3 is independently selected from optionally substituted C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl. In some embodiments, Cy 3 is optionally substituted C 6 -C 10 aryl. In some embodiments, Cy 3 is optionally substituted phenyl. In some embodiments, Cy 3 is optionally substituted 5-10 membered heteroaryl. In some embodiments, Cy 3 is optionally substituted pyrimidinyl. In some embodiments, Cy 3 is optionally substituted pyridazinyl. In some embodiments, Cy 3 is optionally substituted pyrazinyl. In other embodiments, Cy 3 is optionally substituted pyrazolyl.
  • Cy 3 is optionally substituted 3-10 membered cycloalkyl. In other embodiments, Cy 3 is optionally substituted cyclohexanyl. In other embodiments, Cy 3 is optionally substituted cyclopentyl. In other embodiments, Cy 3 is optionally substituted cyclobutyl. In other embodiments, Cy 3 is optionally substituted cyclopropyl.
  • Cy 3 is optionally substituted 4-10 membered heterocycloalkyl. In some embodiments, Cy 3 is 4-methylpiperazin-1-yl.
  • each R 11 is independently selected from H, D, halo, CN, NO 2 , N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, CN, OR a1 , SR a1 , SF 5 , NHOR a1 , C (O) R b1 , C (O) NR c1 R d1 , C (O) OR a1 , OC (O) OR a1 , OC (O) R b1 , OC (O) NR c1 R d1 , NR c1 R d1 , NR c1 C (O) R b1 , NR c1 C (O) NR c1 R d1 ,
  • each R 11 is independently selected from H, D, halo, CN, NO 2 , N 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C (O) R b1 , C (O) NR c1 R d1 , S (O) 2 R b1 , C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl.
  • each R 12 is independently selected from D, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, CN, NO 2 , N 3 , OR a1 , SR a1 , SF 5 , NHOR a1 , C (O) R b1 , C (O) NR c1 R d1 , C (O) OR a1 , OC (O) R b1 , OC (O) NR c1 R d1 , NR c1 R d1 , NR c1 C (O) R b1 , NR c1 C (O) NR c1 C (O) R b1 , NR c1 C (O) OR a1
  • each R 12 is independently selected from D, halo, CN, NO 2 , N 3 , OR a1 , SR a1 , SF 5 , or NHOR a1 .
  • each R 12 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylOH, C 1 -C 6 alkyl-O-C 1 -C 6 alkyl, C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl.
  • R A is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently
  • R A is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, wherein the C 1 -C 6 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C 1 -C 4 alkyl, NO 2 , oxo, OR a , SR a , SF 5 , NHOR a , C (O) R b , C (O) NR c R d , C (O) OR a , OC (O) R b , OC (O) NR c R d , NR c R d , NR c C (O) R b , NR c C (O) NR c R d , NR c C (O) R b
  • R A is independently selected from C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl wherein the C 3 -C 10 cycloalkyl, 4-10 membered heterocyclalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C 1 -C 4 alkyl, NO 2 , oxo, OR a , SR a , SF 5 , NHOR a , C (O) R b , C (O) NR
  • R B is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents
  • R B is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, SF 5 , C (O) R b , OC (O) NR c R d , NR
  • R B is C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, SF 5 , C (O) R b , OC (O) NR c R d , NR c R d , NR c C (O) R b , NR c C (O) NR c R d , NR c C (O) OR a , S (O) R b , S (O) NR b , S
  • R B is C 2 -C 6 alkenyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, SF 5 , C (O) R b , OC (O) NR c R d , NR c R d , NR c C (O) R b , NR c C (O) NR c R d , NR c C (O) OR a , S (O) R b , S (O) NR c
  • R B is C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, SF 5 , C (O) R b , OC (O) NR c R d , NR c R d , NR c C (O) R b , NR c C (O) NR c R d , NR c C (O) OR a , S (O) R b , S (O) NR c R
  • R B is C 3 -C 10 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, SF 5 , C (O) R b , OC (O) NR c R d , NR c R d , NR c C (O) R b , NR c C (O) NR c R d , NR c C (O) OR a , S (O) R b , S (O) NR
  • R B is C 3 -C 10 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl.
  • R B is isopropyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl.
  • R B is cyclobutyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl.
  • R B is cycylopentyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl.
  • R B is cycylohexanyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl.
  • R B is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, SF 5 , C (O) R b , OC (O) NR c R d , NR c R d , NR c C (O) R b , NR c C (O) NR c R d , NR c C (O) OR a , S (O) R b , S (O) NR b , S
  • R B is azetidinyl, pyrrolidinyl, piperidinyl or azepanyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 haloalkyl, C (O) R b , OC (O) NR c R d , NR c R d , NR c C (O) R b , NR c C (O) NR c R d , NR c C (O) OR a , S (O)
  • R B is C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C 6 -C 10 aryl, 5-10 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 1 -C 4 alkyl-O-C 1 -C 4 alkyl, C 1 -C 4 alkyl-O-C 1 -C 4 halo
  • R C and R D are each independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH
  • R C is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN,
  • R D is independently selected from H, D, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN,
  • R C and R D together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, oxo, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, OC 1 -C 4 alkyl, or OC 1 -C 4 haloalkyl.
  • each R E is independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, (C 1 -C 4 alkoxy) -C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 alkyl.
  • each R F is independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl.
  • each R a is independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl; wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1
  • each R b is independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH
  • R c and R d are each independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, or biheteroaryl; wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 6 -C 10 aryl, 5-10 membered
  • R c and R d together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 cyanoalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C (O) OR a1 , C (O) R b1 , S (O) 2 R b1 , C 1 -C 4 alkoxy-C 1 -C 4 alkyl, and C 1 -C 4 alkoxy-
  • each R e is each independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, (C 1 -C 4 alkoxy) -C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 alkyl.
  • each R f is independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl.
  • each R a1 is independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1
  • each R b1 is independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D,
  • R c1 and R d1 are each independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; wherein the C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl,
  • R c1 and R d1 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, and C 1-4 haloalkoxy.
  • each R e1 is each independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, (C 1 -C 4 alkoxy) -C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 alkyl.
  • each R f1 is independently selected from H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl.
  • the compounds of Formula (I) are the pharmaceutically acceptable salts. In some embodiments, the compounds of Formula (I) are stereoisomers. In some embodiments, the compounds of Formula (I) are solvates. In some embodiments, the compounds of Formula (I) are N-oxides of the compounds of Formula (I) .
  • the compounds of Formula (I) are represented by compounds of Formula (II) :
  • each R 1 , R 2 , R 3 , R 4 , Cy 1 , Cy 2 , X, Y 1 , Y 2 and Y 3 are defined with respect to Formula (I) .
  • the compounds of Formula (I) are represented by compounds of Formula (IIa) and (IIb) :
  • each R 1 , R 2 , R 3 , R 4 , R 5 , Cy 1 , Cy 2 , Y 1 , Y 2 and Y 3 are defined with respect to Formula (I) .
  • the compounds of Formula (I) are represented by compounds of Formula (IIIa) and (IIIb) :
  • each R 1 , R 2 , R 3 , R 5 , Cy 1 , Cy 2 , Y 1 , Y 2 and Y 3 are defined with respect to Formula (I) .
  • the compounds of Formula (I) are represented by compounds of Formula (IV) :
  • each R 1 , R 2 , R 3 , R 8 , X, Cy 1 , Cy 2 , X, Y 1 , and Y 2 are defined with respect to Formula (I) .
  • X in Formula (IV) is independently NR 5 . In some embodiments, X in Formula (IV) is independently O.
  • each R 8 is selected from H, D, F, Cl, OH, CN, CF 3 , OMe, OCF 3 , or SF 5 .
  • R 8 is H.
  • R 8 is D.
  • R 8 is F.
  • R 8 is Cl.
  • R 8 is OH.
  • R 8 is CN.
  • R 8 is CF 3 .
  • R 8 is OMe.
  • R 8 is OCF 3 .
  • R 8 is SF 5 .
  • the compounds of Formula (I) are represented by compounds of Formula (IVa) or (IVb) :
  • each R 1 , R 2 , R 3 , R 5 , R 8 , Cy 1 , Cy 2 , Y 1 , and Y 2 are defined with respect to Formula (I) .
  • Cy 1 in Formula (IVa) is independently selected from 5-6 membered heteroaryl, each optionally substituted by 1, 2, 3, or 4 R 9 . In some embodiments, Cy 1 in independently optionally substituted 6 membered heteroaryl. In some embodiments, Cy 1 in independently optionally substituted 5 membered heteroaryl.
  • Cy 1 in Formula (IVb) is independently selected from 5-6 membered heteroaryl, each optionally substituted by 1, 2, 3, or 4 R 9 . In some embodiments, Cy 1 in independently optionally substituted 6 membered heteroaryl. In some embodiments, Cy 1 in independently optionally substituted 5 membered heteroaryl.
  • the compounds of Formula (I) are represented by compounds of Formula (Va) , (Vb) , or (Vc) :
  • Cy 1 in Formula (Va) , (Vb) , or (Vc) is independently selected from 5-6 membered heteroaryl, each optionally substituted by 1, 2, 3, or 4 R 9 . In some embodiments, Cy 1 in independently optionally substituted 6 membered heteroaryl. In some embodiments, Cy 1 in independently optionally substituted 5 membered heteroaryl.
  • Cy 1 is 6 membered heteroaryl optionally substituted by 1, 2, 3, or 4 R 9 .
  • Cy 1 is 5 membered heteroaryl optionally substituted by 1, 2, or 3 R 9 , wherein, the 5 membered heteroaryl is independently selected from:
  • Cy 1 is 5 membered heteroaryl optionally substituted by 1 or 2 R 9 , wherein, the 5 membered heteroaryl is independently selected from:
  • Cy 1 is 5 membered heteroaryl optionally substituted by 1 or 2 R 9 , wherein, the 5 membered heteroaryl is
  • Cy 1 is 5 membered heteroaryl optionally substituted by 1 or 2 R 9 , wherein, the 5 membered heteroaryl is
  • the compounds of Formula (I) are represented by compounds of Formula (VI) :
  • Cy 1 is a 5 membered heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein, the 5 membered heteroaryl optionally substituted by 1, 2, 3, or 4 R 9 ;
  • each R 1 , R 2 , R 3 , R 9 , Cy 2 , X, Y 1 , and Y 2 are defined with respect to Formula (I) .
  • the compounds of Formula (I) are represented by compounds of Formula (VIa) or (VIb) :
  • Cy 1 is a 5 membered heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein, the 5 membered heteroaryl optionally substituted by 1, 2, 3, or 4 R 9 ; each R 1 , R 2 , R 3 , R 5 , R 9 , Cy 2 , Y 1 , and Y 2 are defined with respect to Formula (I) .
  • the compounds of Formula (I) are represented by compounds of Formula (VII) :
  • each R 1 , R 2 , R 3 , R 8 , R 9 , Cy 2 , X, Y 1 , and Y 2 are defined with respect to Formula (I) .
  • X is NR 5 . In some embodiments of Formula (VII) , X is O.
  • the compounds of Formula (I) are represented by compounds of Formula (VIIa) or (VIIb) :
  • each R 1 , R 2 , R 3 , R 5 , R 8 , R 9 , Cy 2 , Y 1 , and Y 2 are defined with respect to Formula (I) .
  • the compounds of Formula (I) are represented by compounds of Formula (VIIIa) , (VIIIb) , or (VIIIc) :
  • each R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , and Cy 2 are defined with respect to Formula (I) .
  • the compounds of Formula (I) are represented by compounds of Formula (IXa) , (IXb) , or (IXc) :
  • each R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , and Cy 2 are defined with respect to Formula (I) .
  • Stereoisomers of the compounds of Formula I, and the pharmaceutical salts and solvates thereof, are also contemplated, described, and encompassed herein. Methods of using compounds of Formula I are described, as well as pharmaceutical compositions including the compounds of Formula I.
  • the compound of Formula (I) is:
  • the compounds of Formula I may have multiple stereogenic centers.
  • the present disclosure contemplates and encompasses each stereoisomer of any compound of Formula I (and subgenera described herein) , as well as mixtures of said stereoisomers.
  • the present disclosure further provides compounds described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.
  • the present disclosure further provides uses 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.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the PARG inhibitors of the present disclosure may be useful in the treatment of various types of cancer, including but not limited to breast, ovarian, gastric, prostate, pancreatic, uterine, cervical, endometrial, lung, brain, bile duct and hematological cancers.
  • Routs of administration for the compounds in the present disclosure include, but not limited to oral, injection, topical and inhalation.
  • the compounds of the present disclosure may be used as single agent or combined with other treatments.
  • Such treatment may include one or more of the following categories of cancer therapies: such as surgery, chemotherapies, radiation therapies, targeted therapy (for example kinase inhibitors, growth factor inhibitors, cyclin dependent kinase inhibitors and so on) , other DDR modulators (for example DNA-PK inhibitor, ATM inhibitor, ATR inhibitor, CHK 1 inhibitor, WEE 1 inhibitor, CDK 1 inhibitor, LIG4 inhibitor, HIF-1 inhibitor, HDAC inhibitor, RAD51 inhibitor, Pol ⁇ inhibitor, WRN inhibitor, PRMT5 inhibitor, MAT2A inhibitor and PKMYT1 inhibitor and so on) , immunotherapies, and gene and cell therapy approaches.
  • cancer therapies such as surgery, chemotherapies, radiation therapies, targeted therapy (for example kinase inhibitors, growth factor inhibitors, cyclin dependent kinase inhibitors and so on) , other DDR modulators (for example DNA-PK inhibitor, ATM inhibitor, ATR inhibitor, CHK
  • each linking substituent include both the forward and backward forms of the linking substituent.
  • -NR (CR′R) -includes both -NR (CR′R") -and - (CR′R”) NR-and is intended to disclose each of the forms individually.
  • the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the "alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • substituted means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group.
  • substituted refers to any level of substitution, e.g., mono-, di-, tri-, tetra-or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency.
  • optionally substituted means unsubstituted or substituted.
  • 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.
  • Cn-Cm indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons.
  • C 1 -C 6 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • C 0 alkyl refers to a covalent bond.
  • stable refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
  • alkyl by itself or as part of another substituent, is meant to refer to a saturated hydrocarbon group which is straight-chained or branched.
  • An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • C 1-8 as in C 1-8 alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched arrangement.
  • Example alkyl groups include, but are not limited to, methyl (Me) , ethyl (Et) , propyl (e.g., n-propyl and isopropyl) , butyl (e.g., n-butyl, isobutyl, t-butyl) , pentyl (e.g., n-pentyl, isopentyl, neopentyl) , and the like.
  • Me methyl
  • Et ethyl
  • propyl e.g., n-propyl and isopropyl
  • butyl e.g., n-butyl, isobutyl, t-butyl
  • pentyl e.g., n-pentyl, isopentyl, neopentyl
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • Example alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.
  • alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
  • Example alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include, but are not limited to, CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.
  • aryl refers to an unsubstituted or substituted monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. In some embodiments, aryl groups have from 6 to about 14 carbon atoms. In some embodiments, aryl groups have from 6 to about 10 carbon atoms.
  • Example aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like.
  • cycloalkyl refers to an unsubstituted or substituted non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups.
  • Cycloalkyl groups can include mono-or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including fused rings, spirocyclic rings, and bridged rings (e.g., a bridged bicycloalkyl group) .
  • cycloalkyl groups can have from 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms.
  • Cycloalkyl groups can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2 triple bonds. Cycloalkyl groups can be optionally substituted by oxo or sulfido (e.g., -C (O) -or -C (S) -) . Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of pentane, pentene, hexane, and the like. A cycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent.
  • the cycloalkyl is a C 3 -C 7 monocyclic cycloalkyl.
  • the cycloalkyl is a C 4 -C 10 spirocycle or bridged cycloalkyl.
  • Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatfienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo [1.1.1] 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.
  • cycloalkyl are cyclic-containing, non-aromatic hydrocarbon groups having from 3 to 12 carbon atoms ( “C 3 -C 12 ” ) , preferably from 3 to 6 carbon atoms ( “C 3 -C 6 ” ) .
  • cycloalkyl groups include, for example, cyclopropyl (C 3 ; 3-membered) , cyclobutyl (C 4 ; 4-membered) , cyclopropylmethyl (C 4 ) , cyclopentyl (C 5 ) , cyclohexyl (C 6 ) , 1-methylcyclopropyl (C 4 ) , 2-methylcyclopentyl (C 4 ) , adamantanyl (C 10 ) , and the like.
  • spirocycloalkyl when used alone or as part of a substituent group refers to a non-aromatic hydrocarbon group containing two cycloalkyl rings, and wherein the two cycloalyl rings share a single carbon atom in common.
  • heteroaryl refers to an unsubstituted or substituted aromatic heterocycle having at least one heteroatom ring member such as boron, sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety.
  • heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1, 2, 4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like.
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
  • heterocycloalkyl refers to an unsubstituted or substituted monocyclic (saturated or partially unsaturated ring) 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 ring-forming carbon atoms and heteroatoms of the 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.
  • Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3-10, 4-10, 3-7, 4-7, and 5-6 membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., a 5-10 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 moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic 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 ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms.
  • the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom.
  • 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.
  • Example heterocycloalkyl groups include, but are not limited to, pyrrolidin-2-one, 1, 3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, 1, 2, 3, 4- tetrahydroisoquinoline, azabicyclo [3.1.0] hexanyl, diazabicyclo [3.1.0] hexanyl, oxabicyclo [2.1.1] hexanyl, azabicyclo [2.2.1
  • heterocycloalkyl refers to any three to ten membered monocyclic or bicyclic, saturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S.
  • the heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
  • heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and the like.
  • the term “spiroheterocycloalkyl” when used alone or as part of a substituent group refers to a non-aromatic group containing two rings, at least one of which is a heterocycloalkyl ring, and wherein the two rings share a single carbon atom in common.
  • arylcycloalkyl refers to cycloalkyl group substituted by an aryl group.
  • arylheterocycloalkyl refers to a heterocycloalkyl group substituted by an aryl group.
  • arylheteroaryl refers to a heteroaryl group substituted by an aryl group.
  • biasing refers to an aryl group substituted by another aryl group.
  • heteroarylcycloalkyl refers to a cycloalkyl group substituted by a heteroaryl group.
  • heteroarylheterocycloalkyl refers to a heterocycloalkyl group substituted by a heteroaryl group.
  • heteroarylaryl refers to an aryl group substituted by a heteroaryl group.
  • heteroaryl refers to a heteroaryl group substituted by another heteroaryl group.
  • halo or “halogen” includes fluoro, chloro, bromo, and iodo.
  • alkoxy refers to an -O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) , t-butoxy, and the like.
  • hydroxylalkyl refers to an alkyl group substituted by OH.
  • cyanoalkyl refers to an alkyl group substituted by CN.
  • alkoxyalkyl refers to an alkyl group substituted by an alkoxy group.
  • alkoxyalkoxy refers to an alkoxy group substituted by alkoxy.
  • haloalkoxy refers to an -O- (haloalkyl) group.
  • arylalkyl refers to alkyl substituted by aryl and “cycloalkylalkyl” refers to alkyl substituted by cycloalkyl.
  • An example arylalkyl group is benzyl.
  • heteroarylalkyl refers to alkyl substituted by heteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted by heterocycloalkyl.
  • substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent (s) .
  • substituents include, but are not limited to, D, halo, oxo, C 1 -C -6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-NR c1 R d1 , - (CH 2 CH 2 O) o C 1 -C 6 alkyl wherein o is 1-10; C 2-6 alkenyl-NR c1 R d1 , C 2-6 alkynyl-NR c1 R d1 , OC 2-6 alkyl-NR c1 R d1 , CN, NO 2 , N 3 , OR a1 , SR a1 , C (O) R b
  • 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.
  • 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, amide-imidic acid pairs, enamine -imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H-and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H-and 2H-isoindole, and 1H-and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • the compounds of the present disclosure may exist as rotational isomers. Descriptions of a compound of the invention that do not indicate a particular rotational isomer are intended to encompass any individual rotational isomers, as well as mixtures of rotational isomers in any proportion. Depiction of a particular rotational isomer is meant to refer to the depicted rotational isomer, substantially free of other rotational isomers.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • the compounds of the invention, and salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99%by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • the present disclosure 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, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17 th 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.
  • 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.
  • a “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • a “solvate” refers to a physical association of a compound of Formula I with one or more solvent molecules.
  • Subject includes humans.
  • the terms “human, ” “patient, ” and “subject” are used interchangeably herein.
  • Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
  • “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
  • “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • isotopic variant refers to a compound that contains proportions of isotopes at one or more of the atoms that constitute such compound that is greater than natural abundance.
  • an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non-radioactive isotopes such as for example, deuterium ( 2 H or D) , carbon-13 ( 13 C) , nitrogen-15 ( 15 N) , or the like.
  • any hydrogen may be 2 H/D
  • any carbon may be 13 C
  • any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • isomers compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers. ” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers, ” for example, diastereomers, enantiomers, and atropisomers.
  • the compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R) -or (S) -stereoisomers at each asymmetric center, or as mixtures thereof.
  • compositions comprising compounds of Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof or prodrugs thereof, and a pharmaceutically acceptable carrier.
  • compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) , for injection use (for example as aqueous or oil suspensions, or emulsions, with sesame oil, com oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles) , for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions) , for administration by inhalation (for example as a finely divided powder or a liquid aerosol) , for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intrave
  • compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • An effective amount of a compound of Formula (I) or a pharmaceutically salt thereof for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0. 1 mg to 1000 mg of Formula (I) or a pharmaceutically salt thereof with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • compositions and methods for preparing the same are non-limiting exemplary pharmaceutical compositions and methods for preparing the same.
  • the compounds of Formula (I) or a pharmaceutically salt thereof or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action) .
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion) ; buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc. ) ; transmucosal (including, e.g., by a patch, plaster, etc.
  • intranasal e.g., by nasal spray
  • ocular e.g., by eye drops
  • pulmonary e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose
  • rectal e.g., by suppository or enema
  • vaginal e.g., by pessary
  • parenteral for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subeutieular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
  • the method typically comprises administering to a subject a therapeutically effective amount of a compound of the invention.
  • the therapeutically effective amount of the subject combination of compounds may vary depending upon the intended application (in vitro or in vivo) , or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of proliferation or downregulation of activity of a target protein.
  • the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • IC 50 refers to the halfmaximal inhibitory concentration of an inhibitor in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular inhibitor is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50%IC, or IC 50 ) .
  • the subject methods utilize a PARG inhibitor with an IC 50 value of about or less than a predetermined value, as ascertained in an in vitro assay.
  • the PARG inhibitor inhibits PARG with an IC 50 value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM
  • the subject methods are useful for treating a disease condition associated with PARG. Any disease condition that results directly or indirectly from an abnormal activity or expression level of PARG can be an intended disease condition.
  • PARG has been implicated, for example, auto-immune diseases, neurodegeneration (such as Parkinson’s disease) , cardiovascular disease (such as ischaemia stroke and myocardial infarction) , inflammatory diseases (such as septic shock) , diabetes, and cancer such as, for example, breast, ovarian, gastric, prostate, pancreatic, uterine, cervical, endometrial, lung, brain, bile duct and hematological cancer.
  • neurodegeneration such as Parkinson’s disease
  • cardiovascular disease such as ischaemia stroke and myocardial infarction
  • inflammatory diseases such as septic shock
  • diabetes and cancer
  • cancer such as, for example, breast, ovarian, gastric, prostate, pancreatic, uterine, cervical, endometrial, lung, brain, bile duct and hematological cancer.
  • Non-limiting examples of such conditions include but are not limited to breast cancer, Invasive duct. al carcinoma, Invasive lobular carcinoma, Paget′s disease of the breast, Hereditary breast-ovarian cancer syndrome, Medullary breast cancer, Mucinous breast cancer, Inflammatory breast cancer, Ovarian Cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Gastric Cancer, Gastric lymphoma, Gastrointestinal cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor, Prostate cancer, Acinar adenocarcinoma of prostate, Prostatic ductal adenocarcinoma, Prostate sarcoma, Small cell prostate cancer, Squamous cell prostate cancer, Pancreatic Cancer, Exocrine pancreatic cancer, Neuroendocrine pancreatic cancer, Uterine cancer, Uterine sarcoma, Uterine corpus sarcoma, Cervical
  • said method is for treating a disease selected from the group consisting of tumor angiogenesis, auto-immune diseases, neurodegeneration (such as Parkinson’s disease) , cardiovascular disease (such as ischaemia stroke and myocardial infarction) , inflammatory diseases (such as septic shock) , diabetes, and cancer such as, for example, breast, ovarian, gastric, prostate, pancreatic, uterine, cervical, endometrial, lung, brain, bile duct and hematological cancer.
  • a disease selected from the group consisting of tumor angiogenesis, auto-immune diseases, neurodegeneration (such as Parkinson’s disease) , cardiovascular disease (such as ischaemia stroke and myocardial infarction) , inflammatory diseases (such as septic shock) , diabetes, and cancer such as, for example, breast, ovarian, gastric, prostate, pancreatic, uterine, cervical, endometrial, lung, brain, bile duct and hematological cancer.
  • said method is for treating a disease selected from breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, uterine cancer, or cervical cancer.
  • said method is for treating a disease selected from leukemia such as acute myeloid leukemia (AML) , acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML) , mastocytosis, chronic lymphocytic leukemia (CLL) , multiple myeloma (MM) , myelodysplastic syndrome (MDS) or epidermoid cancer.
  • AML acute myeloid leukemia
  • CML chronic lymphocytic leukemia
  • CLL chronic lymphocytic leukemia
  • MDS myelodysplastic syndrome
  • Medical therapies include, for example, surgery and radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioactive isotopes) .
  • radiotherapy e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioactive isotopes
  • compounds of the disclosure as well as pharmaceutical compositions comprising them, can be administered to treat any of the described diseases, alone or in combination with one or more other agents.
  • the compounds of the disclosure as well as pharmaceutical compositions comprising them, can be administered in combination with agonists of nuclear receptors agents.
  • the compounds of the disclosure as well as pharmaceutical compositions comprising them, can be administered in combination with antagonists of nuclear receptors agents.
  • the compounds of the disclosure as well as pharmaceutical compositions comprising them, can be administered in combination with an anti-proliferative agent.
  • the compounds of the present invention may be used as a single agent or combined with other treatments.
  • Such treatment may include one or more of the following categories of cancer therapies: such as surgery, chemotherapies, radiation therapies, targeted therapy (for example growth factor inhibitors, kinase inhibitors, cyclin dependent kinase inhibitors and so on) , other DDR modulators (for example DNA-PK inhibitor, ATM inhibitor, ATR inhibitor, CHK1 inhibitor, WEE1 inhibitor, CDK1 inhibitor, LIG4 inhibitor, HIF-1 inhibitor, HDAC inhibitor, RAD51 inhibitor, Pol ⁇ inhibitor, WRN inhibitor, PRMT5 inhibitor, MAT2A inhibitor and PKMYT1 inhibitor and so on) , immunotherapies, and gene and cell therapy approaches.
  • cancer therapies such as surgery, chemotherapies, radiation therapies, targeted therapy (for example growth factor inhibitors, kinase inhibitors, cyclin dependent kinase inhibitors and so on) , other DDR modulators (for example DNA-PK inhibitor, ATM inhibitor, ATR inhibitor,
  • the compounds of the invention can be used in combination with a medical therapy such as surgery, radiotherapy or chemotherapy.
  • a medical therapy such as surgery, radiotherapy or chemotherapy.
  • radiotherapies include gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes.
  • chemotherapeutic agents include one or more of the following categories of anti-tumor agents: other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas) ; antimetabolites (for example gemcitabine and antifolates such as fluoropyrimi dines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea) ; antitumor antibiotics (for example anthracyclines like bleomycin, doxorubicin, daunomycin, epimbicin, idarubicin, mitomycin-C, dactinomycin and mithramycin)
  • the compounds of the invention can be used in combination with targeted therapies, including inhibitors of growth factor function (for example the anti-erbB2 antibody trastuzumab, the anti-EGFR antibody panitumumab, the anti-erbB antibody cetuximab and any growth factor or growth factor receptor antibodies disclosed by Stem et al. (Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors (for example inhibitors of the EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib and Cl 1033) , erbB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib; inhibitors of serine/threonine kinases (for example Ras/Raf inhibitors such as sorafenib, tipifamib and lonafamib) ; inhibitors of cell proliferation through MEK and/or AKT kinases; c-kit inhibitors; abl kinase inhibitors; PI3 kinase inhibitors; Fit3 kinase inhibitors, CSF-IR
  • 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 non-reactive 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 is described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007) ; Robertson, Protecting Group Chemistry, (Oxford University Press, 2000) ; Smith el ah, March′s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007) ; Peturssion et al, "Protecting Groups in Carbohydrate Chemistry, " J Chem. Educ., 1997, 74 (11) , 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006) .
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g., UV-visible) , or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g., UV-visible) , or mass spectrometry
  • 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.
  • a series of tricyclic derivatives of formula 1-7 to 1-13 can be prepared by the methods outlined in Scheme 1.
  • Compounds 1-3 where t and s are an integer (e.g., 2, 3, or 4) can be prepared by reactions of compounds 1-1 where W 1 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) with a suitable amine derivative 1-2 in the presence of a base such as Hunig’s base.
  • halogen e.g., Cl, Br, or I
  • pseudohalogen e.g., OTf or OMs
  • a palladium catalyst such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3 and a base, such as t-Bu
  • Removal of the Boc group in compounds 1-5 to compounds 1-6 can be achieved by the treatment with acid such as TFA in DCM, HCl in dioxane or other acidic media.
  • acid such as TFA in DCM, HCl in dioxane or other acidic media.
  • a base e.g., hunig’s base or K 2 CO 3
  • Tricyclic derivatives of formula 2-2 to 2-4 can be prepared by the methods outlined in Scheme 2.
  • Tricyclic derivatives 2-2 can be prepared by N-alkylation with a suitable reagent R 10 -W where W is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) under alkylation conditions (e.g., in the presence of a base, such as Hunig’s base, NaH, t-BuOK, t-BuONa, Cs 2 CO 3 , or K 2 CO 3 ) .
  • halogen e.g., Cl, Br, or I
  • pseudohalogen e.g., OTf or OMs
  • tricyclic derivatives 2-3 can be obtained by reductive amination with an aldehyde, ketone or cyclic ketone R 10a C (O) R 10b , where R 10a and R 10b are selected from H or alkyl or R 10a and R 10b together with the carbon atom to which they are attached is a C 3 -C 10 eycloalkyl, or 4-10 membered heterocycloalkyl, under standard reductive amination’s conditions (e.g., in the presence of a reductive reagent, such as NaBH (OAc) 3 , or NaBH 3 CN) .
  • a reductive reagent such as NaBH (OAc) 3 , or NaBH 3 CN
  • a series of tricyclic derivatives of formula 3-5 to 3-9 can be prepared by the methods outlined in Scheme 3.
  • a palladium catalyst such as [1, 1′-bis(diphenylphosphino) fer
  • compounds 3-1 can be coupled with R 10 -Ar-M (e.g., Ar is aryl or heteroaryl; M is B (OH) 2 , Bpin, BF 3 K, Sn (Me) 3 , Sn (Bu) 3 , or ZnCl 2 ) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as Xanphos Pd, or [1, 1 ′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K 3 PO 4 ) , or standard Negishi conditions (e.g., in the presence of a palladium catalyst, such as tetrakis (triphenylphosphine) palladium (0) or [1, 1 ′-bis (diphenylphosphino) -ferrocene] dichloropalladium (II) ) , or standard Stille conditions (e.g., in the presence of
  • R 10 group in compounds 3-7 is a carbonate ester group
  • it can be saponified to acid 3-8 under basic conditions in the presence of a base such as LiOH, NaOH or KOH.
  • a base such as LiOH, NaOH or KOH.
  • Coupling of compounds 3-8 with amines R c R d NH 3-4 under standard amide coupling conditions e.g., in the presence of a coupling reagent, such as BOP, PyBOP, HATU or HBTU, and a base, such as Et3N or Hunig’s base
  • a coupling reagent such as BOP, PyBOP, HATU or HBTU
  • a base such as Et3N or Hunig’s base
  • a series of tricyclic intermediates of formula 4-7 can be prepared by the methods outlined in Scheme 4.
  • Sulfonamides 4-3 can be prepared by reaction of the sulfonyl chloride 4-1 with an amine 4-2 in the presence of a base such as Hunig’s base. Coupling of the sulfonamides 4-3 with 2-cyanoacetamide in the presence of a base, such as NaH, t-BuONa, or t-BuOK can afford compounds 4-4 which can be transformed into indole derivatives 4-5 by the nitro group with a reductive reagent such as Zn/FeCl 3 in acid media or Fe/NH 4 Cl followed the ring closure under the reaction conditions.
  • a base such as Hunig’s base.
  • Treatment of the indole derivatives 4-5 with trialkyl orthoformate 4-6 in the presence of an acid such as p-TsOH, or HCl can form the desired product indole-pyrimidone 4-7 which can be transformed into the intermediates 4-8 where W 1 is halogen (e.g., Cl, or Br) or pseudohalogen (e.g., OTf or OMs) either by reaction with a halogenation reagent such as SOCl 2 , POCl 3 or POBr3 with or without the catalytic of DMF (where W 1 is Cl or Br) or reaction with TfCl or MsCl (where W 1 is OTf or OMs) in the presence of a base such as Hunig’s base.
  • W 1 is halogen (e.g., Cl, or Br) or pseudohalogen (e.g., OTf or OMs) either by reaction with a halogenation reagent such as SOCl 2 , POCl 3 or PO
  • a series of tricyclic intermediates of formula 5-8 can be prepared by the methods outlined in Scheme 5. Coupling of compounds 5-1 where W 2 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) , and W 3 is halogen (e.g., Br, or I) or pseudohalogen (e.g., OTf ) with compounds 5-2 under Buchwald coupling conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3 and a base, such as t-BuOK, t-BuONa, Cs 2 CO 3 , or K 2 CO 3 ) , followed by ring closure by intra-molecular Heck reaction under the standard Heck reaction conditions (e.g., in the presence of a palladium catalyst, such as dichlorobis (triphenylphosphine
  • Reaction of the sulfonyl chlorides 5-4 with an amine 5-5 in the presence of a base such as Hunig’s base can produce the sulfonamides 5-6 which can be transformed into 5-7 by oxidative reagents such as hydrogen peroxide, oxone, and m-chloroperbenzoic acid.
  • the compound 5-7 can be converted into the intermediates 5-8 where W 1 is halogen (e.g., Cl, or Br) or pseudohalogen (e.g., OTf or OMs) by reaction with a halogenation reagent such as SOCl 2 , POCl 3 or POBr 3 or reaction with TfCl or MsCl in the presence of a base such as Hunig’s base.
  • Tricyclic compounds 6-3 can be obtained in the similar way as describes in scheme 5 for the tricyclic compounds 5-3 by reaction with a suitable aniline 6-2.
  • the removal of benzyl group in compounds 6-3 to the corresponding OH compounds 6-4 can be achieved by hydrogenation in the presence of a catalyst, such as Pd/C or Pd (OH) 2 /C.
  • oxidation of compounds 6-6 with oxidation reagents such as N-chlorosuccinimide, sodium hypochlorite can form the sulfonyl chloride 6-7 which then can be transformed into the desired intermediates 6-10 by reaction with a suitable amine 6-8 in the presence of a base, such as Hunig’s base, Na 2 CO 3 , or K 2 CO 3 , followed by removal of the protecting group Tf in the products 6-9 under basic conditions such as NaOH, or KOH.
  • a base such as Hunig’s base, Na 2 CO 3 , or K 2 CO 3
  • a series of tricyclic intermediates of formula 7-3 and 7-5 can be prepared by the methods outlined in the scheme 7.
  • the compounds 7-3 and 7-5 can be prepared by Buchwald coupling compounds 7-1 where W 2 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) , with compounds 7-2 and 7-4, respectively under standard conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3 and a base, such as t-BuOK, t-BuONa, Cs 2 CO 3 , or K 2 CO 3 ) , followed by intramolecular ring closure in the presence of a Lewis acid, such as AlCl 3 , ZnCl 2 or other acidic media such as polyphosphoric acid, POCl 3 .
  • a Lewis acid such as AlCl 3 , Z
  • a series of tricyclic intermediates of formula 8-3 and 8-5 can be prepared by the methods outlined in the scheme 8.
  • the compounds 8-3 and 8-5 can be prepared by Buchwald coupling compounds 8-1 where W 3 is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) , with compounds 8-2 and 8-5, respectively under standard conditions (e.g., in the presence of a palladium catalyst, such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3 and a base, such as t-BuOK, t-BuONa, Cs 2 CO 3 , or K 2 CO 3 ) , followed by ring closure by intramolecular Heck reaction under the standard reaction condition (e.g., in the presence of a palladium catalyst, such as dichlorobis (triphenylphosphine) palladium, palladium diacetate,
  • a series of tricyclic intermediates of formula 9-7 where A is O or S can be prepared by the methods outlined in the scheme 9.
  • the compounds 9-3 can be prepared by nucleophile alkylation of compound 9-1 where W 2 is halogen (e.g., F, Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) , with 2-cyanoacetate 9-2 where R is alkyl (e.g., Me, Et or t-Bu) in the presence of a strong base, such as t-BuOK, t-BuONa, NaH) .
  • halogen e.g., F, Cl, Br, or I
  • pseudohalogen e.g., OTf or OMs
  • Reduction of the nitro group in 9-3 can be achieved by treatment with a reductive reagent such as Zn dust, or Fe powder in acidic conditions (such as acetic acid or HCl) , followed by intramolecular ring closure to produce compounds 9-4.
  • a reductive reagent such as Zn dust, or Fe powder in acidic conditions (such as acetic acid or HCl)
  • acidic conditions such as acetic acid or HCl
  • Heating the mixture of compounds 9-4 with an acetal 9-5 bearing alfa-H in the presence of a base such as NaOMe or NaOEt can yield tricyclic compounds 9-6.
  • Halogenation of compounds 9-6 can provide the desired intermediates 9-7 (where W 1 is Cl or Br) with a halogenation reagent such as SOCl 2 , POCl 3 or POBr3 or 9-7 (where W 1 is OTf or OMs) with TfCl or MsCl in the presence of a base such as Hunig’s base.
  • a halogenation reagent such as SOCl 2 , POCl 3 or POBr3 or 9-7 (where W 1 is OTf or OMs) with TfCl or MsCl in the presence of a base such as Hunig’s base.
  • Example 1 4- (4- (Cyclopropanecarbonyl) piperazin-1-yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Step 1 4- (4- (cyclopropanecarbonyl) piperazin-1-yl) -N- (1-methylcyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Step 2 4- (4- (cyclopropanecarbonyl) piperazin-1 -yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2 -yl) -N- (1-methylcyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Step 1 tert-butyl 4- (1-methylcyclobutane-1-carbonyl) piperazine-1-carboxylate
  • Step 3 N- (1-cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (1-methylcyclobutane-1-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Step 1 (R) -cyclobutyl (2-methylpiperazin-1-yl) methanone
  • Step 2 (R) -N- (1-cyanocyclopropyl) -4- (4- (cyclobutanecarbonyl) -3-methylpiperazin-1-yl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Example 6 4- (7- (N- (1-Cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indoi-4-yl) -N, N-dimethylpiperazine-1-earboxamide
  • Example 7 4- (7- (N- (1-Cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indol-4-yl) -N-ethyl-N-methylpiperazine-1-earboxamide
  • Step 1 tert-butyl 4- (ethyl (methyl) carbamoyl) piperazine-1-carboxylate
  • Step 3 4- (7- (N- (1-Cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indol-4-yl) -N-ethyl-N-methylpiperazine-1-carboxamide
  • Example 8 N- (1-Cyanocyelopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (morpholine-4-carbonyl) piperazin-1-yl) -9H-pyrimido [4, S-b] indole-7-sulfonamide
  • Example 9 N- (1-Cyanoeyelopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (4-methylpiperazine-1-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Example 10 N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (1-methylcyclopropane-1-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • This compound was prepared as HCl salt using procedures analogous to those described for Example 4 step 1-2 using 1-methylcyclopropane-1-carboxylic acid and reft-butyl piperazine-1-carboxylate in step 1.
  • Step 2 N- (1-cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (1-methylcyclopropane-1-carbonyl) piperazin-1 -yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Example 12 N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (tetrahydro-2H-pyran-4-carbonyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Example 13 N- (1-Cyanoeyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (4-fluorobenzoyl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Example 14 N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4-picolinoylpiperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfontamide
  • Example 15 Isopropyl 4- (7- (N- (1-cyanocyclopropyl) sulfamoyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -9H-pyrimido [4, 5-b] indol-4-yl) piperazine-1-carboxylate
  • Example 16 N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (thiazol-2-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Example 17 N- (1-Cyanocyelopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (pyridin-2-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Example 18 N- (1-Cyanocyclopropyl) -9- (5- (diflu orom ethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (pyrimidin-2-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Example 19 N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (4- (pyridazin-3-yl) piperazin-1-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Example 20 N- (1-Cyanocyclopropyl) -9- (5- (difluoromethyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-oxa-7-azaspiro [3.5] nonan-7-yl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Step 1 4-chloro-N- (1-cyanocyclopropyl) -3-nitrobenzenesulfonamide
  • the reaction mixture was poured into ice-water (500 mL) , and adjusted to pH ⁇ 3 with aq. HCl solution (1 N) at 0 ⁇ 5 °C.
  • the aqueous phase was extracted with ethyl acetate (300 mL x 3) .
  • the combined organic layers were washed with brine (500 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the residue was triturated with MTBE (100 mL) at 20 °C for 2 hrs.
  • Step 2 2-cyano-2- (4- (N- (1-cyanocyclopropyl) sulfamoyl) -2-nitrophenyl) acetamide
  • Step 3 2-amino-6- (N- (1-cyanocyclopropyl) sulfamoyl) -1H-indole-3-carboxamide
  • Step 4 N- (1-cyanocyclopropyl) -4-oxo-4, 9-dihydro-3 H-pyrimido [4, 5-b] indole-7-sulfonamide
  • Step 5 4-chloro-N- (1-cyanocyclopropyl) -9H-pyrimido [4, 5-b] indole-7-sulfonamide
  • HTRF assay was used to measure the ability of compounds to inhibit the activity of PARG in vitro.
  • C-terminal His6-tag PARG expressed in E. coli was purified and stored at -80°C in aliquots.
  • Assay measurements were performed with 1 ⁇ buffer comprising 50 mM Tris pH 7.4, 0.1 mg/mL BSA, 3 mM EDTA, 0.4 mM EGTA, 1 mM DTT, 50 mM KCl and 0.01%Tween 20.
  • HTRF signal of low control was calculated and as Positive control (PC) .
  • %Inhibition (Signal cmpd -Signal Ave_VC ) / (Signal Ave_PC -Signal Ave_VC ) ⁇ 100.
  • IC 50 values were determined by fitting the data to the standard 4 parameters with Hill Slope using GraphPad Prism software.
  • HC high control
  • LC low control
  • %inhibition (Signal Ave_HC -Signal cmpd ) / (Signal Ave_HC -Signal Ave_LC ) ⁇ 100.
  • IC 50 values were determined by fitting the data to the standard 4 parameters with Hill Slope using GraphPad Prism software.

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Abstract

L'invention concerne des dérivés hétérocycliques tricycliques tels que représentés dans la formule (I), des compositions pharmaceutiques les comprenant, un procédé pour leur préparation et leur utilisation en tant qu'agents thérapeutiques.
PCT/CN2022/000075 2022-04-28 2022-04-28 Dérivés hétérocycliques tricycliques, compositions et utilisations de ceux-ci WO2023205914A1 (fr)

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PCT/CN2022/000075 WO2023205914A1 (fr) 2022-04-28 2022-04-28 Dérivés hétérocycliques tricycliques, compositions et utilisations de ceux-ci
PCT/CN2023/091076 WO2023208092A1 (fr) 2022-04-28 2023-04-27 Dérivés hétérocycliques tricycliques, compositions et utilisations de ceux-ci
CN202380010595.6A CN117157299B (zh) 2022-04-28 2023-04-27 三环杂环衍生物及其组合物和应用
TW112115875A TW202400597A (zh) 2022-04-28 2023-04-27 三環雜環衍生物，其組合物和應用
US18/499,097 US20240140954A1 (en) 2022-04-28 2023-10-31 Tricyclic heterocyclic derivatives, compositions and uses thereof

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DOMINIC I. JAMES, KATE M. SMITH, ALLAN M. JORDAN, EMMA E. FAIRWEATHER, LOUISE A. GRIFFITHS, NICOLA S. HAMILTON, JAMES R. HITCHIN, : "First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib", ACS CHEMICAL BIOLOGY, vol. 11, no. 11, 18 November 2016 (2016-11-18), pages 3179 - 3190, XP055496287, ISSN: 1554-8929, DOI: 10.1021/acschembio.6b00609 *
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