WO2024041440A1 - Tricyclic heterocyclic derivatives, compositions and uses thereof - Google Patents

Tricyclic heterocyclic derivatives, compositions and uses thereof Download PDF

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Publication number
WO2024041440A1
WO2024041440A1 PCT/CN2023/113479 CN2023113479W WO2024041440A1 WO 2024041440 A1 WO2024041440 A1 WO 2024041440A1 CN 2023113479 W CN2023113479 W CN 2023113479W WO 2024041440 A1 WO2024041440 A1 WO 2024041440A1
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Prior art keywords
alkyl
cycloalkyl
independently selected
membered heterocycloalkyl
aryl
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PCT/CN2023/113479
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French (fr)
Inventor
Dan YAN
Huixian CHEN
Wenlai Zhou
Yan Zhang
Zhangqi YU
Jincong Zhuo
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Danatlas Pharmaceuticals Co., Ltd.
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Publication of WO2024041440A1 publication Critical patent/WO2024041440A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the present disclosure relates to tricyclic heterocyclic derivatives as inhibitor of PKMYT1.
  • 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 PKMYT1 including, e.g., cancers and other diseases.
  • Cell cycle is the essential way for cell division and growth regardless of either healthy cells or tumor cells.
  • the cell cycle can be divided into four phases: pre-DNA synthesis (G1 phase) , DNA synthesis (Sphase) , post-DNA synthesis (G2 phase) , and mitosis (M phase) .
  • G1 phase pre-DNA synthesis
  • Sphase DNA synthesis
  • G2 phase post-DNA synthesis
  • M phase mitosis
  • the progressions of cells from G1-phase into S-phase and G2-phase into M-phase are very important stages for the repair of DNA damage as well as complex and active changes of various substances in cell.
  • Cells set a series of cell-cycle checkpoints during the four phases to ensure the integrity of DNA replication and the completion of damage repair (Kevin J. Barnum, 2014) .
  • PKMYT1 The Protein Kinase, Membrane Associated Tyrosine/Threonine 1 (PKMYT1) is a cell cycle regulating protein which belongs to WEE family of kinases. PKMYT1 blocks the progression of cells from G2-phase into M-phase of the cell cycle through negatively regulating CDK1-Cyclin B complex. In the process of DNA damage repair, PKMYT1 phosphorylates CDK1 protein at amino acid sites of Tyr15 and Thr14 to maintain CDK1-Cyclin B complex in an inactive state in G2-phase and finally prevent cells entry into mitosis (Dongjun Jeong, 2018) , which provides enough time for DNA damage repair. At the same time, Wee1 also involve in the CDK1 phosphorylation at amino acid site of Tyr15. PKMYT1 knockdown or inhibition can prompt cells to enter mitosis prematurely without completing DNA damage repair, leading to cell death.
  • CCNE1 amplification can disrupt the regulation of cell entry into S phase, trigger DNA replication stress, and cause genome instability.
  • CCNE1 amplification is prevalent in multiple tumor types, particularly in high-grade serous ovarian cancer, uterine tumor and gastro-oesophageal cancers, ranging in frequency from 5-40%.
  • Cyclin E1 encoded by the CCNE1 gene, promotes the transition of the cell cycle from G1-phase to S-phase by binding and activating cyclin-dependent protein kinase 2 (CDK2) .
  • PKMYT1 inhibitors can be used to treat tumors with certain genetic alterations using a synthetic lethality therapeutic strategy.
  • the invention provides compounds, pharmaceutical compositions containing the same, methods of preparing the compounds, and methods of use.
  • Compounds of the invention may be used to inhibit PKMYT1 in a cell with CCNE1 amplification, FBXW7 loss-of-function mutations or other genetic alterations driving DNA replication stress and genome instability in G1 to S phase progression.
  • the subject may be in need of a treatment for a disease or condition, e.g., a disease or condition having a symptom of cell hyperproliferation, e.g., a cancer.
  • the PKMYT1 inhibitory activity of the compounds disclosed herein is useful for treating a subject in need of a treatment for cancer.
  • the present disclosure relates to, inter alia, compounds of Formula (IA) and (IB) ,
  • composition comprising a compound of formula (IA) and (IB) , or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, Isotopic variants or prodrugs thereof and at least one pharmaceutically acceptable carrier.
  • a method of inhibiting PKMYT1 comprising:
  • a method of treating cancers and other diseases comprising administering to a patient a therapeutically effective amount of a compound of formula (IA) and (IB) , or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, Isotopic variants 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 (IA) and (IB) :
  • ring A is selected from:
  • X is N or CR 3 ;
  • Y is N or CR 9 ;
  • L is (CR 10 R 11 ) n , NR 12 (CH 2 CH 2 ) m , or O (CH 2 CH 2 ) m ;
  • R is selected from H, D or C 1 -C 6 alkyl optionally substituted with F, OH or CN;
  • R 1 , R 2 and R 3 are each independently selected from H, D, halo, CN, SF 5 , NR C R D , OR A , C (O) R B , C (O) NR C R 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alky
  • each R 4 is independently selected from H, D, NH 2 , CN, C 1 -C 3 alkyl optionally substituted with D, halogen or CN;
  • each R 5 is independently selected from H, D, halo, CN, C 1 -C 6 alkyl optionally substituted with D, halogen or CN;
  • each R 6 is independently selected from H, D, halo, CN, OR B , SF 5 , C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl; wherein, the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl is optionally substituted with D, halo, CN, NH 2 , OH, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl;
  • each R 7 is independently selected from H, D, halogen, Me, CF 3 , OH, OMe, OCF 3 ;
  • each R 8 is independently selected from H, D, CN, SF 5 , C 1 -C 6 alkyl optionally substituted with D, halogen or CN;
  • R 9 is selected from H, D, CN, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 3 -C 5 cycloalkyl;
  • R 10 and R 11 are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl; wherein the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, CN, halo, OR a , 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 , NR c S (O) 2 R b , or NR c S (O) 2 NR c R d ;
  • R 10 and R 11 together with the carbon atom (s) 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, OR 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 a , S (O) NR c R d , S (O) 2 R b , NR c S (O) 2
  • R 12 is H, D, C 1 -C 3 alkyl optionally substituted with D, OH, halogen, CN;
  • each R A 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; 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 heterocyclalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6
  • each 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; 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, C
  • 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; 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, C 6 -C 10 ary
  • 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;
  • 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 -C 4 halo
  • 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, 4-7 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; 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, 4-7 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -
  • 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl, C 6 -C 10 aryl-C 3 -C 10 cycloalkyl, C 6 -C 10 aryl-4-10 membered heterocycloalkyl, C 6 -C 10 aryl-5-10 membered heteroaryl, C 6 -C
  • 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 -
  • 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, 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, or 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 -C 4 hal
  • 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, 4-7 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alky; 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, 4-7 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -
  • R is selected from H, D or C 1 -C 6 alkyl optionally substituted with F, OH or CN. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is C 1 -C 6 alkyl optionally substituted with F, OH or CN. In some embodiments, R is Me.
  • X is N.
  • X is CR 3 .
  • R 3 is independently selected from H, D, halo, CN, SF 5 , NR C R D , OR A , C (O) R B , C (O) NR C R 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; wherein, the C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cyclo
  • R 3 is independently selected from H, D, halo, CN, SF 5 , NR C R D , OR A , C (O) R B , C (O) NR C R D , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl 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 ,
  • R 3 is independently selected from H, D, halo, CN, SF 5 , NH 2 , OH, OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 , N (CH 3 ) 2 , CH 3 , CH 2 CH 3 , CF 3 , CH 2 CF 3 , C (O) R B , or C (O) NR C R D .
  • Y is N.
  • Y is CR 9
  • R 9 is selected from H, D, CN, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, C 3 -C 5 cycloalkyl.
  • R 9 is H. In some embodiments, R 9 is D. In some embodiments, R 9 is CN. In some embodiments, R 9 is halogen (such as F, Cl, Br, I) . In some embodiments, R 9 is C 1 -C 4 alkyl. In some embodiments, R 9 is C 1 -C 4 haloalkyl. In some embodiments, R 9 is OC 1 -C 4 alkyl. In some embodiments, R 9 is OC 1 -C 4 haloalkyl. In some embodiments, R 9 is C 3 -C 5 cycloalkyl.
  • R 1 is independently selected from H, D, halo, CN, SF 5 , NR C R D , OR A , C (O) R B , C (O) NR C R 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; wherein, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl
  • L is (CR 10 R 11 ) n , NR 12 (CH 2 CH 2 ) m , or O (CH 2 CH 2 ) m .
  • L is (CR 10 R 11 ) n . In some embodiments, L is CR 10 R 11 . In some embodiments, L is (CR 10 R 11 ) 2 . In some embodiments, L is (CR 10 R 11 ) 3 .
  • L is NR 12 (CH 2 CH 2 ) m . In some embodiments, L is NR 12 . In some embodiments, L is NR 12 CH 2 CH 2 .
  • L is O (CH 2 CH 2 ) m . In some embodiments, L is O. In some embodiments, L is OCH 2 CH 2 .
  • R 1 is independently selected from H, D, halo, CN, SF 5 , NR C R D , OR A , C (O) R B , C (O) NR C R D , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocycloalkyl; wherein, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocycloalkyl 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 ,
  • R 1 is independently selected from H, D, halo, CN, SF 5 , OH, NH 2 , OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 , N (CH 3 ) 2 , CH 3 , CH 2 CH 3 , CF 3 , CH 2 CF 3 , C (O) R B , C (O) NR C R D .
  • R 2 is independently selected from H, D, halo, CN, SF 5 , NR C R D , OR A , C (O) R B , C (O) NR C R D , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-10 membered heterocycloalkyl; wherein, the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl or 4-10 membered heterocycloalkyl 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 ,
  • R 2 is independently selected from H, D, halo, CN, SF 5 , NR C R D , OR A , C (O) R B , C (O) NR C R D , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocycloalkyl; wherein, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, 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
  • R 2 is independently selected from H, D, halo, CN, SF 5 , OH, NH 2 , OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 , N (CH 3 ) 2 , CH 3 , CH 2 CH 3 , CF 3 , CH 2 CF 3 , C (O) R B , C (O) NR C R D .
  • each R 4 is independently selected from H, D, NH 2 , or CN. In some embodiments, R 4 is H. In some embodiments, R 4 is D. In some embodiments, R 4 is NH 2 . In some embodiments, R 4 is CN.
  • R 4 is C 1 -C 3 alkyl optionally substituted with D, halogen or CN. In some embodiments, R 4 is Me. In some embodiments, R 4 is CD 3 . In some embodiments, R 4 is CF 3 .
  • each R 5 is independently selected from H, D, halo, CN or C 1 -C 6 alkyl optionally substituted with D, halogen or CN.
  • R 5 is H. In some embodiments, R 5 is D. In some embodiments, R 5 is halo (such as F, Cl, Br, I) . In some embodiments, R 5 is CN. In some embodiments, R 5 is C 1 -C 6 alkyl optionally substituted with D, halogen or CN.
  • each R 5 is independently selected from H, D, halo, CN, CH 3 , CD 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 OH, CH 2 CH 2 OH.
  • each R 6 is independently selected from H, D, halo, CN, SF 5 , OR B , C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl; wherein, the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl optionally substituted with D, halo, CN, NH 2 , OH, -O-C 1 -C 6 alkyl, -OC 1 -C 6 haloalkyl.
  • R 6 is H, D, halo, CN, CH 3 , CD 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 OH, CH 2 CH 2 OH or cyclopropyl.
  • each R 7 is independently selected from H, D, halogen, Me, CF 3 , OH, OMe, OCF 3 .
  • R 7 is H. In some embodiments, R 7 is D. In some embodiments, R 7 is halogen (such as F, Cl, Br or I) . In some embodiments, R 7 is OH. In some embodiments, R 7 is OMe.
  • each R 8 is independently selected from H, D, CN, SF 5 , C 1 -C 6 alkyl optionally substituted with D, halogen or CN.
  • R 8 is H. In some embodiments, R 8 is D. In some embodiments, R 8 is CN. In some embodiments, R 8 is SF 5 .
  • R 8 is C 1 -C 6 alkyl optionally substituted with D, halogen or CN.
  • R 8 is CH 3 , CD 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 .
  • the compound of formula (IA) and (IB) is represented by the compound of formula (IAa) , (IAb) , (IAc) , (IAd) , (IAe) , (IBa) , (IBb) , (IBc) , (IBd) , or (IBe) :
  • L is (CR 10 R 11 ) n , NR 12 (CH 2 CH 2 ) m , or O (CH 2 CH 2 ) m .
  • L is (CR 10 R 11 ) n . In some embodiments, L is CR 10 R 11 . In some embodiments, L is (CR 10 R 11 ) 2 . In some embodiments, L is (CR 10 R 11 ) 3 .
  • L is NR 12 (CH 2 CH 2 ) m . In some embodiments, L is NR 12 . In some embodiments, L is NR 12 CH 2 CH 2 .
  • L is O (CH 2 CH 2 ) m . In some embodiments, L is O. In some embodiments, L is OCH 2 CH 2 .
  • R is selected from H, D or C 1 -C 6 alkyl optionally substituted with F, OH or CN. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is Me.
  • R 4 is selected from H, D, NH 2 , or CN. In some embodiments, R 4 is H. In some embodiments, R 4 is D. In some embodiments, R 4 is NH 2 . In some embodiments, R 4 is CN.
  • R 4 is C 1 -C 3 alkyl optionally substituted with D, halogen or CN. In some embodiments, R 4 is Me. In some embodiments, R 4 is CD 3 . In some embodiments, R 4 is CF 3 .
  • R 5 is selected from H, D, halo, or CN. In some embodiments, R 5 is H. In some embodiments, R 5 is D. In some embodiments, R 5 is CN. In some embodiments, R 5 is F. In some embodiments, R 5 is Cl.
  • R 5 is C 1 -C 6 alkyl optionally substituted with D, halogen or CN. In some embodiments, R 5 is Me. In some embodiments, R 5 is CD 3 . In some embodiments, R 5 is CF 3 .
  • R 6 is selected from H, D, halo, CN, SF 5 , OR B .
  • R 6 is H.
  • R 6 is D.
  • R 6 is CN.
  • R 6 is F.
  • R 6 is Cl.
  • R 6 is Br.
  • R 6 is SF 5 .
  • R 6 is C 1 -C 6 alkyl optionally substituted with D, halo, 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 6 is Me.
  • R 6 is CD 3 .
  • R 6 is CF 3 .
  • R 6 is cyclopropyl.
  • R 7 is H. In some embodiments, R 7 is D.
  • R 7 is halogen. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl.
  • R 7 is OH. In some embodiments, R 7 is OMe.
  • R 8 is selected from H, D, CN, SF 5 . In some embodiments, R 8 is H. In some embodiments, R 8 is D. In some embodiments, R 8 is CN. In some embodiments, R 8 is SF 5 .
  • R 8 is C 1 -C 6 alkyl optionally substituted with D, halogen or CN. In some embodiments, R 8 is Me. In some embodiments, R 8 is CD 3 . In some embodiments, R 8 is CF 3 .
  • the compound of formula (IA) and (IB) is represented by the compound of formula (IIAa) , (IIAb) , (IIAc) , (IIAd) , (IIAe) , (IIBa) , (IIBb) , (IIBc) , (IIBd) , or (IIBe) :
  • the compound of formula (IA) and (IB) is represented by the compound of formula (IIIAa) , (IIIAb) , (IIIAc) , (IIIAd) , (IIIAe) , (IIIBa) , (IIIBb) , (IIIBc) , (IIIBd) , or (IIIBe) :
  • the compound of formula (IA) and (IB) is represented by the compound of formula (IIAa) , (IIBa) , (IIIAa) , (IIIBa) :
  • L is (CR 10 R 11 ) n , NR 12 (CH 2 CH 2 ) m , or O (CH 2 CH 2 ) m .
  • L is (CR 10 R 11 ) n . In some embodiments, L is CR 10 R 11 . In some embodiments, L is (CR 10 R 11 ) 2 . In some embodiments, L is (CR 10 R 11 ) 3 .
  • L is NR 12 (CH 2 CH 2 ) m . In some embodiments, L is NR 12 . In some embodiments, L is NR 12 CH 2 CH 2 .
  • L is O (CH 2 CH 2 ) m . In some embodiments, L is O. In some embodiments, L is OCH 2 CH 2 .
  • R is selected from H, D or C 1 -C 6 alkyl optionally substituted with F, OH or CN. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is Me.
  • R 4 is selected from H, D, NH 2 , or CN. In some embodiments, R 4 is H. In some embodiments, R 4 is D. In some embodiments, R 4 is NH 2 . In some embodiments, R 4 is CN.
  • R 4 is C 1 -C 3 alkyl optionally substituted with D, halogen or CN. In some embodiments, R 4 is Me. In some embodiments, R 4 is CD 3 . In some embodiments, R 4 is CF 3 .
  • R 5 is selected from H, D, halo, or CN. In some embodiments, R 5 is H. In some embodiments, R 5 is D. In some embodiments, R 5 is CN. In some embodiments, R 5 is F. In some embodiments, R 5 is Cl.
  • R 5 is C 1 -C 6 alkyl optionally substituted with D, halogen or CN. In some embodiments, R 5 is Me. In some embodiments, R 5 is CD 3 . In some embodiments, R 5 is CF 3 .
  • R 6 is selected from H, D, halo, CN, SF 5 , OR B .
  • R 6 is H.
  • R 6 is D.
  • R 6 is CN.
  • R 6 is F.
  • R 6 is Cl.
  • R 6 is Br.
  • R 6 is SF 5 .
  • R 6 is C 1 -C 6 alkyl optionally substituted with at least one of D, halo, 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 6 is Me.
  • R 6 is CD 3 .
  • R 6 is CF 3 .
  • R 6 is cyclopropyl.
  • R 7 is H. In some embodiments, R 7 is D.
  • R 7 is halogen. In some embodiments, F. In some embodiments, Cl.
  • R 7 is OH. In some embodiments, R 7 is OMe.
  • R 8 is selected from H, D, CN, SF 5 . In some embodiments, R 8 is H. In some embodiments, R 8 is D. In some embodiments, R 8 is CN. In some embodiments, R 8 is SF 5 .
  • R 8 is C 1 -C 6 alkyl optionally substituted with D, halogen or CN. In some embodiments, R 8 is Me. In some embodiments, R 8 is CD 3 . In some embodiments, R 8 is CF 3 .
  • the compound of formula (IB) is represented by the compound of formula (IVBa) , (IVBb) , or (IVBc) :
  • each R A 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; 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 heterocyclalkyl, C 6 -C 10 alkyl;
  • R A is independently selected from H. In some embodiments, R A is independently selected from D.
  • R A is independently selected from 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, 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) OR a , 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; wherein the C 3 -C 10 cycloalkyl, 4-10 membered heterocyclalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalky
  • each 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; 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 alkyl;
  • R B is independently selected from H. In some embodiments, R B is independently selected from D.
  • 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 isopropyl, isobutyl, tert-butyl; each 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.
  • R B is isopropyl.
  • R B is isobutyl.
  • R B is tert-butyl.
  • 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 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 cyclopropyl, cyclobutyl, cycylopentyl, cyclohexanyl; each 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.
  • 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; wherein the C 6 -C 10 aryl, 5-10 membered heteroaryl, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C 1 -
  • each 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; 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, C 6 -C 10 alkyl, C
  • each R C is independently selected from H. In some embodiments, each R C is independently selected from D.
  • each R C is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; each 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 , OC (O) NR c R d , NR c R d , NR c C (O) R b , S (O) NR c R d , S (O) 2 R b , NR c
  • each R C is independently selected from C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; each 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
  • each 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; 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, C 6 -C 10 alkyl, C
  • each R D is independently selected from H. In some embodiments, each R D is independently selected from D.
  • each R D is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; each 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 , OC (O) NR c R d , NR c R d , NR c C (O) R b , S (O) NR c R d , S (O) 2 R b , NR c
  • each R D is independently selected from C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; each 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
  • 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 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 -C
  • 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, 4-7 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl; 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, 4-7 membered heterocycloalkyl, C 6 -C 10 aryl-
  • 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, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alkyl, C 6 -C 10 aryl-C 3 -C 10 cycloalkyl, C 6 -C 10 aryl-4-10 membered heterocycloalkyl, C 6 -C 10 aryl-5-10 membered heteroaryl, C
  • 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, 4-7 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 6 alkyl, 5-10 membered heteroaryl-C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 6 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 6 alky; 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, 4-7 membered heterocycloalkyl, C 6 -C 10 aryl-
  • the compounds of Formula (IA) and (IB) are the pharmaceutically acceptable salts. In some embodiments, the compounds of Formula (IA) and (IB) are stereoisomers. In some embodiments, the compounds of Formula (IA) and (IB) are solvates. In some embodiments, the compounds of Formula (IA) and (IB) are N-oxides of the compounds of Formula (IA) and (IB) .
  • Stereoisomers of the compounds of Formula (IA) and (IB) , and the pharmaceutical salts and solvates thereof, are also contemplated, described, and encompassed herein. Methods of using compounds of Formula (IA) and (IB) are described, as well as pharmaceutical compositions including the compounds of Formula (IA) and (IB) .
  • the compound of Formula (IA) and (IB) is:
  • the compound of Formula (IA) and (IB) is:
  • the compounds of Formula (IA) and (IB) may have multiple stereogenic centers.
  • the present disclosure contemplates and encompasses each stereoisomer of any compound of Formula (IA) and (IB) (and subgenera described herein) , as well as mixtures of said stereoisomers.
  • Isotopic variants of the compounds of Formula (IA) and (IB) are also contemplated by the present disclosure.
  • 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 invention provides a method of inhibiting PKMYT1 in a cell expressing PKMYT1, the method comprising contacting the cell with the compound disclosed herein.
  • the cell is associated with CCNE1 amplification, FBXW7 loss-of-function mutations or other genetic alterations which depend on PKMYT1. In some embodiments, the cell is in a subject.
  • the invention provides a method of treating a subject in need thereof comprising administering to the subject the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition disclosed herein.
  • the subject is suffering from, and is in need of a treatment for, a disease or condition having the symptom of cell hyperproliferation.
  • the disease or condition is a cancer.
  • the cancer is a cancer with CCNE1 amplification, FBXW7 loss-of-function mutations or other genetic alterations which depend on PKMYT1.
  • Routs of administration for the compounds in the present disclosure include, but not limited to oral, injection, topical and inhalation.
  • 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, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo [l. l.
  • 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, l, 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.
  • 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
  • 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 -C 4
  • 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, OH, CN, -NH 2
  • 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;
  • 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;
  • 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;
  • R g1 is 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, cycloalkylalkyl or hetero
  • 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 (IA) and (IB) 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.
  • Compounds of the present disclosure, ” and equivalent expressions are meant to embrace compounds of Formula (IA) and (IB) as described herein, as well as its subgenera, which expression includes the stereoisomers (e.g., entaniomers, diastereomers) and constitutional isomers (e.g., tautomers) of compounds of Formula (IA) and (IB) as well as the pharmaceutically acceptable salts, where the context so permits.
  • 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 (IA) and (IB) , or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, Isotopic variants 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, corn 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 intravenous
  • 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 (IA) and (IB) 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 (IA) and (IB) 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 (IA) and (IB) 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 (IA) and (IB) 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, subcuticular, 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 half maximal 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 PKMYT1 inhibitor with an IC 50 value of about or less than a predetermined value, as ascertained in an in vitro assay.
  • the PKMYT1 inhibitor inhibits PKMYT1 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 n
  • PKMYT1 is a synthetic lethal target in the cancers with certain genetic alterations, e.g., CCNE1 amplification or FBXW7 loss-of-function mutations, which may have the symptom of cell hyperproliferation.
  • the subject methods are useful for treating disease conditions associated with CCNE1 amplification, FBXW7 loss-of-function mutations or other genetic alterations which depend on PKMYT1.
  • Non-limiting examples of such disease conditions include but are not limited to breast cancer, invasive ductal 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 cancer, squamous cell cervical cancer, cervical adeno
  • CCNE1 amplification refers to the increased CCNE1 genes which leads to the increased expression of cyclin E protein in a diseased cell e.g., cancer cell, relative to expression of cyclin E protein in a control cell (e.g., non-diseased cell of the same type) .
  • the amount of cyclin E expression can be at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 10-fold, at least 20-fold, at least 50-fold, relative to cyclin E expression in a control cell.
  • CCNE1 amplification cancers include, but are not limited to, uterine Carcinosarcoma, ovarian epithelial tumor, endometrial cancer, esophagogastric cancer, sarcoma, bladder cancer, adrenocortical carcinoma, non-small cell lung cancer, pancreatic cancer, pleural mesothelioma, breast cancer, head and neck cancer, mature B-cell neoplasms, cervical cancer, ovarian cancer, hepatobiliary cancer, glioblastoma, colorectal cancer, melanoma, pheochromocytoma, glioma, prostate cancer, uterine cancer, sarcoma, stomach cancer, lung cancer, esophageal cancer, endometrial cancer, osteosarcoma, leukemia, lymphoma, and biliary tract carcinoma.
  • FBXW7 loss-of-function mutations cancers include, but are not limited to, uterine cancer, endometrial cancer, colorectal cancer, cervical cancer, esophagogastric cancer, bladder cancer, head and neck cancer, melanoma, non-small cell lung cancer, pancreatic cancer, sarcoma, breast cancer, stomach cancer, ovarian epithelial tumor, glioma, hepatobiliary cancer, ocular melanoma, glioblastoma, thyroid cancer, renal clear cell carcinoma, renal non-clear cell carcinoma, ovarian cancer, lung cancer, and esophageal cancer.
  • said method is for use in the treatment or prevention of lymphoma, soft tissue, rhabdoid, multiple myeloma, uterus, gastric, peripheral nervous system, rhabdomyosarcoma, bone, colorectal, mesothelioma, breast, ovarian, lung, fibroblast, central nervous system, urinary tract, upper aerodigestive, leukemia, kidney, skin, esophagus, and pancreas (data from large scale drop out screens in cancer cell lines indicate that some cell lines from the above cancers are dependent on polymerase theta for proliferation see https: //depmap. org/portal/) .
  • 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 the cancers with poor chemotherapy response or chemotherapy resistance, e.g., Epithelial Ovarian Cancer.
  • said method is for treating a disease selected from the cancers with P53 or ATM mutations, e.g., head and neck cancer, non-small cell lung cancer, ovarian epithelial tumor, esophagogastric cancer, pancreatic cancer, colorectal cancer, bladder cancer, glioma, sarcoma, endometrial cancer, breast cancer, hepatobiliary cancer, glioblastoma, adrenocortical carcinoma, melanoma, pleural Mesothelioma, prostate cancer, cholangiocarcinoma, mature B-cell neoplasms, cervical cancer, leukemia, renal non-clear cell carcinoma, thymic epithelial tumor, renal clear cell carcinoma, seminoma, pheochromocytoma, thyroid cancer, and non-seminomatous germ cell tumor.
  • a disease selected from the cancers with P53 or ATM mutations, e.g., head and neck cancer, non-small cell lung 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 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 PARP inhibitor, DNA-PK inhibitor, ATM inhibitor, ATR inhibitor, CHK1 inhibitor, LIG4 inhibitor, HIF-1 inhibitor, HDAC inhibitor, RAD51 inhibitor, WRN inhibitor, PRMT5 inhibitor, MAT2A inhibitor and PolQ 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 PARP inhibitor, DNA-PK inhibitor, ATM inhibitor, ATR inhibitor, CHK1 inhibitor, LIG4 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; Flt3 kinase inhibitors, CSF-
  • 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 (IA) can be prepared as the methods described in Scheme 1.
  • the 2-amino derivatives 1-1 can be converted to the 2-hydroxy derivatives 1-2, which can be transformed into the corresponding derivatives 1-3 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 POBr 3 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.
  • a halogenation reagent such as SOCl 2 , POCl 3 or POBr 3
  • a base such as Hunig’s base.
  • Coupling of compounds 1-3 with aromatic amines 1-4 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
  • a palladium catalyst such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3
  • a base such as t-BuOK, t-BuONa, Cs 2 CO 3 , or K 2 CO 3
  • Reaction of the amine derivatives 1-5 with malononitrile to produce aminopyrroles 1-6 can be achieved under palladium-mediated conditions (e.g., in the presence of a palladium catalyst, such as Pd (PPh 3 ) 2 Cl 2 or Pd (OAc) 2 /PPh 3 , and a base, such as t-BuOK or t-BuONa) .
  • a palladium catalyst such as Pd (PPh 3 ) 2 Cl 2 or Pd (OAc) 2 /PPh 3
  • a base such as t-BuOK or t-BuONa
  • Hydrolysis of the nitrile in 1-6 can be conducted under acidic or basic conditions to yield pyrrole-amide derivatives 1-7 which can be transformed into indole-pyrimidone 1-9 by treatment of with trialkyl orthoformate 1-8 (where R is methyl or ethyl) in the presence of an acid such as p-TsOH, or HCl.
  • trialkyl orthoformate 1-8 where R is methyl or ethyl
  • the indole-pyrimidone 1-9 can be converted into intermediates 1-10 where W 2 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 POBr 3 with or without the catalytic of DMF (where W 2 is Cl or Br) or reaction with TfCl or MsCl (where W 2 is OTf or OMs) in the presence of a base such as Hunig’s base. Reaction of the intermediates 1-10 with ammonia or amine derivatives can afford the desired tricyclic derivatives of formula (IA) .
  • W 2 is halogen (e.g., Cl, or Br) or pseudohalogen (e.g., OTf or OMs)
  • a halogenation reagent such as SOCl 2 , POCl 3 or POBr 3
  • a base such as Hunig’
  • a series of intermediates 2-4 for preparations of tricyclic derivatives of formula (IA) can be prepared as the methods described in Scheme 2.
  • Substitution of compounds 2-1 (W 1 and W 2 are halogen e.g., Cl, or Br) with malononitrile can form malononitrile derivatives 2-2 under palladium-mediated conditions (e.g., in the presence of a palladium catalyst, such as Pd (PPh 3 ) 2 Cl 2 or Pd (OAc) 2 /PPh 3 , and a base, such as t-BuOK or t-BuONa) .
  • a palladium catalyst such as Pd (PPh 3 ) 2 Cl 2 or Pd (OAc) 2 /PPh 3
  • a base such as t-BuOK or t-BuONa
  • Coupling of malononitrile derivatives 2-2 with aromatic amines 2-3 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
  • a palladium catalyst such as BrettPhos Pd G3, t-BuXphos Pd G3, RuPhos Pd G3 or XantPhos Pd G3
  • a base such as t-BuOK, t-BuONa, Cs 2 CO 3 , or K 2 CO 3
  • a series of intermediates 3-6 for preparations of tricyclic derivatives of formula (IA) can be prepared as the methods described in Scheme 3.
  • Reaction of the aromatic amines 3-1 with alkyl 2-cyanoacetate 3-2 (where, R is Me or Et) to yield aminopyrrole ester 3-3 can be achieved under palladium-mediated conditions (e.g., in the presence of a palladium catalyst, such as Pd (PPh 3 ) 2 Cl 2 or Pd (OAc) 2 /PPh 3 , and a base, such as t-BuOK or t-BuONa) .
  • a palladium catalyst such as Pd (PPh 3 ) 2 Cl 2 or Pd (OAc) 2 /PPh 3
  • a base such as t-BuOK or t-BuONa
  • Tricyclic derivatives 3-6 can be prepared by reactions of the aminopyrrole ester 3-3 with cyano derivatives 2-4 in the presence of an acid, such as dry HCl, TsOH or H 2 SO 4 ) or ethyl alkyl-carbimidate 3-5.
  • a series of intermediates 4-3 for preparations of tricyclic derivatives of formula (IA) can be prepared as the methods described in Scheme 4.
  • Suzuki coupling of compounds 4-1 with boronate ester 4-2 can afford the intermediates 4-3 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K 3 PO 4 ) .
  • a palladium catalyst such as [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K 3 PO 4
  • a series of tricyclic derivatives of formula 5-8 can be prepared as the methods described in Scheme 5.
  • Compounds 5-1 where W 2 is halogen (e.g., Cl, Br, or I) and W 1 is halogen (e.g., Br, or Cl) can be transformed into aminopyrrole derivatives 5-4 either by consequently reactions with malononitrile and Buchwald’s amination with aromatic amines 5-3 as described in the scheme 2 or Buchwald’s amination with aromatic amines 5-3 first and then reactions with malononitrile under palladium-mediated conditions for transformations of compounds 1-3 to aminopyrroles 1-6 as described in scheme 1 (e.g., in the presence of a palladium catalyst, such as Pd (PPh 3 ) 2 Cl 2 or Pd (OAc) 2 /PPh 3 , and a base, such as t-BuOK or t-BuONa) .
  • a palladium catalyst such as Pd (PPh 3 ) 2 Cl 2 or Pd
  • the aminopyrrole derivatives 5-4 can be halogenated with suitable reagents, such as N-chlorosuccimide (NCS) , N-bromosuccimide (NBS) or N-iodosuccimide (NIS) to provide compounds 5-5 where W 3 is a halogen (e.g., Cl, Br, or I) in which a suitable group R 1 can be installed in the presence of a metal-mediated coupling such as standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [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
  • a series of tricyclic derivatives of formula 6-10 can be prepared as the methods described in Scheme 6.
  • O-alkylation of pyrazin-2 (1H) -one 6-1 with benzyl bromide or benzyl chloride in the presence of a base such as NaH, or K 2 CO 3 can afford pyrazine 6-2 which can be transformed into aminopyrrole amide 6-6 by consequently reactions with aromatic amines 6-3 and malononitrile, and hydrolysis as those described for the transformations of compounds 1-3 to 1-7 in scheme 1.
  • Hydrogenation of compounds 6-6 can produce the corresponding compounds 6-7 in the presence of a palladium catalyst such as Pd/C or Pd (OH) 2 /C.
  • the hydroxyl group in compounds 6-7 can be converted to the corresponding triflate derivatives 6-8 by treatment with a triflation reagent such as PhNTf 2 or Tf 2 O in the presence of a base such as Et 3 N or Hunig’s base.
  • a triflation reagent such as PhNTf 2 or Tf 2 O
  • a base such as Et 3 N or Hunig’s base.
  • the triflate derivatives 6-8 can be transformed into desired compounds 6-9 which can lead to the final tricyclic derivatives 6-10 as those described in scheme 1.
  • a series of tricyclic derivatives of formula 7-8 can be prepared as the methods described in the scheme 7.
  • the compounds 7-3 can be prepared by halogenation with N-chlorosuccimide (NCS) , N-bromosuccimide (NBS) or N-iodosuccimide (NIS) and a metal-mediated coupling to install R 1 group under Suzuki conditions, Negishi conditions or Stille conditions as described in scheme 5.
  • NCS N-chlorosuccimide
  • NBS N-bromosuccimide
  • N-iodosuccimide N-iodosuccimide
  • Compounds 7-3 can be converted to the desired tricyclic derivatives 7-8 as those described in scheme 6.
  • a series of tricyclic derivatives of formula 8-10 can be prepared as the methods described in Scheme 8.
  • the 2-amino bromo derivatives 8-1 (n is 0, 1 or 2) can be transformed into the corresponding derivatives 8-2 where W is halogen (e.g., Cl, Br or I) by treatment with NaNO 2 in the presence of an acid such as HCl, or HBr and following reaction with a halogenation reagent such as CuCl, CuBr or CuI.
  • Coupling of compounds 8-2 with a suitable aromatic amine 8-3 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
  • 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
  • the carboxylate group in 8-4 can be reduced to the corresponding alcohol 8-5 by using a reducing reagent such as LiBH 4 or NaBH 4 .
  • Substitution of the 3-Br in aromatic amines 8-5 with malononitrile to produce aminopyrroles 8-6 can be achieved under copper-mediated coupling conditions (e.g., CuI in the presence of diamine-based ligands, such as N 1 , N 2 -dimethylethane-1, 2-diamine, N 1 , N 2 -dimethylcyclohexane-1, 2-diamine or cyclohexane-1, 2-diamine) or under palladium-mediated conditions (e.g., in the presence of a palladium catalyst, such as Pd (PPh 3 ) 2 Cl 2 or Pd (OAc) 2 /PPh 3 , and a base, such as t-BuOK or t-BuONa) .
  • copper-mediated coupling conditions e.g., CuI in the presence of diamine-based ligands, such as N 1 , N 2 -dimethylethane-1, 2-diamine, N 1 , N 2
  • Hydrolysis of the nitrile in 8-6 can be done under acidic or basic conditions to yield pyrrole-amide derivatives 8-7 which can be transformed into compounds 8-8 by treatment of with DPPA (diphenyl phosphorazidate) and DBU or by Mitsunobo reaction with azide or sodium azide and DEAD or DIAD.
  • DPPA diphenyl phosphorazidate
  • DBU dibenzyl phosphorazidate
  • Reduction of the azide group in compounds 8-8 to the corresponding amines 8-9 can be achieved by treatment with triphenylphosphine or by hydrogenation in the presence of a palladium catalyst such as Pd/C.
  • Intramolecular amide formation can afford the desired tricyclic derivatives of formula 8-10.
  • a series of tricyclic lactam derivatives of formula 9-10 can be prepared as the methods described in Scheme 9.
  • Condensation of 3-bromopyridin-2-amines 9-1 with pyruvic acid can give azaindole acids 9-2 in the presence of a palladium catalyst such as bis (tri-tert-butylphosphine) palladium (0) , and a base such as potassium phosphate.
  • the azaindole acids 9-2 can be conveniently transformed into the corresponding azaindole ester 9-3 (where R is Me or Et) by treatment with diazomethane (where R is Me) or treatment with oxalyl chloride following by alcohol ROH.
  • Azaindole derivatives 9-4 can be prepared from the azaindole ester 9-3 in various ways: 1) treatment 9-3 with POCl 3 in a catalytic amount of DMF, and following by treatment with an oxidative reagent such as Ag 2 O) treatment 9-3 with anhydrous trifluoroacetic acid following with NaOH; 3) treatment 9-3 with 2, 2, 2-trichloroacetyl chloride following with NaOH.
  • the indole derivatives 9-4 can be transformed into azaindole lactams 9-5 by treatment with a protected amine such as p-methoxybenzylamine PMB-NH 2 in the presence of an amide coupling reagent such BOP, ByBOP, HATU or HBTU, and a base such as Et 3 N or Hunig’s base.
  • a protected amine such as p-methoxybenzylamine PMB-NH 2
  • an amide coupling reagent such BOP, ByBOP, HATU or HBTU
  • a base such as Et 3 N or Hunig’s base.
  • Removal of the protecting group PMB in 9-9 to give the final tricyclic lactam derivatives 9-10 can be achieved by hydrogenation in the presence of a palladium catalyst such as Pd/C or Pd (OH) 2/C or under acid conditions such as TFA.
  • a palladium catalyst such as Pd/C or Pd (OH) 2/C or under acid conditions such as TFA.
  • a series of intermediates 10-6 for preparations of tricyclic derivatives of formula (IB) can be prepared as the methods described in Scheme 10.
  • a palladium catalyst such as Pd (PPh 3 ) 2 Cl 2 or Pd (OAc) 2 /PPh 3
  • a base such as t-BuOK or t-BuONa
  • Tricyclic derivatives 10-6 can be prepared by reactions of the aminopyrrole ester 10-3 with cyano derivatives 10-4 in the presence of an acid, such as dry HCl, TsOH or H 2 SO 4 ) or ethyl alkyl-carbimidate 10-5.
  • a series of intermediates 11-3 for preparations of tricyclic derivatives of formula (IB) can be prepared as the methods described in Scheme 11. Suzuki coupling of compounds 4-1 with boronate ester 11-2 can afford the intermediates 11-3 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K 3 PO 4 ) .
  • a palladium catalyst such as [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K 3 PO 4
  • a series of tricyclic derivatives of formula 12-8 can be prepared as the methods described in Scheme 12.
  • Compounds 12-1 where W 2 is halogen (e.g., Cl, Br, or I) and W 1 is halogen (e.g., Br, or Cl) can be transformed into aminopyrrole derivatives 12-4 either by consequently reactions with malononitrile and Buchwald’s amination with aromatic amines 12-3 as described in the scheme 9 or Buchwald’s amination with aromatic amines 12-3 first and then reactions with malononitrile under palladium-mediated conditions for transformations of compounds 8-3 to aminopyrroles 8-6 as described in scheme 8.
  • a palladium catalyst such as Pd (PPh 3 ) 2 Cl 2 or Pd (OAc) 2 /PPh 3
  • a base such as t-BuOK or t-BuONa
  • the aminopyrrole derivatives 12-4 can be halogenated with suitable reagents, such as N-chlorosuccimide (NCS) , N-bromosuccimide (NBS) or N-iodosuccimide (NIS) to provide compounds 12-5 where W 3 is a halogen (e.g., Cl, Br, or I) in which a suitable group R 1 can be installed in the presence of a metal-mediated coupling such as standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [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
  • Step 7 5- (benzyloxy) -3-chloro-N- (3-methoxy-2, 6-dimethylphenyl) pyrazin-2-amine
  • reaction mixture was cooled to r.t, and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0.25–2%) to afford the title compound (2.40 g, 60.9%yield) as light-yellow oil.
  • Step 8 6-amino-2- (benzyloxy) -5- (3-methoxy-2, 6-dimethylphenyl) -5H-pyrrolo [2, 3-b] pyrazine-7-carbonitrile
  • the reaction mixture was degassed and recharged with nitrogen for three cycles, and stirred at 80 ⁇ 85 °C for 2 h. After cooling, the mixture was quenched with H 2 O (100 mL) at 0 °C, and extracted with DCM (2 x 20 mL) . The combined organic layers were washed with brine (30 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with MeOH/DCM (1-50%) to afford the title compound (1.90 g, 78.7%yield) as yellow oil.
  • Step 9 6-amino-2-hydroxy-5- (3-methoxy-2, 6-dimethylphenyl) -5H-pyrrolo [2, 3-b] pyrazine-7-carboxamide
  • Step 10 6-amino-7-carbamoyl-5- (3-methoxy-2, 6-dimethylphenyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl trifluoromethanesulfonate
  • Step 11 6-amino-5- (3-methoxy-2, 6-dimethylphenyl) -2-morpholino-5H-pyrrolo [2, 3-b] pyrazine-7-carboxamide
  • Step 12 9- (3-methoxy-2, 6-dimethylphenyl) -6-morpholino-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-ol
  • Step 13 4- (4-chloro-9- (3-methoxy-2, 6-dimethylphenyl) -9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-6-yl) morpholine
  • Step 14 9- (3-methoxy-2, 6-dimethylphenyl) -6-morpholino-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-amine
  • Step 15 3- (4-amino-6-morpholino-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol
  • This compound is a mixture of (3Ra) - (4-Amino-6-morpholino-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol and its enantiomer (3Sa) - (4-Amino-6-morpholino-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol.
  • Step 1 6-amino-5- (3-methoxy-2, 6-dimethylphenyl) -2-methyl-5H-pyrrolo [2, 3-b] pyrazine-7-carboxamide
  • Step 2 3- (4-amino-6-methyl-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol
  • This compound is a mixture of (3Ra) - (4-Amino-6-methyl-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol and its enantiomer (3Sa) - (4-Amino-6-methyl-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol.
  • Step 3 3-bromo-N- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethylpyridin-2-amine
  • This compound was prepared using procedures analogous to those described for Example 1 Step 7 using 2, 3-dibromo-5, 6-dimethylpyridine to replace 5- (benzyloxy) -2-bromo-3-chloropyrazine, and cesium carbonate to replace potassium tert-butoxide.
  • Step 4 2-amino-1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile
  • the reaction mixture was degassed and recharged with nitrogen for 3 cycles, stirred at 85 °C for 12 h under N 2 atmosphere. After cooling to r.t., the mixture was diluted with water (40.0 mL) and extracted with EtOAc (2 x 20 mL) . The combined organic layers were washed with brine (10 mL) , dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (10-50%) to afford the title compound (4.30 g, 90.0%yield) as a light brown solid.
  • Step 5 2-amino-1- (3-hydroxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile
  • Step 6 2-amino-1- (3-hydroxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carboxamide
  • Step 7 9- (3-hydroxy-2, 6-dimethylphenyl) -6, 7-dimethyl-3, 9-dihydro-4H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-one
  • Step 8 3- (4-chloro-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol
  • Step 9 3- (4-amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol
  • This compound is a mixture of (3Ra) - (4-Amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol and its enantiomer (3Sa) - (4-Amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol.
  • Step 8 methyl 3-bromo-2- [ (3-methoxy-2, 6-dimethylphenyl) amino] -5-methylpyridine-4-carboxylate
  • Step 9 ⁇ 3-bromo-2- [ (3-methoxy-2, 6-dimethylphenyl) amino] -5-methylpyridin-4-yl ⁇ methanol
  • Step 10 2-amino-4- (hydroxymethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5-methylpyrrolo [2, 3-b] pyridine-3-carbonitrile
  • Step 11 methyl 2-amino-4- (hydroxymethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5-methylpyrrolo [2, 3-b] pyridine-3-carboxylate
  • Step 12 methyl 2-amino-4- (azidomethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5-methylpyrrolo [2, 3-b] pyridine-3-carboxylate
  • Step 13 methyl 2-amino-4- (aminomethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5-methylpyrrolo [2, 3-b] pyridine-3-carboxylate
  • Step 14 3-amino-2- (3-methoxy-2, 6-dimethylphenyl) -9-methyl-2, 6, 11-triazatricyclo [6.3.1.0 ⁇ ⁇ 4, 12 ⁇ ] dodeca-1 (11) , 3, 8 (12) , 9-tetraen-5-one
  • Step 15 3-amino-2- (3-hydroxy-2, 6-dimethylphenyl) -9-methyl-2, 6, 11-triazatricyclo [6.3.1.0 ⁇ ⁇ 4, 12 ⁇ ] dodeca-1 (11) , 3, 8 (12) , 9-tetraen-5-one
  • the desired compound for Example 1 step 15 was a mixture of 2-Amino- (1Ra) - (3-hydroxy-2, 6-dimethylphenyl) -6-methyl-4, 5-dihydropyrrolo [4, 3, 2-de] [2, 6] naphthyridin-3 (1H) -one and its enantiomer 2-Amino- (1Sa) - (3-hydroxy-2, 6-dimethylphenyl) -6-methyl-4, 5-dihydropyrrolo [4, 3, 2-de] [2, 6] naphthyridin-3 (1H) -one.
  • Step 1 methyl 2- ( (diphenylmethylene) amino) -6-methylisonicotinate
  • Step 4 methyl 6-amino-2, 3-dimethylisonicotinate
  • Step 6 methyl 2, 3-dibromo-5, 6-dimethylisonicotinate
  • Step 7 methyl 3-bromo-2- ( (3-methoxy-2, 6-dimethylphenyl) amino) -5, 6-dimethylisonicotinate
  • Step 8 (3-bromo-2- ( (3-methoxy-2, 6-dimethylphenyl) amino) -5, 6-dimethylpyridin-4-yl) methanol
  • Step 9 2-amino-4- (hydroxymethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyr rolo [2, 3-b] pyridine-3-carbonitrile
  • Step 10 methyl 2-amino-4- (hydroxymethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethyl -1H-pyrrolo [2, 3-b] pyridine-3-carboxylate
  • Step 11 methyl 2-amino-4- (azidomethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carboxylate
  • Step 12 methyl 2-amino-4- (aminomethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethy l-1H-pyrrolo [2, 3-b] pyridine-3-carboxylate
  • Step 13 2-amino-1- (3-methoxy-2, 6-dimethylphenyl) -6, 7-dimethyl-4, 5-dihydropyrrolo [4, 3, 2-de] [2, 6] naphthyridin-3 (1H) -one
  • Step 14 2-amino-1- (3-hydroxy-2, 6-dimethylphenyl) -6, 7-dimethyl-4, 5-dihydropyrrolo [4, 3, 2-de] [2, 6] naphthyridin-3 (1H) -one
  • Example 8 6, 7-Dimethyl-9- (6-methylquinolin-5-yl) -9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-amine
  • Step 1 N- (3-bromo-5, 6-dimethylpyridin-2-yl) -6-methylquinolin-5-amine
  • the reaction mixture was cooled to r.t., diluted with water (250 mL) , extracted with EA (50 mL x 2) . The combined organic layers were washed with brine (20 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EA/PE (0 ⁇ 5%) to afford the title compound (7.50 g, 58.1%yield) as a yellow solid.
  • Step 2 2-amino-5, 6-dimethyl-1- (6-methylquinolin-5-yl) -1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile
  • Step 4 6, 7-dimethyl-9- (6-methylquinolin-5-yl) -3, 9-dihydro-4H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-one
  • Step 5 6, 7-dimethyl-9- (6-methylquinolin-5-yl) -9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-amine
  • Step 1 3-bromo-N- (2, 6-dichloro-3, 5-dimethoxyphenyl) -5, 6-dimethylpyridin-2-amine
  • Step 2 2-amino-1- (2, 6-dichloro-3, 5-dimethoxyphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile
  • Step 3 2-amino-1- (2, 6-dichloro-3, 5-dimethoxyphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carboxamide
  • Step 4 9- (2, 6-dichloro-3, 5-dimethoxyphenyl) -6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-amine
  • Step 5 5- (4-amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -4, 6-dichlorobenzene-1, 3-diol
  • Step 1 3-bromo-N- (2, 6-difluoro-3, 5-dimethoxyphenyl) -5, 6-dimethylpyridin-2-amine
  • Step 2 2-amino-1- (2, 6-difluoro-3, 5-dimethoxyphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile
  • Step 3 2-amino-1- (2, 6-difluoro-3, 5-dimethoxyphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carboxamide
  • Step 4 9- (2, 6-difluoro-3, 5-dimethoxyphenyl) -6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-amine
  • Step 5 5- (4-amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -4, 6-difluorobenzene-1, 3-diol (Example 10) and 3- (4-amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-difluoro-5-methoxyphenol (Example 11)
  • PKMYT1 kinase assay was initiated for evaluating potential inhibitory effect of candidate compounds.
  • PKMYT1 was ordered from Carna, 05-176 and stored at -80°C in aliquots.
  • ADP quantity produced from ATP hydrolysis by PKMYT1 catalytic reaction was measured using a commercially available ADP-Glo Assay (ADP-Glo TM Kinase Assay from Promega, 10 000 assays, #V9102) .
  • the plates were covered and left to incubate for 10 minutes at RT before the addition of 2.5 ⁇ l 2X substrate mix [Unactive CDK1 (SignalChem, C22-14G-20) and ATP (Promega, V910B) ] to initiate reaction.
  • the final PKMYT1 enzyme concentration was 2.5ng/ul; the final ATP concentration was 200uM and the final unactive CDK1 concentration was 0.01ug/ul.
  • 4 ⁇ L of ADP-Glo reagent was added and the plate was spun briefly and sealed and incubated in the dark for 40 minutes at RT.
  • kinase detection reagent 8 ⁇ L was added and the plate was spun briefly, sealed and incubated for 40 minutes at RT in the dark.
  • %inhibition 100 -100* (Signal cmpd -Signal Ave_LC ) / (Signal Ave_HC -Signal Ave_LC ) .
  • HCC1569 cell line Cells were cultured in RPMI 1640 (Hyclone, SH3080901B) with 10%FBS (AusGeneX, FBS500-S) and 1%penicillin-streptomycin (Gibco, 15140122) . Cells were seeded in 96-well cell culture plates (PerkinElmer, 6005680) at a density of 1500 cells/well. Compounds dissolved in DMSO were plated in duplicate using a multichannel pipette, and tested on a 9-point 3-fold serial dilution. DMSO final concentration was 0.2%for all wells. Cells were incubated for 7 days in a 37 °C active humidified incubator at 5%CO 2 .
  • HC high control
  • LC low control
  • %inhibition 100 -100* (Signal cmpd -Signal Ave_LC ) / (Signal Ave_HC -Signal Ave_LC ) .
  • IC 50 values were determined by fitting the data to the standard 4 parameters with Hill Slope using GraphPad Prism software. IC 50 data is proved below in Table 2.

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Abstract

Provided tricyclic heterocyclic derivatives as shown in Formulas (IA) and (IB), pharmaceutical compositions comprising them, a process for their preparation, and their use as therapeutic agents.

Description

TRICYCLIC HETEROCYCLIC DERIVATIVES, COMPOSITIONS AND USES THEREOF TECHNICAL FIELD
The present disclosure relates to tricyclic heterocyclic derivatives as inhibitor of PKMYT1. 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 PKMYT1 including, e.g., cancers and other diseases.
BACKGROUND
Cell cycle is the essential way for cell division and growth regardless of either healthy cells or tumor cells. Generally, the cell cycle can be divided into four phases: pre-DNA synthesis (G1 phase) , DNA synthesis (Sphase) , post-DNA synthesis (G2 phase) , and mitosis (M phase) . The progressions of cells from G1-phase into S-phase and G2-phase into M-phase (the mitotic phase) are very important stages for the repair of DNA damage as well as complex and active changes of various substances in cell. Cells set a series of cell-cycle checkpoints during the four phases to ensure the integrity of DNA replication and the completion of damage repair (Kevin J. Barnum, 2014) . For some reason, if cells enter mitosis with compromised genomic material, it may happen for cells with cell cycle disorder, apoptosis, cancer and other malignant results. Additionally, because cancers also utilize cell cycle for tumor cell division, long-term accumulation of DNA damage unrepaired in the period of G1 to S-phase and G2 to M-phase will lead to mitotic catastrophe and tumor cell death.
The Protein Kinase, Membrane Associated Tyrosine/Threonine 1 (PKMYT1) is a cell cycle regulating protein which belongs to WEE family of kinases. PKMYT1 blocks the progression of cells from G2-phase into M-phase of the cell cycle through negatively regulating CDK1-Cyclin B complex. In the process of DNA damage repair, PKMYT1 phosphorylates CDK1 protein at amino acid sites of Tyr15 and Thr14 to maintain CDK1-Cyclin B complex in an inactive state in G2-phase and finally prevent cells entry into mitosis (Dongjun Jeong, 2018) , which provides enough time for DNA damage repair. At the same time, Wee1 also involve in the CDK1 phosphorylation at amino acid site of Tyr15. PKMYT1 knockdown or inhibition can prompt cells to enter mitosis prematurely without completing DNA damage repair, leading to cell death.
On the other hand, CCNE1 amplification can disrupt the regulation of cell entry into S phase, trigger DNA replication stress, and cause genome instability. CCNE1 amplification is prevalent in multiple tumor types, particularly in high-grade serous ovarian cancer, uterine tumor and gastro-oesophageal cancers, ranging in frequency from 5-40%. Cyclin E1, encoded by the CCNE1 gene,  promotes the transition of the cell cycle from G1-phase to S-phase by binding and activating cyclin-dependent protein kinase 2 (CDK2) . In a genome screening study based on CRISPR technology, it was found that the high expression/amplification of CCNE1 and the inhibition of PKMYT1 have a high degree of synthetic lethal effect (David Gallo, 2022) , that is excessively accelerated cycle transition make the cells lose the opportunity for adequate DNA damage repair and cause cell death. During normal cell cycles, Cyclin E1 levels are tightly regulated, accumulating at the G1/Stransition and being completely degraded by the end of S phase. The Cyclin E1 degradation can be mediated by FBXW7, which is an E3 ubiquitin ligase (Chien-Hung Yeh, 2018) . The loss-of-function mutation of FBXW7 will lead to the loss of its ubiquitination function to Cyclin E, such that Cyclin E cannot be degraded and thus overexpressed.
Therefore, PKMYT1 inhibitors can be used to treat tumors with certain genetic alterations using a synthetic lethality therapeutic strategy. The invention provides compounds, pharmaceutical compositions containing the same, methods of preparing the compounds, and methods of use. Compounds of the invention may be used to inhibit PKMYT1 in a cell with CCNE1 amplification, FBXW7 loss-of-function mutations or other genetic alterations driving DNA replication stress and genome instability in G1 to S phase progression. The subject may be in need of a treatment for a disease or condition, e.g., a disease or condition having a symptom of cell hyperproliferation, e.g., a cancer. The PKMYT1 inhibitory activity of the compounds disclosed herein is useful for treating a subject in need of a treatment for cancer.
SUMMARY
The present disclosure relates to, inter alia, compounds of Formula (IA) and (IB) ,
or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, Isotopic variants or prodrugs thereof; wherein the variables are as defined below.
In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (IA) and (IB) , or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, Isotopic variants or prodrugs thereof and at least one pharmaceutically acceptable carrier.
In another aspect, provided herein is a method of inhibiting PKMYT1 comprising:
contacting a PKMYT1 with a compound of formula (IA) and (IB) , or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, Isotopic variants or prodrugs thereof.
In another aspect, provided herein is a method of treating cancers and other diseases comprising administering to a patient a therapeutically effective amount of a compound of formula (IA) and (IB) , or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, Isotopic variants or prodrugs thereof.
The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and from the claims.
DETAILED DESCRIPTION
The present disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any sub-combination.
Before the present invention is further described, it is to be understood that the invention is not limited to the particular embodiments set forth herein, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
The present disclosure provides, inter alia, a compound of formula (IA) and (IB) : 
or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variants or prodrugs thereof, wherein:
ring A is selected from:
X is N or CR3;
Y is N or CR9;
L is (CR10R11) n, NR12 (CH2CH2) m, or O (CH2CH2) m;
n is 1, 2 or 3; m is 0 or 1;
R is selected from H, D or C1-C6 alkyl optionally substituted with F, OH or CN;
R1, R2 and R3 are each independently selected from H, D, halo, CN, SF5, NRCRD, ORA, C (O) RB, C (O) NRCRD, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocyclalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb;
or R1 and R2 together with the carbon atoms to which they are attached form a C3-C7 cycloalkyl, or 4-7 membered heterocycloalkyl, wherein, the C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, oxo, ORa, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb;
or R2 and R3 together with the carbon atom to which they are attached form a C3-C7 cycloalkyl, or 4-7 membered heterocycloalkyl, wherein, the C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, oxo, ORa, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb;
each R4 is independently selected from H, D, NH2, CN, C1-C3 alkyl optionally substituted with D, halogen or CN;
each R5 is independently selected from H, D, halo, CN, C1-C6 alkyl optionally substituted with D, halogen or CN;
each R6 is independently selected from H, D, halo, CN, ORB, SF5, C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl; wherein, the C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl is optionally substituted with D, halo, CN, NH2, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl;
each R7 is independently selected from H, D, halogen, Me, CF3, OH, OMe, OCF3;
each R8 is independently selected from H, D, CN, SF5, C1-C6 alkyl optionally substituted with D, halogen or CN;
R9 is selected from H, D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C3-C5 cycloalkyl;
R10 and R11 are each independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, CN, halo, ORa, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, NRcS (O) 2Rb, or NRcS (O) 2NRcRd;
or R10 and R11 together with the carbon atom (s) to which they are attached form a C3-C7 cycloalkyl, or 4-7 membered heterocycloalkyl, wherein, the C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, oxo, ORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, or NRcS (O) 2NRcRd;
R12 is H, D, C1-C3 alkyl optionally substituted with D, OH, halogen, CN;
each RA is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocyclalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb;
each RB is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C (O) Rb,  OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) ;
RC and RD are each independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC (O) NRcRd, NRcRd, NRcC (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) ;
or RC and RD 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, or C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl;
each Ra is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
each Rb is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl;
Rc and Rd are each independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10  aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, C6-C10 aryl-C6-C10 aryl, 5-10 membered heteroaryl-C3-C10 cycloalkyl, 5-10 membered heteroaryl-4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C6-C10 aryl, or 5-10 membered heteroaryl-5-10 membered heteroaryl; wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, 4-10 membered heterocycloalkyl-C1-C6 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, C6-C10 aryl-C6-C10 aryl, 5-10 membered heteroaryl-C3-C10 cycloalkyl, 5-10 membered heteroaryl-4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C6-C10 aryl, or 5-10 membered heteroaryl-5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C (O) ORa1, C (O) Rb1, S (O) 2Rb1, C1-C4 alkyl-O-C1-C4 alkyl, and C1-C4 alkyl-O-C1-C4 alkyl-O-;
or Rc and Rd 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C (O) ORa1, C (O) Rb1, S (O) 2Rb1, C1-C4 alkoxy-C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkoxy;
each Re is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy) -C1-C4 alkyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl;
each Rf is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, or 4-10 membered heterocycloalkyl;
each Ra1 is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
each Rb1 is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alky; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10  membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alky is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.
In some embodiments, R is selected from H, D or C1-C6 alkyl optionally substituted with F, OH or CN. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is C1-C6 alkyl optionally substituted with F, OH or CN. In some embodiments, R is Me.
In some embodiments, X is N.
In some embodiments, X is CR3.
In some embodiments, R3 is independently selected from H, D, halo, CN, SF5, NRCRD, ORA, C (O) RB, C (O) NRCRD, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein, the C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
In some embodiments, R3 is independently selected from H, D, halo, CN, SF5, NRCRD, ORA, C (O) RB, C (O) NRCRD, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
In some embodiments, for example, but not limited to, R3 is independently selected from H, D, halo, CN, SF5, NH2, OH, OCH3, OCH2CH3, NHCH3, NHCH2CH3, N (CH3) 2, CH3, CH2CH3, CF3, CH2CF3, C (O) RB, or C (O) NRCRD.
In some embodiments, Y is N.
In some embodiments, Y is CR9, and R9 is selected from H, D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C3-C5 cycloalkyl.
In some embodiments, R9 is H. In some embodiments, R9 is D. In some embodiments, R9 is CN. In some embodiments, R9 is halogen (such as F, Cl, Br, I) . In some embodiments, R9 is C1-C4 alkyl. In some embodiments, R9 is C1-C4 haloalkyl. In some embodiments, R9 is OC1-C4 alkyl. In some embodiments, R9 is OC1-C4 haloalkyl. In some embodiments, R9 is C3-C5 cycloalkyl.
In some embodiments, R1 is independently selected from H, D, halo, CN, SF5, NRCRD, ORA, C (O) RB, C (O) NRCRD, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
In some embodiments, L is (CR10R11) n, NR12 (CH2CH2) m, or O (CH2CH2) m.
In some embodiments, L is (CR10R11) n. In some embodiments, L is CR10R11. In some embodiments, L is (CR10R11) 2. In some embodiments, L is (CR10R11) 3.
In some embodiments, L is NR12 (CH2CH2) m. In some embodiments, L is NR12. In some embodiments, L is NR12CH2CH2.
In some embodiments, L is O (CH2CH2) m. In some embodiments, L is O. In some embodiments, L is OCH2CH2.
In some embodiments, R1 is independently selected from H, D, halo, CN, SF5, NRCRD, ORA, C (O) RB, C (O) NRCRD, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl; wherein, the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
In some embodiments, R1 is independently selected from H, D, halo, CN, SF5, OH, NH2, OCH3, OCH2CH3, NHCH3, NHCH2CH3, N (CH3) 2, CH3, CH2CH3, CF3, CH2CF3, C (O) RB, C (O) NRCRD. In some embodiments, R2 is independently selected from H, D, halo, CN, SF5, NRCRD, ORA, C (O) RB, C (O) NRCRD, C1-C6 alkyl, C3-C10 cycloalkyl or 4-10 membered heterocycloalkyl; wherein, the C1-C6 alkyl, C3-C10 cycloalkyl or 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, or 3  substituents independently selected from D, OH, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
In some embodiments, R2 is independently selected from H, D, halo, CN, SF5, NRCRD, ORA, C (O) RB, C (O) NRCRD, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl; wherein, the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
In some embodiments, for example, but not limited to, R2 is independently selected from H, D, halo, CN, SF5, OH, NH2, OCH3, OCH2CH3, NHCH3, NHCH2CH3, N (CH3) 2, CH3, CH2CH3, CF3, CH2CF3, C (O) RB, C (O) NRCRD.
In some embodiments, R1 and R2 together with the carbon atoms to which they are attached form a C3-C7 cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, oxo, ORa, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
In some embodiments, R1 and R2 together with the carbon atoms 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, NO2, oxo, ORa, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
In some embodiments, R2 and R3 together with the carbon atom to which they are attached form a C3-C7 cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, oxo, ORa, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
In some embodiments, R2 and R3 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, NO2, oxo, ORa, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
In some embodiments, each R4 is independently selected from H, D, NH2, or CN. In some embodiments, R4 is H. In some embodiments, R4 is D. In some embodiments, R4 is NH2. In some embodiments, R4 is CN.
In some embodiments, R4 is C1-C3 alkyl optionally substituted with D, halogen or CN. In some embodiments, R4 is Me. In some embodiments, R4 is CD3. In some embodiments, R4 is CF3.
In some embodiments, each R5 is independently selected from H, D, halo, CN or C1-C6 alkyl optionally substituted with D, halogen or CN.
In some embodiments, R5 is H. In some embodiments, R5 is D. In some embodiments, R5 is halo (such as F, Cl, Br, I) . In some embodiments, R5 is CN. In some embodiments, R5 is C1-C6 alkyl optionally substituted with D, halogen or CN.
In some embodiments, for example, but not limited to, each R5 is independently selected from H, D, halo, CN, CH3, CD3, CH2CH3, CH2CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH2CH2OH.
In some embodiments, each R6 is independently selected from H, D, halo, CN, SF5, ORB, C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl; wherein, the C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl optionally substituted with D, halo, CN, NH2, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl.
In some embodiments, for example, but not limited to, R6 is H, D, halo, CN, CH3, CD3, CH2CH3, CH2CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH2CH2OH or cyclopropyl.
In some embodiments, each R7 is independently selected from H, D, halogen, Me, CF3, OH, OMe, OCF3.
In some embodiments, R7 is H. In some embodiments, R7 is D. In some embodiments, R7 is halogen (such as F, Cl, Br or I) . In some embodiments, R7 is OH. In some embodiments, R7 is OMe.
In some embodiments, each R8 is independently selected from H, D, CN, SF5, C1-C6 alkyl optionally substituted with D, halogen or CN.
In some embodiments, R8 is H. In some embodiments, R8 is D. In some embodiments, R8 is CN. In some embodiments, R8 is SF5.
In some embodiments, R8 is C1-C6 alkyl optionally substituted with D, halogen or CN. In some embodiments, for example, but not limited to, R8 is CH3, CD3, CH2CH3, CH2CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3.
In some embodiments, the compound of formula (IA) and (IB) is represented by the compound of formula (IAa) , (IAb) , (IAc) , (IAd) , (IAe) , (IBa) , (IBb) , (IBc) , (IBd) , or (IBe) :
or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variants or prodrugs thereof; wherein X, Y, L, R, R1, R2, R4, R5, R6, R7, R8 are defined with respect to Formula (IA) and (IB) .
In some embodiments, L is (CR10R11) n, NR12 (CH2CH2) m, or O (CH2CH2) m.
In some embodiments, L is (CR10R11) n. In some embodiments, L is CR10R11. In some embodiments, L is (CR10R11) 2. In some embodiments, L is (CR10R11) 3.
In some embodiments, L is NR12 (CH2CH2) m. In some embodiments, L is NR12. In some embodiments, L is NR12CH2CH2.
In some embodiments, L is O (CH2CH2) m. In some embodiments, L is O. In some embodiments, L is OCH2CH2.
In some embodiments, R is selected from H, D or C1-C6 alkyl optionally substituted with F, OH or CN. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is Me.
In some embodiments, R4 is selected from H, D, NH2, or CN. In some embodiments, R4 is H. In some embodiments, R4 is D. In some embodiments, R4 is NH2. In some embodiments, R4 is CN.
In some embodiments, R4 is C1-C3 alkyl optionally substituted with D, halogen or CN. In some embodiments, R4 is Me. In some embodiments, R4 is CD3. In some embodiments, R4 is CF3.
In some embodiments, R5 is selected from H, D, halo, or CN. In some embodiments, R5 is H. In some embodiments, R5 is D. In some embodiments, R5 is CN. In some embodiments, R5 is F. In some embodiments, R5 is Cl.
In some embodiments, R5 is C1-C6 alkyl optionally substituted with D, halogen or CN. In some embodiments, R5 is Me. In some embodiments, R5 is CD3. In some embodiments, R5 is CF3.
In some embodiments, R6 is selected from H, D, halo, CN, SF5, ORB. In some embodiments, R6 is H. In some embodiments, R6 is D. In some embodiments, R6 is CN. In some embodiments, R6 is F. In some embodiments, R6 is Cl. In some embodiments, R6 is Br. In some embodiments, R6 is SF5.
In some embodiments, R6 is C1-C6 alkyl optionally substituted with D, halo, CN, NH2, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 4-7 membered heterocycloalkyl. In some embodiments, R6 is Me. In some embodiments, R6 is CD3. In some embodiments, R6 is CF3. In some embodiments, R6 is cyclopropyl.
In some embodiments, R7 is H. In some embodiments, R7 is D.
In some embodiments, R7 is halogen. In some embodiments, R7 is F. In some embodiments, R7 is Cl.
In some embodiments, R7 is OH. In some embodiments, R7 is OMe.
In some embodiments, R8 is selected from H, D, CN, SF5. In some embodiments, R8 is H. In some embodiments, R8 is D. In some embodiments, R8 is CN. In some embodiments, R8 is SF5.
In some embodiments, R8 is C1-C6 alkyl optionally substituted with D, halogen or CN. In some embodiments, R8 is Me. In some embodiments, R8 is CD3. In some embodiments, R8 is CF3.
In some embodiments, the compound of formula (IA) and (IB) is represented by the compound of formula (IIAa) , (IIAb) , (IIAc) , (IIAd) , (IIAe) , (IIBa) , (IIBb) , (IIBc) , (IIBd) , or (IIBe) :

or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, isotopic variants or prodrugs thereof; wherein X, Y, L, R, R1, R2, R4, R5, R6, R7, R8 are defined with respect to Formula (IA) and (IB) .
In some embodiments, the compound of formula (IA) and (IB) is represented by the compound of formula (IIIAa) , (IIIAb) , (IIIAc) , (IIIAd) , (IIIAe) , (IIIBa) , (IIIBb) , (IIIBc) , (IIIBd) , or (IIIBe) :
or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, Isotopic variants or prodrugs thereof; wherein X, Y, L, R, R1, R2, R4, R5, R6, R7, R8 are defined with respect to Formula (IA) and (IB) .
In some embodiments, the compound of formula (IA) and (IB) is represented by the compound of formula (IIAa) , (IIBa) , (IIIAa) , (IIIBa) :
or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, isotopic variants or prodrugs thereof; wherein X, Y, L, R, R1, R2, R4, R5, R6, R7 are defined with respect to Formula (IA) and (IB) .
In some embodiments, L is (CR10R11) n, NR12 (CH2CH2) m, or O (CH2CH2) m.
In some embodiments, L is (CR10R11) n. In some embodiments, L is CR10R11. In some embodiments, L is (CR10R11) 2. In some embodiments, L is (CR10R11) 3.
In some embodiments, L is NR12 (CH2CH2) m. In some embodiments, L is NR12. In some embodiments, L is NR12CH2CH2.
In some embodiments, L is O (CH2CH2) m. In some embodiments, L is O. In some embodiments, L is OCH2CH2.
In some embodiments, R is selected from H, D or C1-C6 alkyl optionally substituted with F, OH or CN. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is Me.
In some embodiments, R4 is selected from H, D, NH2, or CN. In some embodiments, R4 is H. In some embodiments, R4 is D. In some embodiments, R4 is NH2. In some embodiments, R4 is CN.
In some embodiments, R4 is C1-C3 alkyl optionally substituted with D, halogen or CN. In some embodiments, R4 is Me. In some embodiments, R4 is CD3. In some embodiments, R4 is CF3.
In some embodiments, R5 is selected from H, D, halo, or CN. In some embodiments, R5 is H. In some embodiments, R5 is D. In some embodiments, R5 is CN. In some embodiments, R5 is F. In some embodiments, R5 is Cl.
In some embodiments, R5 is C1-C6 alkyl optionally substituted with D, halogen or CN. In some embodiments, R5 is Me. In some embodiments, R5 is CD3. In some embodiments, R5 is CF3.
In some embodiments, R6 is selected from H, D, halo, CN, SF5, ORB. In some embodiments, R6 is H. In some embodiments, R6 is D. In some embodiments, R6 is CN. In some embodiments, R6 is F. In some embodiments, R6 is Cl. In some embodiments, R6 is Br. In some embodiments, R6 is SF5.
In some embodiments, R6 is C1-C6 alkyl optionally substituted with at least one of D, halo, CN, NH2, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted 4-7 membered heterocycloalkyl. In some embodiments, R6 is Me. In some embodiments, R6 is CD3. In some embodiments, R6 is CF3. In some embodiments, R6 is cyclopropyl.
In some embodiments, R7 is H. In some embodiments, R7 is D.
In some embodiments, R7 is halogen. In some embodiments, F. In some embodiments, Cl.
In some embodiments, R7 is OH. In some embodiments, R7 is OMe.
In some embodiments, R8 is selected from H, D, CN, SF5. In some embodiments, R8 is H. In some embodiments, R8 is D. In some embodiments, R8 is CN. In some embodiments, R8 is SF5.
In some embodiments, R8 is C1-C6 alkyl optionally substituted with D, halogen or CN. In some embodiments, R8 is Me. In some embodiments, R8 is CD3. In some embodiments, R8 is CF3.
In some embodiments, the compound of formula (IB) is represented by the compound of formula (IVBa) , (IVBb) , or (IVBc) :
or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variant or prodrugs thereof; wherein Y, R1, R2, R5, R6, R7, R10, R11 are defined with respect to Formula (IB) .
In compounds of Formula (IA) and (IB) , each RA is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocyclalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
In some embodiments, RA is independently selected from H. In some embodiments, RA is independently selected from D.
In some embodiments, RA is independently selected from C1-C6 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, wherein the C1-C6 alkyl, C2-C4 alkenyl or C2-C4 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, NRcS (O) (=NRb) Rb.
In other embodiments, RA is independently selected from C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C3-C10 cycloalkyl, 4-10 membered heterocyclalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, NRcS (O) (=NRb) Rb.
In compounds of Formula (IA) and (IB) , each RB is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In some embodiments, RB is independently selected from H. In some embodiments, RB is independently selected from D.
In some embodiments, RB is C1-C6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) . In some embodiments, RB is C1-C6 alkyl.
In some embodiments, RB is isopropyl, isobutyl, tert-butyl; each is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl. In some embodiments, RB is isopropyl. In some embodiments, RB is isobutyl. In some embodiments, RB is tert-butyl.
In some embodiments, RB is C2-C6 alkynyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In some embodiments, RB is C2-C6 alkenyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In some embodiments, RB is C3-C10 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In some embodiments, RB is cyclopropyl, cyclobutyl, cycylopentyl, cyclohexanyl; each is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl.
In other embodiments, RB is 4-10 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In some embodiments, RB is azetidinyl, pyrrolidinyl, piperidinyl or azepanyl optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, C (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In other embodiments, RB is C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C (O) Rb,  OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In some embodiments, each RC is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC (O) NRcRd, NRcRd, NRcC (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In some embodiments, each RC is independently selected from H. In some embodiments, each RC is independently selected from D.
In some embodiments, each RC is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; each is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC (O) NRcRd, NRcRd, NRcC (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In some embodiments, each RC is independently selected from C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; each is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC (O) NRcRd, NRcRd, NRcC (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In some embodiments, each RD is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC (O) NRcRd,  NRcRd, NRcC (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In some embodiments, each RD is independently selected from H. In some embodiments, each RD is independently selected from D.
In some embodiments, each RD is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; each is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC (O) NRcRd, NRcRd, NRcC (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In some embodiments, each RD is independently selected from C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; each is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC (O) NRcRd, NRcRd, NRcC (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) .
In other embodiments, RC and RD 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl.
In some embodiments, each Ra is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy.
In some embodiments, each Rb is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.
In some embodiments, Rc and Rd are each independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, C6-C10 aryl-C6-C10 aryl, 5-10 membered heteroaryl-C3-C10 cycloalkyl, 5-10 membered heteroaryl-4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C6-C10 aryl, or 5-10 membered heteroaryl-5-10 membered heteroaryl; wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, C6-C10 aryl-C6-C10 aryl, 5-10 membered heteroaryl-C3-C10 cycloalkyl, 5-10 membered heteroaryl-4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C6-C10 aryl, or 5-10 membered heteroaryl-5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C (O) ORa1, C (O) Rb1, S (O) 2Rb1, C1-C4 alkyl-O-C1-C4 alkyl, and C1-C4 alkyl-O-C1-C4 alkyl-O-.
In some embodiments, Rc and Rd 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C (O) ORa1, C (O) Rb1, S (O) 2Rb1, C1-C4 alkoxy-C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkoxy.
In some embodiments, each Re is each independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy) -C1-C4 alkyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl.
In some embodiments, each Rf is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl.
In some embodiments, each Ra1 is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy.
In some embodiments, each Rb1 is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alky; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alky is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.
In some embodiments, the compounds of Formula (IA) and (IB) are the pharmaceutically acceptable salts. In some embodiments, the compounds of Formula (IA) and (IB) are stereoisomers. In some embodiments, the compounds of Formula (IA) and (IB) are solvates. In some embodiments, the compounds of Formula (IA) and (IB) are N-oxides of the compounds of Formula (IA) and (IB) .
Stereoisomers of the compounds of Formula (IA) and (IB) , and the pharmaceutical salts and solvates thereof, are also contemplated, described, and encompassed herein. Methods of using compounds of Formula (IA) and (IB) are described, as well as pharmaceutical compositions including the compounds of Formula (IA) and (IB) .
In some embodiments, the compound of Formula (IA) and (IB) is:
or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variants or prodrugs thereof.
In some embodiments, the compound of Formula (IA) and (IB) is:
or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variants or prodrugs thereof.
It will be apparent that the compounds of Formula (IA) and (IB) , including all subgenera described herein, may have multiple stereogenic centers. As a result, there exist multiple stereoisomers (enantiomers and diastereomers) of the compounds of Formula (IA) and (IB) (and subgenera described herein) . The present disclosure contemplates and encompasses each stereoisomer of any compound of Formula (IA) and (IB) (and subgenera described herein) , as well as mixtures of said stereoisomers.
Pharmaceutically acceptable salts and solvates of the compounds of Formula (IA) and (IB) (including all subgenera described herein) are also within the scope of the disclosure.
Isotopic variants of the compounds of Formula (IA) and (IB) (including all subgenera described herein) are also contemplated by the present disclosure.
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.
The present disclosure further provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention provides a method of inhibiting PKMYT1 in a cell expressing PKMYT1, the method comprising contacting the cell with the compound disclosed herein.
In some embodiments, the cell is associated with CCNE1 amplification, FBXW7 loss-of-function mutations or other genetic alterations which depend on PKMYT1. In some embodiments, the cell is in a subject.
The invention provides a method of treating a subject in need thereof comprising administering to the subject the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition disclosed herein.
In some embodiments, the subject is suffering from, and is in need of a treatment for, a disease or condition having the symptom of cell hyperproliferation. In some embodiments, the disease or condition is a cancer. In some embodiments, the cancer is a cancer with CCNE1 amplification, FBXW7 loss-of-function mutations or other genetic alterations which depend on PKMYT1.
Routs of administration for the compounds in the present disclosure include, but not limited to oral, injection, topical and inhalation.
Definitions
Unless other indicated, the following terms are intended to have the meaning set forth below. Other terms are defined elsewhere throughout the specification.
As used herein, the singular forms “a” , “an” , and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology such as “solely” , “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.
At various places in the present specification, variables defining divalent linking groups are described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -NR (CR'R”) -includes both -NR (CR'R”) -and - (CR'R”) NR-and is intended to disclose each of the forms individually. Where the structure requires a linking group, 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.
The term “substituted” means that an atom or group of atoms formally replaces hydrogen as a “substituent” attached to another group. The term “substituted” , unless otherwise indicated, 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. The phrase “optionally substituted” means unsubstituted or substituted. The term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.
The term “Cn-Cm” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. For example, the term “C1-C6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. “C0 alkyl” refers to a covalent bond.
It is further intended that the compounds of the invention are stable. As used herein “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.
It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination.
As used herein, unless otherwise indicated, the term “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. Similary, C1-8, as in C1-8 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.
As used herein, unless otherwise indicated, “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.
As used herein, unless otherwise indicated, “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.
As used herein, unless otherwise indicated, “haloalkyl” refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include, but are not limited to, CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, and the like.
As used herein, unless otherwise indicated, “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.
As used herein, unless otherwise indicated, “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) . In some embodiments, 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. In some embodiments, the cycloalkyl is a C3-C7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C4-C10 spirocycle or bridged cycloalkyl. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo [l. l. l] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptanyl, bicyclo [3.1.1] heptanyl, bicyclo [2.2.2] octanyl, spiro [3.3] heptanyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, cycloalkyl are cyclic-containing, non-aromatic hydrocarbon groups having from 3 to 12 carbon atoms ( “C3-C12” ) , preferably from 3 to 6 carbon atoms ( “C3-C6” ) . Examples of cycloalkyl groups include, for example, cyclopropyl (C3; 3-membered) , cyclobutyl (C4; 4-membered) , cyclopropylmethyl (C4) , cyclopentyl (C5) , cyclohexyl (C6) , 1-methylcyclopropyl (C4) , 2-methylcyclopentyl (C4) , adamantanyl (C10) , and the like.
The term “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.
As used herein, unless otherwise indicated, a “heteroaryl” group 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. Examples of 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. In some embodiments, 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.
As used herein, unless otherwise indicated, “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. ) . 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.
Also included in the definition of heterocycloalkyl are 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. In some embodiments, 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. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S and B and having one or more oxidized ring members.
Example heterocycloalkyl groups include, but are not limited to, pyrrolidin-2-one, l, 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. l. 0] hexanyl, oxabicyclo [2.1. l] hexanyl, azabicyclo [2.2. l] heptanyl, diazabicyclo [2.2.1] heptanyl, azabicyclo [3.1. l] heptanyl, diazabicyclo [3.1. l] heptanyl, azabicyclo [3.2. l] octanyl, diazabicyclo [3.2.1] octanyl, oxabicyclo [2.2.2] octanyl, azabicyclo [2.2.2] octanyl, diazabicyclo [2.2.2] octanyl, azaadamantanyl, diazaadamantanyl, oxa-adamantanyl, azaspiro [3.3] heptanyl, diazaspiro [3.3] heptanyl, oxa-azaspiro [3.3] heptanyl, azaspiro [3.4] octanyl, diazaspiro [3.4] octanyl, oxa-azaspiro [3.4] octanyl, oxa-azaspiro [3.5] nonanyl, azaspiro [2.5] octanyl, diazaspiro [2.5] octanyl, azaspiro [4.4] nonanyl, diazaspiro [4.4] nonanyl, oxa-azaspiro [4.4] nonanyl, azaspiro [4.5] decanyl, diazaspiro [4.5] decanyl, diazaspiro [4.4] nonanyl, oxa-diazaspiro [4.4] nonanyl, octahydropyrrolo [3, 4-c] pyrrolyl and the like.
In some embodiments, 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. Examples of suitable 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.
In some embodiments, 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.
As used herein, unless otherwise indicated, “arylcycloalkyl” refers to cycloalkyl group substituted by an aryl group.
As used herein, unless otherwise indicated, “arylheterocycloalkyl” refers to a heterocycloalkyl group substituted by an aryl group.
As used herein, unless otherwise indicated, “arylheteroaryl” refers to a heteroaryl group substituted by an aryl group.
As used herein, unless otherwise indicated, “biaryl” refers to an aryl group substituted by another aryl group.
As used herein, unless otherwise indicated, “heteroarylcycloalkyl” refers to a cycloalkyl group substituted by a heteroaryl group.
As used herein, unless otherwise indicated, “heteroarylheterocycloalkyl” refers to a heterocycloalkyl group substituted by a heteroaryl group.
As used herein, unless otherwise indicated, “heteroarylaryl” refers to an aryl group substituted by a heteroaryl group.
As used herein, unless otherwise indicated, “biheteroaryl” refers to a heteroaryl group substituted by another heteroaryl group.
As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, and iodo.
As used herein, unless otherwise indicated, “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.
As used herein, unless otherwise indicated, “hydroxylalkyl” refers to an alkyl group substituted by OH.
As used herein, unless otherwise indicated, “cyanoalkyl” refers to an alkyl group substituted by CN.
As used herein, unless otherwise indicated, “alkoxyalkyl” refers to an alkyl group substituted by an alkoxy group.
As used herein, unless otherwise indicated, “alkoxyalkoxy” refers to an alkoxy group substituted by alkoxy.
As used herein, unless otherwise indicated, “haloalkoxy” refers to an –O- (haloalkyl) group.
As used herein, unless otherwise indicated, “arylalkyl” refers to alkyl substituted by aryl and “cycloalkylalkyl” refers to alkyl substituted by cycloalkyl. An example arylalkyl group is benzyl.
As used herein, unless otherwise indicated, “heteroarylalkyl” refers to alkyl substituted by heteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted by heterocycloalkyl.
As used herein, unless otherwise indicated, “oxo” refers to an oxygen substituent that is connected by a double bond (i.e., =O) .
As used herein, unless otherwise indicated, the phrase “optionally substituted” means unsubstituted or substituted.
As used herein, unless otherwise indicated, the term “substituted” refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent (s) . Typical substituents include, but are not limited to, D, halo, oxo, C1-C-6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkyl-NRc1Rd1, - (CH2CH2O) oC1-C6 alkyl wherein o is 1-10; C2-6 alkenyl-NRc1Rd1, C2-6 alkynyl-NRc1Rd1, OC2-6 alkyl-NRc1Rd1, CN, NO2, N3, ORa1, SRa1, C (O) Rb1, C (O) NRc1Rd1, -CH2C (O) NRc1Rd1, C (O) ORa1, OC (O) Rb1, OC (O) NRc1Rd1, -NRc1Rd1, NRc1C (O) Rb1, NRc1C (O) NRc1Rd1, NRc1C (O) ORa1, C (=NRg1) NRc1Rd1, NRc1C (=NRg1) NRc1Rd1, P (Rf1) 2, P (ORe1) 2, P (O) Re1Rf1, P (O) ORe1ORf1, S (O) Rb1, -SO (=NRb1) ; S (O) NRc1Rd1, S (O) 2Rb1, NRc1S (O) 2Rb1, S (O) 2NRc1Rd1, aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, spirocycloalkyl, spiroheterocycloalkyl, cycloalkyl, or heterocycloalkyl are optionally substituted with D, halo, oxo, C1-C-6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkyl-NRc1Rd1, C2-6 alkenyl-NRc1Rd1, C2-6 alkynyl-NRc1Rd1, OC2-6 alkyl-NRc1Rd1, CN, NO2, N3, ORa1, SRa1, C (O) Rb1, C (O) NRc1Rd1, -CH2C (O) NRc1Rd1, C (O) ORa1,  OC (O) Rb1, OC (O) NRc1Rd1, -NRc1Rd1, NRc1C (O) Rb1, NRc1C (O) NRc1Rd1, NRc1C (O) ORa1, C (=NRg1) NRc1Rd1, NRc1C (=NRg1) NRc1Rd1, P (Rf1) 2, P (ORe1) 2, P (O) Re1Rf1, P (O) ORe1ORf1, S (O) Rb1, S (O) NRc1Rd1, S (O) 2Rb1, NRc1S (O) 2Rb1, S (O) 2NRc1Rd1;
wherein, Ra1 is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
Rb1 is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 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, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl;
Rc1 and Rd1 are each independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; wherein the C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
Rc1 and Rd1 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-4 haloalkoxy;
each Re1 is each independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy) -C1-C4 alkyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4alkyl;
Rf1 is independently selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl;
Rg1 is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl; wherein the C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy.
The compounds described herein can be asymmetric (e.g., having one or more stereocenters) . All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.
Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone–enol pairs, amide-imidic acid pairs, lactam–lactim pairs, 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.
In some cases, 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. For example, isotopes of hydrogen include tritium and deuterium.
In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially  separated from the environment in which 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. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977) , each of which is incorporated herein by reference in its entirety.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
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. Examples of 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 (IA) and (IB) 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) . In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “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. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.
“Compounds of the present disclosure, ” and equivalent expressions, are meant to embrace compounds of Formula (IA) and (IB) as described herein, as well as its subgenera, which expression includes the stereoisomers (e.g., entaniomers, diastereomers) and constitutional isomers (e.g., tautomers) of compounds of Formula (IA) and (IB) as well as the pharmaceutically acceptable salts, where the context so permits.
As used herein, the term “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. For example, 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 (2H or D) , carbon-13 (13C) , nitrogen-15 (15N) , or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be 2H/D, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined within the skill of the art.
It is also to be understood that 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. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include all stereoisomers and mixtures, racemic or otherwise, thereof. Where one chiral center exists in a structure, but no specific stereochemistry is shown for that center, both enantiomers, individually or as a mixture of enantiomers, are encompassed by that structure. Where more than one chiral center exists in a structure, but no specific stereochemistry is shown for the centers, all enantiomers and diastereomers, individually or as a mixture, are encompassed by that structure. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
Pharmaceutical Compositions
Also provided are pharmaceutical compositions comprising compounds of Formula (IA) and (IB) , or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, Isotopic variants or prodrugs thereof, and a pharmaceutically acceptable carrier.
The 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, corn 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 intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing) .
The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, 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 (IA) and (IB) 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.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.1 mg to 1000 mg of Formula (IA) and (IB) 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 (IA) and (IB) 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.
Described below are non-limiting exemplary pharmaceutical compositions and methods for preparing the same.
Methods of Administration
The compounds of Formula (IA) and (IB) 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, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
Methods of Use
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.
As used herein, the term “IC50” refers to the half maximal 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 IC50) .
In some embodiments, the subject methods utilize a PKMYT1 inhibitor with an IC50 value of about or less than a predetermined value, as ascertained in an in vitro assay. In some embodiments, the PKMYT1 inhibitor inhibits PKMYT1 with an IC50 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 or less, 350 nM or less,  375 nM or less, 400 nM or less, 425 nM or less, 450 nM or less, 475 nM or less, 500 nM or less, 550 nM or less, 600 nM or less, 650 nM or less, 700 nM or less, 750 nM or less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or less, 1 μΜ or less, 1.1 μΜ or less, 1.2 μΜ or less, 1.3 μΜ or less, 1.4 μΜ or less, 1.5 μΜ or less, 1.6 μΜ or less, 1.7 μΜ or less, 1.8 μΜ or less, 1.9 μΜ or less, 2 μΜor less, 5 μΜ or less, 10 μΜ or less, 15 μΜ or less, 20 μΜ or less, 25 μΜ or less, 30 μΜ or less, 40 μΜ or less, 50 μΜ, 60 μΜ, 70 μΜ, 80 μΜ, 90 μΜ, 100 μΜ, 200 μΜ, 300 μΜ, 400 μΜ, or 500 μΜ, or less, (or a number in the range defined by and including any two numbers above) .
PKMYT1 is a synthetic lethal target in the cancers with certain genetic alterations, e.g., CCNE1 amplification or FBXW7 loss-of-function mutations, which may have the symptom of cell hyperproliferation. The subject methods are useful for treating disease conditions associated with CCNE1 amplification, FBXW7 loss-of-function mutations or other genetic alterations which depend on PKMYT1.
Non-limiting examples of such disease conditions include but are not limited to breast cancer, invasive ductal 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 cancer, squamous cell cervical cancer, cervical adenocarcinoma, cervical adenosquamous carcinoma, small cell cervical cancer, cervical mucinous tumor, clear cell cervical cancer, cervical lymphoma, cervical sarcoma, endometrial cancer, endometrial uterine cancer, endometrioid tumor, lung cancer, non-small cell lung cancer, small cell lung cancer, brain stem glioma, brain cancer, cerebellar astrocytoma, cerebral astrocytoma, head and neck cancer, glioblastoma multiforme, glioma, gliomatosis cerebri, ganglioglioma, ganglioneuroma, paraganglioma, primitive neuroectodermal tumor, supratentorial primitive neuroectodermal tumor, visual pathway glioma, neurinoma, neuroblastoma, neuroblastoma, neurofibroma, neuroma, esthesioneuroblastoma, extrahepatic bile duct cancer, Bellini duct carcinoma, cholangiocarcinoma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblasts leukemia with maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aggressive NK-cell leukemia, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, erythroleukemia, hairy Cell leukemia, leukemia, lymphoid leukemia, lymphoma, macroglobulinemia, mast cell leukemia, monocytic  leukemia, myeloid leukemia, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell prolymphocytic leukemia, AIDS-related lymphoma, angioimmunoblastic T-cell lymphoma, B-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, diffuse large B cell lymphoma, enteropathy-associated T-cell lymphoma, follicular lymphoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, Hodgkin’s lymphoma, lymphangioma, lymphangiosarcoma, lymphoepithelioma, MALT lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, non-Hodgkin lymphoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, small cell lymphoma, T-cell lymphoma, terminal lymphatic cancer.
The term “CCNE1 amplification” refers to the increased CCNE1 genes which leads to the increased expression of cyclin E protein in a diseased cell e.g., cancer cell, relative to expression of cyclin E protein in a control cell (e.g., non-diseased cell of the same type) . The amount of cyclin E expression can be at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 10-fold, at least 20-fold, at least 50-fold, relative to cyclin E expression in a control cell. Examples of CCNE1 amplification cancers include, but are not limited to, uterine Carcinosarcoma, ovarian epithelial tumor, endometrial cancer, esophagogastric cancer, sarcoma, bladder cancer, adrenocortical carcinoma, non-small cell lung cancer, pancreatic cancer, pleural mesothelioma, breast cancer, head and neck cancer, mature B-cell neoplasms, cervical cancer, ovarian cancer, hepatobiliary cancer, glioblastoma, colorectal cancer, melanoma, pheochromocytoma, glioma, prostate cancer, uterine cancer, sarcoma, stomach cancer, lung cancer, esophageal cancer, endometrial cancer, osteosarcoma, leukemia, lymphoma, and biliary tract carcinoma.
Examples of FBXW7 loss-of-function mutations cancers include, but are not limited to, uterine cancer, endometrial cancer, colorectal cancer, cervical cancer, esophagogastric cancer, bladder cancer, head and neck cancer, melanoma, non-small cell lung cancer, pancreatic cancer, sarcoma, breast cancer, stomach cancer, ovarian epithelial tumor, glioma, hepatobiliary cancer, ocular melanoma, glioblastoma, thyroid cancer, renal clear cell carcinoma, renal non-clear cell carcinoma, ovarian cancer, lung cancer, and esophageal cancer.
In some embodiments, said method is for use in the treatment or prevention of lymphoma, soft tissue, rhabdoid, multiple myeloma, uterus, gastric, peripheral nervous system, rhabdomyosarcoma, bone, colorectal, mesothelioma, breast, ovarian, lung, fibroblast, central nervous system, urinary tract, upper aerodigestive, leukemia, kidney, skin, esophagus, and pancreas (data from large scale drop out screens in cancer cell lines indicate that some cell lines from the above cancers are dependent on polymerase theta for proliferation see https: //depmap. org/portal/) .
In other embodiments, 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.
In other embodiments, said method is for treating a disease selected from the cancers with poor chemotherapy response or chemotherapy resistance, e.g., Epithelial Ovarian Cancer.
In other embodiments, said method is for treating a disease selected from the cancers with P53 or ATM mutations, e.g., head and neck cancer, non-small cell lung cancer, ovarian epithelial tumor, esophagogastric cancer, pancreatic cancer, colorectal cancer, bladder cancer, glioma, sarcoma, endometrial cancer, breast cancer, hepatobiliary cancer, glioblastoma, adrenocortical carcinoma, melanoma, pleural Mesothelioma, prostate cancer, cholangiocarcinoma, mature B-cell neoplasms, cervical cancer, leukemia, renal non-clear cell carcinoma, thymic epithelial tumor, renal clear cell carcinoma, seminoma, pheochromocytoma, thyroid cancer, and non-seminomatous germ cell tumor.
In other embodiments, 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.
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 a medical therapy. Medical therapies include, for example, surgery and radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioactive isotopes) .
In other methods, 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.
In other methods, the compounds of the disclosure, as well as pharmaceutical compositions comprising them, can be administered in combination with agonists of nuclear receptors agents.
In other methods, the compounds of the disclosure, as well as pharmaceutical compositions comprising them, can be administered in combination with antagonists of nuclear receptors agents.
Combination Therapies
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 PARP inhibitor, DNA-PK inhibitor, ATM inhibitor, ATR inhibitor, CHK1 inhibitor, LIG4 inhibitor, HIF-1 inhibitor, HDAC inhibitor, RAD51 inhibitor, WRN inhibitor, PRMT5 inhibitor, MAT2A inhibitor and PolQ inhibitor and so on) , immunotherapies, and gene and cell therapy approaches.
For treating cancers and other proliferative diseases, the compounds of the invention can be used in combination with a medical therapy such as surgery, radiotherapy or chemotherapy. Examples of radiotherapies include gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes. Examples of suitable 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) ; antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and antineoplastic drugs like taxol and taxotere and polokinase inhibitors) ; and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin) ; cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene) , antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate) , LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin) , progestogens (for example megestrol acetate) , aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase (for example finasteride) ; anti-invasion agents such as c-Src kinase family inhibitors (for example AZD0530, dasatinib and bosutinib) , and metalloproteinase inhibitors (for example marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to heparanase) .
For treating cancer and other proliferative diseases, 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. 54, ppl 1-29) ; such 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; Flt3 kinase inhibitors, CSF-IR kinase inhibitors and aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) ;  antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib, pazopanib, AZD2171; compounds such as those disclosed in International Patent Applications WO97/22596, WO97/30035, WO97/32856 and WO98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ανβ3 function and angiostatin) ) ; vascular damaging agents such as combretastatin A4 and compounds disclosed in International Patent Applications WO99/02166, WO00/40529, WO00/41669, WO01/92224, WO02/04434 and WO02/08213; an endothelin receptor antagonist, for example zibotentan or atrasentan; PARP inhibitors such as olaparib, rucaparib, niraparib, talazoparib, veliparib, and pamiparib; PARP1 selective inhibitors such as AZD9547, AZD5305, AG-14361 and NMS-P118; other DNA damage repair modulator such as DNA-PK inhibitor (for example LY294002, NU7026, NU7441, IC86621, IC87102, IC87361, OK-1035, SU11752, vanillin, NK314, IC486241, BVAN08, M3814, AZD7648, VX-984, Doxycycline) , ATM inhibitor (for example caffeine, wortmannin, CP-466722, KU-55933, KU-60019, and KU-559403) , ATR inhibitor (for example schisandrin B, NU6027, NVP-BEZ235, VE-821, VE-822, AZ20, Elimusertib, RP-3500 and AZD6738) , CHK1 inhibitor (for example LY2606368, PF-00477736, SRA737, SCH900776, MK8776, CCT244747 and AZD6738) , DNA LIG4 inhibitor (for example SCR7) , HIF-1 inhibitor (for example LW6 and PX-478) , HDAC inhibitor (for example short-chain fatty acids, benzamides, hydroxamic acids, and cyclic tetrapeptides, suberoylanilide hydroxamic acid (SAHA) , trichostatin A) , RAD51 inhibitor (for example CYT-0851, SCR-6992, SAT-93/101, CAM833, JKYN-1 (IBR120-series, B02-iso) ) , WRN (for example NCGC00029283) , antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; gene therapy approaches, including for example approaches to produce aberrant genes such as aberrant p53, CCNE1 amplification or FBXW7 loss-of-function mutations; GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotypic antibodies, approaches using immune checkpoint inhibitors such as CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, 0X40, 41BB, VISTA, CD96, TGF, CD73, CD39, A2AR, A2BR, IDOl, TD02, Arginase, B7-H3, B7-H4; approaches using inhibitors of the aforementioned immune-checkpoint receptors and ligands, for  example ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab, and durvalumab..
Synthesis
Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those in the Schemes below.
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. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.
Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups 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. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C) , infrared spectroscopy, spectrophotometry (e.g., UV-visible) , or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
The expressions, “ambient temperature” , “room temperature” , and “r.t. ” as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 ℃ to about 30 ℃.
Compounds of the invention can be prepared according to numerous preparatory routes known in the literature. The Schemes below provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare  various compounds of the invention. Example synthetic methods for preparing compounds of the invention are provided in the Schemes below.
The following Examples are provided to illustrate some of the concepts described within this disclosure. While the Examples are considered to provide an embodiment, it should not be considered to limit the more general embodiments described herein.
General Synthetic Procedures
A series of tricyclic derivatives of formula (IA) can be prepared as the methods described in Scheme 1. The 2-amino derivatives 1-1 can be converted to the 2-hydroxy derivatives 1-2, which can be transformed into the corresponding derivatives 1-3 where W1 is halogen (e.g., Cl, or Br) or pseudohalogen (e.g., OTf or OMs) either by reaction with a halogenation reagent such as SOCl2, POCl3 or POBr3 with or without the catalytic of DMF (where W1 is Cl or Br) or reaction with TfCl or MsCl (where W1 is OTf or OMs) in the presence of a base such as Hunig’s base. Coupling of compounds 1-3 with aromatic amines 1-4 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, Cs2CO3, or K2CO3) can afford aromatic amine derivatives 1-5. Reaction of the amine derivatives 1-5 with malononitrile to produce aminopyrroles 1-6 can be achieved under palladium-mediated conditions (e.g., in the presence of a palladium catalyst, such as Pd (PPh3) 2Cl2 or Pd (OAc) 2/PPh3, and a base, such as t-BuOK or t-BuONa) . Hydrolysis of the nitrile in 1-6 can be conducted under acidic or basic conditions to yield pyrrole-amide derivatives 1-7 which can be transformed into indole-pyrimidone 1-9 by treatment of with trialkyl orthoformate 1-8 (where R is methyl or ethyl) in the presence of an acid such as p-TsOH, or HCl. The indole-pyrimidone 1-9 can be converted into intermediates 1-10 where W2 is halogen (e.g., Cl, or Br) or pseudohalogen (e.g., OTf or OMs) either by reaction with a halogenation reagent such as SOCl2, POCl3 or POBr3 with or without the catalytic of DMF (where W2 is Cl or Br) or reaction with TfCl or MsCl (where W2 is OTf or OMs) in the presence of a base such as Hunig’s base. Reaction of the intermediates 1-10 with ammonia or amine derivatives can afford the desired tricyclic derivatives of formula (IA) .
Scheme 1
A series of intermediates 2-4 for preparations of tricyclic derivatives of formula (IA) can be prepared as the methods described in Scheme 2. Substitution of compounds 2-1 (W1 and W2 are halogen e.g., Cl, or Br) with malononitrile can form malononitrile derivatives 2-2 under palladium-mediated conditions (e.g., in the presence of a palladium catalyst, such as Pd (PPh3) 2Cl2 or Pd (OAc) 2/PPh3, and a base, such as t-BuOK or t-BuONa) . Coupling of malononitrile derivatives 2-2 with aromatic amines 2-3 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, Cs2CO3, or K2CO3) can afford aminopyrrole derivatives 2-4.
Scheme 2
A series of intermediates 3-6 for preparations of tricyclic derivatives of formula (IA) can be prepared as the methods described in Scheme 3. Reaction of the aromatic amines 3-1 with alkyl 2-cyanoacetate 3-2 (where, R is Me or Et) to yield aminopyrrole ester 3-3 can be achieved under palladium-mediated conditions (e.g., in the presence of a palladium catalyst, such as Pd (PPh3) 2Cl2 or Pd (OAc) 2/PPh3, and a base, such as t-BuOK or t-BuONa) . Tricyclic derivatives 3-6 can be prepared by reactions of the aminopyrrole ester 3-3 with cyano derivatives 2-4 in the presence of an acid, such as dry HCl, TsOH or H2SO4) or ethyl alkyl-carbimidate 3-5.
Scheme 3
A series of intermediates 4-3 for preparations of tricyclic derivatives of formula (IA) can be prepared as the methods described in Scheme 4. Suzuki coupling of compounds 4-1 with boronate ester 4-2 can afford the intermediates 4-3 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K3PO4) .
Scheme 4
A series of tricyclic derivatives of formula 5-8 can be prepared as the methods described in Scheme 5. Compounds 5-1 where W2 is halogen (e.g., Cl, Br, or I) and W1 is halogen (e.g., Br, or Cl) can be transformed into aminopyrrole derivatives 5-4 either by consequently reactions with malononitrile and Buchwald’s amination with aromatic amines 5-3 as described in the scheme 2 or Buchwald’s amination with aromatic amines 5-3 first and then reactions with malononitrile under palladium-mediated conditions for transformations of compounds 1-3 to aminopyrroles 1-6 as described in scheme 1 (e.g., in the presence of a palladium catalyst, such as Pd (PPh3) 2Cl2 or Pd (OAc) 2/PPh3, and a base, such as t-BuOK or t-BuONa) . The aminopyrrole derivatives 5-4 can be halogenated with suitable reagents, such as N-chlorosuccimide (NCS) , N-bromosuccimide (NBS) or N-iodosuccimide (NIS) to provide compounds 5-5 where W3 is a halogen (e.g., Cl, Br, or I) in which a suitable group R1 can be installed in the presence of a metal-mediated coupling such as standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K3PO4) , 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 a palladium (0) catalyst, such as tetrakis (triphenyl-phosphine) palladium (0) ) to afford compounds 5-6. Compounds 5-6 can be further converted to the desired tricyclic derivatives of formula 5-8 as those described for compounds 1-6 to formula (IA) and (IB) in scheme 1.
Scheme 5
Alternatively, a series of tricyclic derivatives of formula 6-10 can be prepared as the methods described in Scheme 6. O-alkylation of pyrazin-2 (1H) -one 6-1 with benzyl bromide or benzyl chloride in the presence of a base such as NaH, or K2CO3 can afford pyrazine 6-2 which can be transformed into aminopyrrole amide 6-6 by consequently reactions with aromatic amines 6-3 and malononitrile, and hydrolysis as those described for the transformations of compounds 1-3 to 1-7 in scheme 1. Hydrogenation of compounds 6-6 can produce the corresponding compounds 6-7 in the presence of a palladium catalyst such as Pd/C or Pd (OH) 2/C. The hydroxyl group in compounds 6-7 can be converted to the corresponding triflate derivatives 6-8 by treatment with a triflation reagent such as PhNTf2 or Tf2O in the presence of a base such as Et3N or Hunig’s base. The triflate derivatives 6-8 can be transformed into desired compounds 6-9 which can lead to the final tricyclic derivatives 6-10 as those described in scheme 1.
Scheme 6
Alternatively, a series of tricyclic derivatives of formula 7-8 can be prepared as the methods described in the scheme 7. The compounds 7-3 can be prepared by halogenation with N-chlorosuccimide (NCS) , N-bromosuccimide (NBS) or N-iodosuccimide (NIS) and a metal-mediated coupling to install R1 group under Suzuki conditions, Negishi conditions or Stille conditions as  described in scheme 5. Compounds 7-3 can be converted to the desired tricyclic derivatives 7-8 as those described in scheme 6.
Scheme 7
A series of tricyclic derivatives of formula 8-10 can be prepared as the methods described in Scheme 8. The 2-amino bromo derivatives 8-1 (n is 0, 1 or 2) can be transformed into the corresponding derivatives 8-2 where W is halogen (e.g., Cl, Br or I) by treatment with NaNO2 in the presence of an acid such as HCl, or HBr and following reaction with a halogenation reagent such as CuCl, CuBr or CuI. Coupling of compounds 8-2 with a suitable aromatic amine 8-3 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, Cs2CO3, or K2CO3) can afford aromatic amine derivatives 8-4. The carboxylate group in 8-4 can be reduced to the corresponding alcohol 8-5 by using a reducing reagent such as LiBH4 or NaBH4. Substitution of the 3-Br in aromatic amines 8-5 with malononitrile to produce aminopyrroles 8-6 can be achieved under copper-mediated coupling conditions (e.g., CuI in the presence of diamine-based ligands, such as N1, N2-dimethylethane-1, 2-diamine, N1, N2-dimethylcyclohexane-1, 2-diamine or cyclohexane-1, 2-diamine) or under palladium-mediated conditions (e.g., in the presence of a palladium catalyst, such as Pd (PPh3) 2Cl2 or Pd (OAc) 2/PPh3, and a base, such as t-BuOK or t-BuONa) . Hydrolysis of the nitrile in 8-6 can be done under acidic or basic conditions to yield pyrrole-amide derivatives 8-7 which can be transformed into compounds 8-8 by treatment of with DPPA (diphenyl phosphorazidate) and DBU or by Mitsunobo reaction with azide or sodium azide and DEAD or DIAD. Reduction of the azide group in compounds 8-8 to the corresponding amines 8-9 can be achieved by treatment with triphenylphosphine or by hydrogenation in the presence of a palladium catalyst such as Pd/C. Intramolecular amide formation can afford the desired tricyclic derivatives of formula 8-10.
Scheme 8
Alternatively, a series of tricyclic lactam derivatives of formula 9-10 can be prepared as the methods described in Scheme 9. Condensation of 3-bromopyridin-2-amines 9-1 with pyruvic acid can give azaindole acids 9-2 in the presence of a palladium catalyst such as bis (tri-tert-butylphosphine) palladium (0) , and a base such as potassium phosphate. The azaindole acids 9-2 can be conveniently transformed into the corresponding azaindole ester 9-3 (where R is Me or Et) by treatment with diazomethane (where R is Me) or treatment with oxalyl chloride following by alcohol ROH. Azaindole derivatives 9-4 can be prepared from the azaindole ester 9-3 in various ways: 1) treatment 9-3 with POCl3 in a catalytic amount of DMF, and following by treatment with an oxidative reagent such as Ag2O) treatment 9-3 with anhydrous trifluoroacetic acid following with NaOH; 3) treatment 9-3 with 2, 2, 2-trichloroacetyl chloride following with NaOH. The indole derivatives 9-4 can be transformed into azaindole lactams 9-5 by treatment with a protected amine such as p-methoxybenzylamine PMB-NH2 in the presence of an amide coupling reagent such BOP, ByBOP, HATU or HBTU, and a base such as Et3N or Hunig’s base. Coupling of the indole lactams 9-5 with aromatic iodide or bromides 9-6 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, Cs2CO3, or K2CO3) can afford aza-indole derivatives 9-7 which then can be transformed into amino-azaindole derivatives 9-9 by Curtius rearrangement of the products of the reactions of azaindole acids 9-8 with DPPA (diphenylphosphoryl azide) . Removal of the protecting group PMB in 9-9 to give the final tricyclic lactam derivatives 9-10 can be achieved by hydrogenation in the presence of a palladium catalyst such as Pd/C or Pd (OH) 2/C or under acid  conditions such as TFA.
Scheme 9
A series of intermediates 10-6 for preparations of tricyclic derivatives of formula (IB) can be prepared as the methods described in Scheme 10. Substitution of the 3-bromo in aromatic amines 10-1 with alkyl 2-cyanoacetate 10-2 (R = Me or Et) to yield aminopyrrole ester 10-3 can be achieved under palladium-mediated conditions (e.g., in the presence of a palladium catalyst, such as Pd (PPh3) 2Cl2 or Pd (OAc) 2/PPh3, and a base, such as t-BuOK or t-BuONa) . Tricyclic derivatives 10-6 can be prepared by reactions of the aminopyrrole ester 10-3 with cyano derivatives 10-4 in the presence of an acid, such as dry HCl, TsOH or H2SO4) or ethyl alkyl-carbimidate 10-5.
Scheme 10
A series of intermediates 11-3 for preparations of tricyclic derivatives of formula (IB) can be prepared as the methods described in Scheme 11. Suzuki coupling of compounds 4-1 with boronate ester 11-2 can afford the intermediates 11-3 under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K3PO4) .
Scheme 11
A series of tricyclic derivatives of formula 12-8 can be prepared as the methods described in Scheme 12. Compounds 12-1 where W2 is halogen (e.g., Cl, Br, or I) and W1 is halogen (e.g., Br, or Cl) can be transformed into aminopyrrole derivatives 12-4 either by consequently reactions with malononitrile and Buchwald’s amination with aromatic amines 12-3 as described in the scheme 9 or Buchwald’s amination with aromatic amines 12-3 first and then reactions with malononitrile under palladium-mediated conditions for transformations of compounds 8-3 to aminopyrroles 8-6 as described in scheme 8. (e.g., in the presence of a palladium catalyst, such as Pd (PPh3) 2Cl2 or Pd (OAc) 2/PPh3, and a base, such as t-BuOK or t-BuONa) . The aminopyrrole derivatives 12-4 can be halogenated with suitable reagents, such as N-chlorosuccimide (NCS) , N-bromosuccimide (NBS) or N-iodosuccimide (NIS) to provide compounds 12-5 where W3 is a halogen (e.g., Cl, Br, or I) in which a suitable group R1 can be installed in the presence of a metal-mediated coupling such as standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as [1, 1′- bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K3PO4) , 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 a palladium (0) catalyst, such as tetrakis (triphenyl-phosphine) palladium (0) ) to afford compounds 12-6. Compounds 12-6 can be further converted to the desired tricyclic derivatives of formula 12-8 as those described for compounds 8-6 to formula (IA) and (IB) in scheme 8.
Scheme 12
Examples
Example 1: 3- (4-Amino-6-morpholino-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) - 2, 4-dimethylphenol
Step 1: 1-bromo-2, 4-dimethyl-3-nitrobenzene
To a suspension of 1, 3-dimethyl-2-nitrobenzene (20.0 g, 132 mmol) and Fe (2.96 g, 52.9 mmol) in CHCl3 (200 mL) was added a solution of Br2 (22.2 g, 139 mmol) in CHCl3 (100 mL) . The reaction mixture was stirred at 15 ℃ for 12 h., and then diluted with water (500 mL) . The mixture was extracted with DCM (2 x 250 mL) . The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude title compound (26.0 g) as a light brown solid, which was used in next step without purification. 1H NMR: (400 MHz, CDCl3) δ 7.55 (d, J = 8.4, 1H) , 7.01 (d, J = 8.4, 1H) , 2.35 (s, 3H) , 2.26 (s, 3H) .
Step 2: 2, 4-dimethyl-3-nitrophenol
A mixture of 1-bromo-2, 4-dimethyl-3-nitrobenzene (20.0 g, 86.9 mmol) , KOH (14.6 g, 261 mmol) , 2’-di-tert-butylphosphino-2, 4, 6-triisopropylbiphenyl (7.38 g, 17.4 mmol) and bis (dibenzylideneacetone) palladium (7.96 g, 8.69 mmol) in dioxane (200 mL) and H2O (200 mL) was degassed and recharged with N2 for 3 cycles, and stirred at 90 ℃ for 12 h under N2 atmosphere. After cooling to r.t., the reaction mixture was diluted with water (600 mL) , adjusted with 1M HCl aq. to pH ～3 and extracted with EtOAc (250 mL) . The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (2-20%) to afford the title compound (10.0 g, crude) as a light brown solid. 1H NMR: (400 MHz, CDCl3) δ 6.95 (d, J = 8.4, 1H) , 6.78 (d, J = 8.4, 1H) , 2.22 (s, 3H) , 2.17 (s, 3H) .
Step 3: 1-methoxy-2, 4-dimethyl-3-nitrobenzene
To a solution of 2, 4-dimethyl-3-nitrophenol (12.0 g, 71.8 mmol) in acetone (84.0 mL) was added cesium carbonate (46.8 g, 144 mmol) and CH3I (15.3 g, 108 mmol) . The reaction mixture was stirred at 15 ℃ for 12 h. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (2-20%) to afford crude title compound (10 g) as a light-yellow solid.
Step 4: 3-methoxy-2, 6-dimethylaniline
To a solution of 1-methoxy-2, 4-dimethyl-3-nitrobenzene (7 g, 38.6 mmol) in EtOH (35.0 mL) and H2O (35.0 mL) was added Fe (21.6 g, 386 mmol) and NH4Cl (20.7 g, 386 mmol) . The reaction mixture was stirred at 80 ℃ for 2 h. The solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (2-20%) to afford the title compound (5.00 g) as a light-yellow oil. 1H NMR: (400 MHz, CDCl3) δ 6.90 (d, J = 12, 1H) , 6.32 (d, J = 8.0, 1H) , 3.80 (s, 3H) , 3.62 (brs, 2H) , 2.15 (s, 3H) , 2.09 (s, 3H) .
Step 5: 5-bromo-6-chloropyrazin-2-ol
To a solution of 5-bromo-6-chloropyrazin-2-amine (20.0 g, 96.0 mmol) in conc. H2SO4 (98%, 140 mL) was carefully added NaNO2 (7.28 g, 106 mmol) in small portions at 0℃. The reaction mixture  was stirred at 0 ℃ for 1 h., and poured into ice-water. The solid crashed out was collected by filtration, dried under vacuum to afford the title compound (20.0 g) as a light brown solid, which was used in next step without further purification.
Step 6: 5- (benzyloxy) -2-bromo-3-chloropyrazine
To a solution of 5-bromo-6-chloropyrazin-2-ol (8.00 g, 38.2 mmol) in toluene (140 mL) was added (bromomethyl) benzene (7.19 g, 42.0 mmol) and Ag2CO3 (21.1 g, 76.4 mmol) . The reaction mixture was stirred at 15 ℃ for 3 h. The solid was removed by filtration and the filtrate was collected and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel. column eluting with EtOAc/PE (10-50%) to afford the title compound (6.90 g, 60.3%yield) as a brown solid. 1H NMR: (400 MHz, CDCl3) δ 7.99 (s, 1H) , 7.39-7.47 (m, 5H) , 5.38 (s, 2H) .
Step 7: 5- (benzyloxy) -3-chloro-N- (3-methoxy-2, 6-dimethylphenyl) pyrazin-2-amine
To a solution of 5- (benzyloxy) -2-bromo-3-chloropyrazine (3.19 g, 10.6 mmol) in toluene (15.0 mL) was added potassium tert-butoxide (1.59 g, 14.2 mmol) , 3-methoxy-2, 6-dimethylaniline (1.61 g, 10.6 mmol) , bis (dibenzylideneacetone) palladium (487 mg, 0.53 mmol) and Xantphos (616 mg, 1.06 mmol) at r.t. The reaction mixture was degassed and recharged with nitrogen 3 cycles and stirred at 80 ℃ for 1 h. The reaction mixture was cooled to r.t, and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0.25–2%) to afford the title compound (2.40 g, 60.9%yield) as light-yellow oil. 1H NMR: (400 MHz, CDCl3) δ 7.75 (s, 1H) , 7.27-7.65 (m, 5H) , 7.08 (d, J = 8.4, 1H) , 6.77 (d, J = 8.4, 1H) , 6.06 (s, 1H) , 5.30 (s, 2H) , 3.84 (s, 3H) , 2.15 (s, 3H) , 2.09 (s, 3H) .
Step 8: 6-amino-2- (benzyloxy) -5- (3-methoxy-2, 6-dimethylphenyl) -5H-pyrrolo [2, 3-b] pyrazine-7-carbonitrile
To a solution of propanedinitrile (1.04 g, 15.8 mmol) in dimethyl ether (73.0 mL) was added sodium hydride (632 mg, 15.8 mmol) at r.t. The reaction mixture was stirred at r.t for 30 mins, followed by addition of a solution of 5- (benzyloxy) -3-chloro-N- (3-methoxy-2, 6-dimethylphenyl) pyrazin-2-amine (1.46 g, 3.95 mmol) in 1, 2-dimethoxyethane (7.30 mL) and tetrakis (triphenylphosphine) palladium (2.28 g, 1.97 mmol) at r.t.. The reaction mixture was degassed  and recharged with nitrogen for three cycles, and stirred at 80 ～ 85 ℃ for 2 h. After cooling, the mixture was quenched with H2O (100 mL) at 0 ℃, and extracted with DCM (2 x 20 mL) . The combined organic layers were washed with brine (30 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with MeOH/DCM (1-50%) to afford the title compound (1.90 g, 78.7%yield) as yellow oil. 1H NMR: (400 MHz, CDCl3) δ 7.65 (s, 1H) , 7.23-7.53 (m, 6H) , 6.97 (d, J = 8.4, 1H) , 5.49 (s, 2H) , 4.85 (s, 2H) , 3.87 (s, 3H) , 1.93 (s, 3H) , 1.86 (s, 3H) .
Step 9: 6-amino-2-hydroxy-5- (3-methoxy-2, 6-dimethylphenyl) -5H-pyrrolo [2, 3-b] pyrazine-7-carboxamide
A solution of 6-Amino-2- (benzyloxy) -5- (3-methoxy-2, 6-dimethylphenyl) -5H-pyrrolo [2, 3-b] pyrazine-7-carbonitrile (1.90 g, 4.76 mmol) in conc. H2SO4 (98%, 10 mL) was stirred at 15 ℃ for 2 h, and quenched by adding the reaction mixture into ice (～50 g) below 10 ℃. The mixture was adjusted with NH3. H2O (25-30%, ～40 mL) to pH ～8, extracted with EtOAc (3 x 20 mL) . The combined organic layers were washed with brine (10 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (1.30 g) as brown oil which was used directly in next step without purification. 1H NMR: (400 MHz, CDCl3) δ 7.52 (s, 1H) , 7.21 (d, J = 8.4, 1H) , 6.95 (d, J = 8.4, 1H) , 6.05 (brs, 2H) , 3.87 (s, 3H) , 1.95 (s, 3H) , 1.88 (s, 3H) . LCMS calc. for C16H18N5O3 [M+H] +: m/z = 328.1; found: 327.9.
Step 10: 6-amino-7-carbamoyl-5- (3-methoxy-2, 6-dimethylphenyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl trifluoromethanesulfonate
To a solution of 6-amino-2-hydroxy-5- (3-methoxy-2, 6-dimethylphenyl) -5H-pyrrolo [2, 3-b] pyrazine-7-carboxamide (1.30 g, 3.97 mmol) in DMF (6.00 mL) was added cesium carbonate (2.85 g, 8.74 mmol) at r.t., followed by addition of N-phenyl-bis (trifluoromethanesulfonimide) (1.56 g, 4.37 mmol) at 0 ～5 ℃. The reaction mixture was stirred at 0 ～ 5 ℃ for 0.5 h, quenched with water (20.0 mL) and extracted with EtOAc (2 x 5 mL) . The combined organic layers were washed with brine (5mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (10-50%) to afford the title  compound (0.64 g, 35.1%yield) as a light brown oil. 1H NMR: (400 MHz, CDCl3) δ 7.70 (s, 1H) , 7.16 (s, 1H) , 6.92 (d, J = 8.4, 1H) , 3.81 (s, 3H) , 1.86 (s, 3H) , 1.79 (s, 3H) .
Step 11: 6-amino-5- (3-methoxy-2, 6-dimethylphenyl) -2-morpholino-5H-pyrrolo [2, 3-b] pyrazine-7-carboxamide
To a solution of 6-amino-7-carbamoyl-5- (3-methoxy-2, 6-dimethylphenyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl trifluoromethanesulfonate (0.64 g, 1.39 mmol) in DMSO (2.0 mL) was added morpholine (3.0 g, 34.4 mmol) . The reaction mixture was stirred at 135 ℃ for 2 h. The reaction mixture was cooled to r.t., quenched with water (6.00 mL) and extracted with EtOAc (2 x 5 mL) . The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (10-50%) to afford the title compound (0.34 g, 0.86 mmol) as a light brown foam. 1H NMR: (400 MHz, CDCl3) δ 7.70 (brs, 1H) , 7.44 (s, 1H) , 7.21 (d, J = 8.4, 1H) , 6.95 (d, J = 8.4, 1H) , 6.02 (brs, 2H) , 3.89-3.92 (m, 4H) , 3.87 (s, 3H) , 3.48-3.50 (m, 4H) , 1.95 (s, 3H) , 1.88 (s, 3H) .
Step 12: 9- (3-methoxy-2, 6-dimethylphenyl) -6-morpholino-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-ol
A mixture of 6-amino-5- (3-methoxy-2, 6-dimethylphenyl) -2-morpholino-5H-pyrrolo [2, 3-b] pyrazine-7-carboxamide (0.2 g, 0.5 mmol) and trimethyl orthoformate (4 mL) was added TsOH. H2O (9.60 mg, 0.05 mmol) . The reaction mixture was stirred at 40 ℃ for 1 h., and concentrated under reduced pressure to afford crude title compound (0.2 g) as brown oil which was used directly in next step without purification. LCMS calc. for C21H23N6O3 [M+H] +: m/z = 407.2; found: 407.1.
Step 13: 4- (4-chloro-9- (3-methoxy-2, 6-dimethylphenyl) -9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-6-yl) morpholine
A mixture of 9- (3-methoxy-2, 6-dimethylphenyl) -6-morpholino-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-ol (0.20 g, 0.49 mmol) and POCl3 (7.55 g, 49.2 mmol)  was stirred at 100 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with water (1 mL) , adjusted with saturated NaHCO3 (1 mL) to pH ～8, and extracted with EtOAc (2 x 2 mL) . The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude title compound (0.2 g) as a light brown oil which was used directly in next step without purification. LCMS calc. for C21H22ClN6O2 [M+H] +: m/z = 425.1; found: 425.0.
Step 14: 9- (3-methoxy-2, 6-dimethylphenyl) -6-morpholino-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-amine
To a solution of 4- (4-chloro-9- (3-methoxy-2, 6-dimethylphenyl) -9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-6-yl) morpholine (0.2 g, 0.47 mmol) in MeOH (1.0 mL) was added NH3/MeOH (6 M, 20.0 mL) in a sealed tube. The reaction mixture was stirred at 80 ℃overnight, and concentrated under reduced pressure to afford crude title compound (0.2 g) as a light brown oil, which was used directly in next step without purification. 1H NMR: (400 MHz, MeOD) δ 8.25 (s, 1H) , 7.99 (s, 1H) , 7.23 (d, J = 8.4, 1H) , 7.08 (d, J = 8.4, 1H) , 3.87-3.90 (m, 7H) , 3.64-3.66 (m, 4H) , 1.80-1.81 (m, 2H) , 1.72-1.73 (m, 2H) . LCMS calc. for C21H24N7O2 [M+H] +: m/z = 406.2; found: 406.3.
Step 15: 3- (4-amino-6-morpholino-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol
A mixture of 9- (3-methoxy-2, 6-dimethylphenyl) -6-morpholino-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-amine (0.2 g, 0.49 mmol) in HBr (40%) (4.47 g, 22.1 mmol, 3 mL) was stirred at 80 ℃ for 1 h. The reaction mixture was poured into ice-water, adjusted with NH3. H2O (25-30%) to pH 7～8 at 0 ℃, and extracted with EtOAc (3 x 5 mL) . The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC on a C18 column eluting with MeCN/water (30-60%with 1%NH4HCO3) to afford the desired compound (0.048 g, 24.5%yield) as a light-yellow solid. 1H NMR: (400 MHz, MeOD) δ 8.25 (s, 1H) , 7.99 (s, 1H) , 7.08 (d, J = 8.4, 1H) , 6.91 (d, J = 8.4, 1H) , 3.87-3.90 (m, 4H) , 3.64-3.66 (m, 4H) , 1.78 (s, 3H) , 1.72 (s, 3H) . LCMS calc. for C20H22N7O2 [M+H] +: m/z = 392.2; found: 392.1.
This compound is a mixture of (3Ra) - (4-Amino-6-morpholino-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol and its enantiomer (3Sa) - (4-Amino-6-morpholino-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol.
Example 2: 3- (4-Amino-6-methyl-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol
Step 1: 6-amino-5- (3-methoxy-2, 6-dimethylphenyl) -2-methyl-5H-pyrrolo [2, 3-b] pyrazine-7-carboxamide
A mixture of 6-amino-7-carbamoyl-5- (3-methoxy-2, 6-dimethylphenyl) -5H-pyrrolo [2, 3-b] pyrazin-2-yl trifluoromethanesulfonate (1.00 g, 2.18 mmol, Example 1 Step 10) , 2, 4, 6-trimethyl-1, 3, 5, 2, 4, 6-trioxatriborinane (601 mg, 2.39 mmol, 0.67 mL, 50%purity) , tetrakis (triphenylphosphine) palladium (252 mg, 0.22 mmol) and potassium carbonate (902 mg, 6.53 mmol) in dioxane (10.0 mL) was degassed and recharged with N2 for 3 cycles, and stirred at 140 ℃for 2 h under N2 atmosphere. After cooling to 15 ℃, the reaction mixture was diluted with H2O (50 mL) , and extracted with EtOAc (3 x 25 mL) . The combined organic layers were washed with brine (50 mL) , dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel. column eluting with EtOAc/PE (10-50%) to afford the title compound (0.40 g, 56.5%yield) as a light brown foam. LCMS calc. for C17H20N5O2 [M+H] +: m/z = 326.2; found: 325.9
Step 2: 3- (4-amino-6-methyl-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol
This compound was prepared using procedures analogous to those described for Example 1 Step 12-15 using 6-amino-5- (3-methoxy-2, 6-dimethylphenyl) -2-methyl-5H-pyrrolo [2, 3-b] pyrazine-7-carboxamide in Step 12. 1H NMR: (400 MHz, MeOD) δ 8.34 (s, 1H) , 8.25 (s, 1H) , 7.05 (d, J = 8.4, 1H) , 6.92 (d, J = 8.4, 1H) , 2.67 (s, 3H) , 1.68 (s, 3H) , 1.58 (s, 3H) . LCMS calc. for C17H17N6O [M+H] +: m/z = 321.1; found: 321.1.
This compound is a mixture of (3Ra) - (4-Amino-6-methyl-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol and its enantiomer (3Sa) - (4-Amino-6-methyl-9H-pyrazino [2', 3': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol.
Example 3: 3- (4-Amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol
Step 1: 3-bromo-5, 6-dimethylpyridin-2-ol
This compound was prepared using procedures analogous to those described for Example 1 Step 5 using 3-bromo-5, 6-dimethylpyridin-2-amine to replace 5-bromo-6-chloropyrazin-2-amine. 1H NMR: (400 MHz, DMSO-d6) δ 11.96 (brs, 1H) , 7.73 (s, 1H) , 2.11 (s, 3H) , 1.96 (s, 3H) . LCMS calc. for C7H9BrNO [M+H] +: m/z = 201.9; found: 201.8.
Step 2: 2, 3-dibromo-5, 6-dimethylpyridine
To a solution of 3-bromo-5, 6-dimethylpyridin-2-ol (12.3 g, 60.9 mmol) in DMF (37.0 mL) and toluene (62.0 mL) was added dropwise a solution of POBr3 (26.2 g, 91.3 mmol, 9.28 mL) in xylene (30.0 mL) at 90 ℃ under nitrogen. The reaction mixture was stirred at 90 ℃ for 12 h. After cooling to r.t., the mixture was slowly poured into water (100 mL) and extracted with EtOAc (2 x 50 mL) . The combined organic layers were washed sequentially with NaOH aq. (0.5 N, 30 mL) , water (30 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (5-20%) to afford the title compound (12.0 g, 74.4%yield) as a white solid. 1H NMR: (400 MHz, CDCl3) δ 7.62 (s, 1H) , 2.45 (s, 3H) , 2.24 (s, 3H) . LCMS calc. for C7H8Br2N [M+H] +: m/z = 263.8; found: 263.8.
Step 3: 3-bromo-N- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethylpyridin-2-amine
This compound was prepared using procedures analogous to those described for Example 1 Step 7 using 2, 3-dibromo-5, 6-dimethylpyridine to replace 5- (benzyloxy) -2-bromo-3-chloropyrazine, and  cesium carbonate to replace potassium tert-butoxide. 1H NMR: (400 MHz, CDCl3) δ 7.44 (s, 1H) , 7.05 (d, J = 8.4 Hz, 1H) , 6.73 (d, J = 8.4 Hz, 1H) , 6.20 (s, 1H) , 3.85 (s, 3H) , 2.19 (s, 3H) , 2.17 (s, 3H) , 2.13 (s, 3H) , 2.11 (s, 3H) . LCMS calc. for C16H20BrN2O [M+H] +: m/z = 335.1; found: 335.0.
Step 4: 2-amino-1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile
To a solution of propanedinitrile (1.97 g, 29.8 mmol) in 1, 2-dimethoxyethane (35.0 mL) was added sodium tert-butoxide (2.87 g, 29.8 mmol) under N2 atmosphere. The mixture was stirred at 15 ℃ for 30 min, followed by addition of 3-bromo-N- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethylpyridin-2-amine (5.00 g, 14.9 mmol) , 1, 1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (1.22 g, 1.49 mmol) . The reaction mixture was degassed and recharged with nitrogen for 3 cycles, stirred at 85 ℃ for 12 h under N2 atmosphere. After cooling to r.t., the mixture was diluted with water (40.0 mL) and extracted with EtOAc (2 x 20 mL) . The combined organic layers were washed with brine (10 mL) , dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (10-50%) to afford the title compound (4.30 g, 90.0%yield) as a light brown solid. 1H NMR: (400 MHz, CDCl3) δ 7.51 (s, 1H) , 7.19 (d, J = 8.4 Hz, 1H) , 6.95 (d, J = 8.4 Hz, 1H) , 4.50 (brs, 1H) , 3.88 (s, 3H) , 2.38 (s, 3H) , 2.33 (s, 3H) , 1.92 (s, 3H) , 1.85 (s, 3H) . LCMS calc. for C19H21N4O [M+H] +: m/z = 321.2; found: 321.0.
Step 5: 2-amino-1- (3-hydroxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile
To a solution of 2-amino-1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile (4.00 g, 12.5 mmol) in DCM (40.0 mL) was added dropwise BBr3 (6.26 g, 25.0 mmol, 2.41 mL) at 0 ℃. The mixture was stirred at 25 ℃ for 1 h. The reaction mixture was quenched with water (100 mL) at 0 ℃, and extracted with 2-methyltetrahydrofuran (2 x 100 mL) . The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude title compound (2.00 g) as a light-yellow solid, which was used directly in next step without purification. 1H NMR: (400 MHz, DMSO-d6) δ 9.50 (s, 1H) , 7.37 (s, 1H) , 7.03 (d, J = 8.0 Hz, 1H) , 6.89 (d, J = 6.4 Hz, 1H) , 6.72 (s, 2H) , 2.25 (s, 3H) , 2.24 (s, 3H) , 1.74 (s, 3H) , 1.65 (s, 3H) . LCMS calc. for C18H19N4O [M+H] +: m/z = 307.1; found: 307.1.
Step 6: 2-amino-1- (3-hydroxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carboxamide
This compound was prepared using procedures analogous to those described for Example 1 Step 9. 1H NMR: (400 MHz, DMSO-d6) δ 9.47 (s, 1H) , 7.82 (s, 1H) , 7.04 (d, J = 8.0 Hz, 1H) , 6.89 (d, J = 8.4 Hz, 1H) , 6.71 (s, 2H) , 6.63 (s, 2H) , 2.26 (s, 3H) , 2.24 (s, 3H) , 1.73 (s, 3H) , 1.65 (s, 3H) . LCMS calc. for C18H21N4O2 [M+H] +: m/z = 325.2; found: 325.2.
Step 7: 9- (3-hydroxy-2, 6-dimethylphenyl) -6, 7-dimethyl-3, 9-dihydro-4H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-one
This compound was prepared using procedures analogous to those described for Example 1 Step 12. 1H NMR: (400 MHz, DMSO-d6) δ 12.48 (s, 1H) , 9.49 (s, 1H) , 8.16 (s, 1H) , 8.09 (s, 1H) , 7.04 (d, J = 8.4 Hz, 1H) , 6.91 (d, J = 8.0 Hz, 1H) , 2.42 (s, 3H) , 2.38 (s, 3H) , 1.67 (s, 3H) , 1.57 (s, 3H) . LCMS calc. for C19H19N4O2 [M+H] +: m/z = 335.1; found: 335.1.
Step 8: 3- (4-chloro-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol
This compound was prepared using procedures analogous to those described for Example 1 Step 13. 1H NMR: (400 MHz, MeOD) δ 8.69 (s, 1H) , 8.54 (s, 1H) , 7.11 (d, J = 8.4 Hz, 1H) , 6.95 (d, J = 8.0 Hz, 1H) , 2.59 (s, 3H) , 2.53 (s, 3H) , 1.74 (s, 3H) , 1.68 (s, 3H) . LCMS calc. for C19H18ClN4O [M+H] +: m/z = 353.1; found: 353.2.
Step 9: 3- (4-amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol
This compound was prepared using procedures analogous to those described for Example 1 Step 14. 1H NMR: (400 MHz, DMSO-d6) δ 9.52 (brs, 1H) , 8.72 (s, 1H) , 8.37 (s, 1H) , 8.17 (brs, 2H) , 7.05 (d, J = 8.0 Hz, 1H) , 6.92 (d, J = 8.0 Hz, 1H) , 2.45 (s, 3H) , 2.41 (s, 3H) , 1.66 (s, 3H) , 1.56 (s, 3H) . LCMS calc. for C19H20N5O [M+H] +: m/z = 334.2; found: 334.1.
This compound is a mixture of (3Ra) - (4-Amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol and its enantiomer (3Sa) - (4-Amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol.
Example 4: (3Ra) -3- (4-Amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol and
Example 5: (3Sa) -3- (4-amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-dimethylphenol
The Example 3 (204 mg) was separated by Chiral-HPLC to give P1 (the earlier eluted product, 49.8 mg, Retention time = 2.478 min. in chiral analytic HPLC) and P2 (the latter eluted product, 62.9 mg, Retention time = 2.783 min. in chiral analytic HPLC) . Chiral HPLC separation conditions: Instrument: Waters-SFC80; Column: DAICEL CHIRALCEL OJ (250 mm×30 mm, 10 μm) ; Mobile phase A: Supercritical CO2, Mobile phase B: MeOH (0.1%IPAM) , Gradient: B%= 33%isocratic elution mode; Flow rate: 60 g/min; Sample preparation: methanol; Injection Volume: 2.0 mL; Detector Wavelength: 220 nm; Column temperature: 40 ℃; Back pressure: 100 bar. The separated products were determined by chiral analytic HPLC. Chiral HPLC conditions: Column: Chiralcel OJ-3, 150×4.6 mm I. D., 3 μm; Mobile phase A: CO2, Mobile phase B: MeOH (0.1%IPAm) ; Flow rate: 2.5 ml/min and Run time: 5 min; Detector Wavelength: 220 nm.
P1 was assigned Example 4. 1H NMR: (400 MHz, DMSO-d6) δ 9.39 (s, 1H) , 8.59 (s, 1H) , 8.19 (s, 1H) , 7.34 (s, 2H) , 7.03 (d, J = 8.4 Hz, 1H) , 6.90 (d, J = 8.4 Hz, 1H) , 2.42 (s, 3H) , 2.39 (s, 3H) , 1.65 (s, 3H) , 1.55 (s, 3H) . LCMS calc. for C19H20N5O [M+H] +: m/z = 334.2; Found: 334.1.
P2 was assigned Example 5. 1H NMR: (400 MHz, DMSO-d6) δ 9.42 (s, 1H) , 8.59 (s, 1H) , 8.19 (s, 1H) , 7.34 (s, 2H) , 7.03 (d, J = 8.4 Hz, 1H) , 6.90 (d, J = 8.4 Hz, 1H) , 2.42 (s, 3H) , 2.39 (s, 3H) , 1.65 (s, 3H) , 1.55 (s, 3H) . LCMS calc. for C19H20N5O [M+H] +: m/z = 334.2; Found: 334.1.
Example 6: 2-Amino-1- (3-hydroxy-2, 6-dimethylphenyl) -6-methyl-4, 5-dihydropyrrolo [4, 3, 2-de] [2, 6] naphthyridin-3 (1H) -one
Step 1: methyl 2-amino-5-methylpyridine-4-carboxylate
To a solution of methyl 2-amino-5-bromopyridine-4-carboxylate (10.0 g, 43.2 mmol) in 1, 4-dioxane (100 mL) was added trimethyl-1, 3, 5, 2, 4, 6-trioxatriborinane (27.1 g, 216 mmol) , [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (3.17 g, 4.32 mmol) and potassium carbonate (17.9 g, 129 mmol) . The reaction mixture was degassed and recharged with nitrogen for 3 cycles, and stirred at 100℃ for 5 h. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -40%) to afford the title compound (7.00 g, 97%yield) as a yellow solid. LCMS calc. for C8H11N2O2 [M+H] +: m/z = 167.1; found: 167.1.
Step 2: methyl 2-amino-3-bromo-5-methylpyridine-4-carboxylate
To a solution of methyl 2-amino-5-methylpyridine-4-carboxylate (7.00 g, 42.1 mmol) in acetonitrile (50 mL) was added N-bromosuccinimide (7.50 g, 42.1 mmol) . The reaction mixture was stirred at r.t. overnight, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -50%) to afford the title compound (8.20 g, 79%yield) as a white solid. LCMS calc. for C8H10BrN2O2 [M+H] +: m/z = 245.0; found: 245.0.
Step 3: methyl 2, 3-dibromo-5-methylpyridine-4-carboxylate
To a mixture of methyl 2-amino-3-bromo-5-methylpyridine-4-carboxylate (2.00 g, 8.16 mmol) and HBr (10 mL, 40%aq. ) was added dropwise a solution of NaNO2 (0.56 g, 8.16 mmol) in H2O (2 mL) at -10 ℃. The reaction mixture was stirred at -10 ℃ for 30 mins, followed by addition of CuBr (1.40 g, 9.75 mmol) , and stirred at -5 ℃ for an additional 2 h. The reaction mixture was extracted with EtOAc (3 x 50 mL) . The combined organic layers were washed with brine (3 x 10 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash  chromatography on a silica gel column eluting with EtOAc/PE (0 -30%) to afford the title compound (800 mg, 31%yield) as a light-yellow solid. LCMS calc. for C8H8Br2NO2 [M+H] +: m/z = 307.9; found: 307.9.
Step 4: 1-bromo-2, 4-dimethyl-3-nitrobenzene
To a suspension of 1, 3-dimethyl-2-nitrobenzene (20.0 g, 132 mmol) and Fe (2.96 g, 52.9 mmol) in CHCl3 (200 mL) was added a solution of Br2 (22.2 g, 139 mmol) in CHCl3 (100 mL) . The reaction mixture was stirred at 15 ℃ for 12 h, and then diluted with water (500 mL) . The mixture was extracted with DCM (2 x 250 mL) . The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude title compound (26.0 g) as a light brown solid which was used in next step without purification. 1H NMR: (400 MHz, CDCl3) δ 7.55 (d, J = 8.4, 1H) , 7.01 (d, J = 8.4, 1H) , 2.35 (s, 3H) , 2.26 (s, 3H) .
Step 5: 2, 4-dimethyl-3-nitrophenol
A mixture of 1-bromo-2, 4-dimethyl-3-nitrobenzene (20.0 g, 86.9 mmol) , KOH (14.6 g, 261 mmol) , 2’-di-tert-butylphosphino-2, 4, 6-triisopropylbiphenyl (7.38 g, 17.4 mmol) and bis (dibenzylideneacetone) palladium (7.96 g, 8.69 mmol) in dioxane (200 mL) and H2O (200 mL) was degassed and recharged with N2 for 3 cycles, and stirred at 90 ℃ for 12 h. under N2 atmosphere. After cooling to r.t., the reaction mixture was diluted with water (600 mL) , adjusted with 1M HCl aq. to pH ～3 and extracted with EtOAc (250 mL) . The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (2-20%) to afford the title compound (10.0 g, crude) as a light brown solid. 1H NMR: (400 MHz, CDCl3) δ 6.95 (d, J = 8.4, 1H) , 6.78 (d, J = 8.4, 1H) , 2.22 (s, 3H) , 2.17 (s, 3H) .
Step 6: 1-methoxy-2, 4-dimethyl-3-nitrobenzene
To a solution of 2, 4-dimethyl-3-nitrophenol (12.0 g, 71.8 mmol) in acetone (84.0 mL) was added cesium carbonate (46.8 g, 144 mmol) and CH3I (15.3 g, 108 mmol) . The reaction mixture was stirred at 15 ℃ for 12 h. The mixture was filtered. The filtrate was concentrated under reduced pressure. The  residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (2-20%) to afford crude title compound (10 g) as a light-yellow solid.
Step 7: 3-methoxy-2, 6-dimethylaniline
To a solution of 1-methoxy-2, 4-dimethyl-3-nitrobenzene (7 g, 38.6 mmol) in EtOH (35.0 mL) and H2O (35.0 mL) was added Fe (21.6 g, 386 mmol) and NH4Cl (20.7 g, 386 mmol) . The reaction mixture was stirred at 80 ℃ for 2 h. The solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (2-20%) to afford the title compound (5.00 g) as a light-yellow oil. 1H NMR: (400 MHz, CDCl3) δ 6.90 (d, J = 12, 1H) , 6.32 (d, J = 8.0, 1H) , 3.80 (s, 3H) , 3.62 (brs, 2H) , 2.15 (s, 3H) , 2.09 (s, 3H) .
Step 8: methyl 3-bromo-2- [ (3-methoxy-2, 6-dimethylphenyl) amino] -5-methylpyridine-4-carboxylate
A mixture of methyl 2, 3-dibromo-5-methylpyridine-4-carboxylate (100 mg, 0.324 mmol) , 3-methoxy-2, 6-dimethylaniline (58.7 mg, 0.389 mmol) , bis (dibenzylideneacetone) palladium (29.6 mg, 0.032 mmol) , XantPhos (37.4 mg, 0.065 mmol) and potassium t-butoxide (108 mg, 0.972 mmol) in toluene (5 mL) was degassed and recharged with nitrogen for 3 cycles, stirred at 80℃ overnight under nitrogen atmosphere. After cooling to r.t., the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc /PE (0 -50%) to afford the title compound (45.0 mg, 36%yield) as a yellow solid. LCMS calc. for C17H20BrN2O3 [M+H] +: m/z = 379.1; found: 379.1.
Step 9: {3-bromo-2- [ (3-methoxy-2, 6-dimethylphenyl) amino] -5-methylpyridin-4-yl} methanol
To a solution of methyl 3-bromo-2- [ (3-methoxy-2, 6-dimethylphenyl) amino] -5-methylpyridine-4-carboxylate (1.15 g, 3.03) in tetrahydrofuran (25 mL) was added dropwise a solution of lithium borohydride in tetrahydrofuran (2 M, 7.6 mL, 15.2 mmol) at 0℃. The reaction mixture was stirred at 60℃ overnight before quenched with water (150 mL) . The mixture was extracted with EtOAc (3 x 200 mL) . The combined organic layers were washed with brine (2 x 50 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography  on a silica gel column eluting with EtOAc /PE (0-50%) to afford the title compound (640 mg, 60%yield) as an off-white solid. LCMS calc. for C16H20BrN2O2 [M+H+2] +: m/z =353.1; Found: 353.0.
Step 10: 2-amino-4- (hydroxymethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5-methylpyrrolo [2, 3-b] pyridine-3-carbonitrile
A mixture of {3-bromo-2- [ (3-methoxy-2, 6-dimethylphenyl) amino] -5-methylpyridin-4-yl} methanol (540 mg, 1.54 mmol) , malononitrile (203 mg, 3.07 mmol) , N1, N2-dimethylethane-1, 2-diamine (54.2 mg, 0.615 mmol) , CuI (58.6 mg, 0.307 mmol) and potassium carbonate (637 mg, 4.61 mmol) in DMSO (5 mL) was degassed and recharged with nitrogen for 3 cycles. The reaction mixture was irradiated with microwave radiation at 130℃ for 1 h before quenched with water (80 mL) . The mixture was extracted with EtOAc (3 x 120 mL) . The combined organic layers were washed with brine (2 x 40 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (EtOAc/PE, 1: 1) to afford the title compound (198 mg, 38%yield) as a yellow solid. LCMS calc. for C19H21N4O2 [M+H] +: m/z = 337.2; Found: 337.1.
Step 11: methyl 2-amino-4- (hydroxymethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5-methylpyrrolo [2, 3-b] pyridine-3-carboxylate
A mixture of 2-amino-4- (hydroxymethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5-methylpyrrolo [2, 3-b] pyridine-3-carbonitrile (198 mg, 0.589 mmol) and HCl (g) in MeOH (4M, 5 mL) was stirred at 60 ℃ for 8 h. The reaction mixture was concentrated under reduced pressure, the residue was purified by Prep-TLC (EtOAc/PE, 1: 1) to afford the title compound (121 mg, 56%yield) as a yellow solid. LCMS calc. for C20H24N3O4 [M+H] +: m/z = 370.2 found: 370.1.
Step 12: methyl 2-amino-4- (azidomethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5-methylpyrrolo [2, 3-b] pyridine-3-carboxylate
A mixture of methyl 2-amino-4- (hydroxymethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5-methylpyrrolo [2, 3-b] pyridine-3-carboxylate (121 mg, 0.328 mmol) , diphenylphosphoryl azide (450 mg, 1.64 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (249 mg, 1.64 mmol) in tetrahydrofuran (10 mL) was stirred at 60℃ for 6 h before quenched with water (50 mL) . The resulting mixture was extracted with EtOAc (3 x 80 mL) . The combined organic layers were washed with brine (2 x 30 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc/PE, 1/1) to afford the title compound (77 mg, 60%yield) as a yellow solid. LCMS calc. for C20H23N6O3 [M+H] +: m/z = 395.2; Found: 395.2.
Step 13: methyl 2-amino-4- (aminomethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5-methylpyrrolo [2, 3-b] pyridine-3-carboxylate
A mixture of methyl 2-amino-4- (azidomethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5-methylpyrrolo [2, 3-b] pyridine-3-carboxylate (77.0 mg, 0.195 mmol) and triphenylphosphine (102 mg, 0.39 mmol) in water (2 mL) and tetrahydrofuran (10 mL) was stirred at r.t. overnight under nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 80 mL) . The combined organic layers were washed with brine (2 x 30 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (MeOH /DCM, 1/10) to afford the title compound (56 mg, 78%yield) as an off-white solid. LCMS calc. for C20H25N4O3 [M+H] +: m/z =369.2; Found: 369.1.
Step 14: 3-amino-2- (3-methoxy-2, 6-dimethylphenyl) -9-methyl-2, 6, 11-triazatricyclo [6.3.1.0^ {4, 12} ] dodeca-1 (11) , 3, 8 (12) , 9-tetraen-5-one
A mixture of methyl 2-amino-4- (aminomethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5-methylpyrrolo [2, 3-b] pyridine-3-carboxylate (56 mg, 0.152 mmol) and potassium carbonate (63.02 mg, 0.456 mmol) in methanol (4 mL) was stirred at 80 ℃ overnight before quenching with water (50 mL) . The mixture was extracted with EtOAc (3 x 80 mL) . The combined organic layers were washed with brine (2 x 30 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc/PE, 1/9) to afford the title compound (46 mg, 90%yield) as a yellow solid. LCMS calc. for C19H21N4O2 [M+H] +: m/z =337.2; Found: 337.1.
Step 15: 3-amino-2- (3-hydroxy-2, 6-dimethylphenyl) -9-methyl-2, 6, 11-triazatricyclo [6.3.1.0^ {4, 12} ] dodeca-1 (11) , 3, 8 (12) , 9-tetraen-5-one
A solution of 3-amino-2- (3-methoxy-2, 6-dimethylphenyl) -9-methyl-2, 6, 11-triazatricyclo [6.3.1.0^ {4, 12} ] dodeca-1 (11) , 3, 8 (12) , 9-tetraen-5-one (50.0 mg, 0.149 mmol) in dichloromethane (3 mL) was added dropwise to a solution of BBr3 (0.447 mL, 1M in DCM, 0.447 mmol) in dichloromethane (5 mL) at -78℃. The reaction mixture was stirred at r.t. for 1 h and concentrated under reduced pressure. The residue was dissolved in a mix-solvents of water and methanol (H2O/MeOH=1: 5, 5 ml) and stirred at r.t. for 1 h, which was purified directly by Prep-HPLC eluting with MeCN/H2O (20%to 50%with 0.1%FA) to afford the desired product (16.8 mg, 35%yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H) , 7.55 (s, 1H) , 7.04 (d, J = 8.3 Hz, 1H) , 6.90 (d, J = 8.3 Hz, 1H) , 6.79 (s, 1H) , 5.99 (s, 2H) , 4.75 (s, 2H) , 2.13 (s, 3H) , 1.78 (s, 3H) , 1.69 (s, 3H) . LCMS calc. for C18H19N4O2 [M+H] +: m/z =323.2; Found: 323.1.
The desired compound for Example 1 step 15 was a mixture of 2-Amino- (1Ra) - (3-hydroxy-2, 6-dimethylphenyl) -6-methyl-4, 5-dihydropyrrolo [4, 3, 2-de] [2, 6] naphthyridin-3 (1H) -one and its enantiomer 2-Amino- (1Sa) - (3-hydroxy-2, 6-dimethylphenyl) -6-methyl-4, 5-dihydropyrrolo [4, 3, 2-de] [2, 6] naphthyridin-3 (1H) -one.
Example 7: 2-Amino-1- (3-hydroxy-2, 6-dimethylphenyl) -6, 7-dimethyl-4, 5-dihydropyrrolo [4, 3, 2-de] [2, 6] naphthyridin-3 (1H) -one
Step 1: methyl 2- ( (diphenylmethylene) amino) -6-methylisonicotinate
A mixture of methyl 2-bromo-6-methylisonicotinate (83 g, 361 mmol) , benzophenone imine (71.9 g, 399 mmol) , Cs2CO3 (353 g, 108 mmol) and Xantphos (20.9 g, 36.1 mmol) in dioxane (581 mL) was degassed and purged with N2 for 3 cycles, Pd2 (dba) 3 (16.5 g, 18.0 mmol) was added to the mixture. The mixture was degassed and purged with N2 for 3 cycles and then the mixture was stirred at 80 ℃ overnight under N2 atmosphere. After cooled to r.t., the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate/petroleum ether (0.5～3.3%) to afford the title compound (160 g, 44.7%yield) as light yellow oil. 1H NMR: (400 MHz, CDCl3) δ 7.73–7.74 (m, 2H) , 7.62–7.64 (m, 3H) , 7.42–7.43  (m, 4H) , 7.11–7.19 (m, 2H) , 6.82 (s, 1H) , 3.77 (s, 3H) , 2.42 (s, 3H) . LCMS calc. for C21H19N2O2 [M+H] +: m/z = 331.1; Found: 331.2.
Step 2: methyl 2-amino-6-methylisonicotinate
To a solution of methyl 2- ( (diphenylmethylene) amino) -6-methylisonicotinate (51.6 g, 156 mmol) in THF (50 mL) was added HCl (6 M, 104 mL) . The mixture was stirred at 20 ℃ for 2 h. The reaction mixture was diluted with H2O (200 mL) , adjusted pH value to 8～9 with NH3. H2O (30 mL) , extracted with EA (150 mL x 3) . The combined organic layers were washed with brine (150 mL x 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (180 mL) at 20℃ for 2 h to afford the title compound (60 g, 77.0%yield) as a light yellow solid. 1H NMR: (400 MHz, DMSO-d6) δ 6.76 (s, 2H) , 6.20 (s, 2H) , 3.82 (s, 3H) , 2.28 (s, 3H) . LCMS calc. for C8H11N2O2 [M+H] +: m/z = 167.1; Found: 167.2.
Step 3: methyl 6-amino-3-bromo-2-methylisonicotinate
To a solution of methyl 2-amino-6-methylisonicotinate (18.3 g, 110 mmol) in ACN (112 mL) was added NBS (19.6 g, 110 mmol) . The mixture was stirred at 20 ℃ for 0.5 h. The reaction mixture was diluted with H2O (200 mL) , extracted with EA (100 mL x 3) . The combined organic layers were washed with brine (200 mL x 2) , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (150 mL) at 20 ℃ for 1 h to afford the title compound (49 g, 60.5%yield) as a yellow solid. 1H NMR: (400 MHz, CDCl3) δ 6.53 (s, 1H) , 4.58 (s, 2H) , 3.93 (s, 3H) , 2.55 (s, 3H) . LCMS calc. for C8H10BrN2O2 [M+H] +: m/z = 244.9; Found: 244.9.
Step 4: methyl 6-amino-2, 3-dimethylisonicotinate
A mixture of methyl 6-amino-3-bromo-2-methylisonicotinate (11 g, 44.9 mmol) , methylboronic acid (8.06 g, 135 mmol) , and K2CO3 (24.8 g, 180 mmol) in dioxane (77 mL) was degassed and purged with N2 for 3 cycles. Pd (dppf) Cl2 (3.28 g, 4.49 mmol) was added to the mixture and was degassed and purged with N2 for 3 cycles. Then the mixture was stirred at 80 ℃ for overnight under N2 atmosphere. The reaction mixture was diluted with H2O (200 mL) , extracted with EA (150 mL x 4) . The combined organic layers were washed with brine (500 mL x 2) , dried over Na2SO4, filtered and concentrated  under reduced pressure to give a residue. The residue was triturated with MTBE: EA (15/1, 84 mL) at 20 ℃ for 1 h, filtered and the cake was triturated with ACN (40 mL) at 20 ℃ for 1 h to afford the title compound (28 g, 86.5%yield) as a yellow solid. 1H NMR: (400 MHz, DMSO-d6) δ 6.51 (s, 1H) , 5.85 (s, 2H) , 3.80 (s, 3H) , 2.27 (s, 3H) , 2.13 (s, 3H) . LCMS calc. for C9H13N2O2 [M+H] +: m/z = 181.1; Found: 180.9.
Step 5: methyl 2-amino-3-bromo-5, 6-dimethylisonicotinate
This compound was prepared using procedures analogous to those described for Example 6 Step 2 using methyl 6-amino-2, 3-dimethylisonicotinate to replace methyl 2-amino-5-methylpyridine-4-carboxylate to afford the title product as a yellow solid. 1H NMR: (400 MHz, DMSO-d6) δ 6.13 (s, 1H) , 3.87 (s, 3H) , 2.24 (s, 3H) , 1.98 (s, 3H) . LCMS calc. for C9H12BrN2O2 [M+H] +: m/z = 259.0; Found: 258.9.
Step 6: methyl 2, 3-dibromo-5, 6-dimethylisonicotinate
To a solution of methyl 2-amino-3-bromo-5, 6-dimethylisonicotinate (9.5 g, 36.7 mmol) in dibromomethane (67 mL) was added benzyltriethylammonium bromide (44.9 g, 165 mmol) and tert-butyl nitrite (37.8 g, 367 mmol) . The mixture was stirred at 20 ℃ for 3 h., diluted with H2O (80 mL) , and extracted with DCM (150 mL x 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EA/PE (0.5～35%) to afford the title compound (16 g, 67.5%yield) as a colorless oil. 1H NMR: (400 MHz, DMSO-d6) δ 3.98 (s, 3H) , 2.44 (s, 3H) , 2.19 (s, 3H) . LCMS calc. for C9H10Br2NO2 [M+H] +: m/z = 323.9; Found: 323.9.
Step 7: methyl 3-bromo-2- ( (3-methoxy-2, 6-dimethylphenyl) amino) -5, 6-dimethylisonicotinate
A mixture of methyl 2, 3-dibromo-5, 6-dimethylisonicotinate (5.0 g, 15.5 mmol) , 3-methoxy-2, 6-dimethyl-aniline (2.34 g, 15.5 mmol, ) , Cs2CO3 (12.6 g, 38.7 mmol) and Xantphos (896 mg, 1.55 mmol) , Pd2 (dba) 3 (709 mg, 0.774 mmol) in DME (35 mL) was degassed and purged with N2 for 3 times, then the mixture was stirred at 80 ℃ overnight under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica  gel column eluting with EA/PA (0.5～35%) to afford the title compound (8.0 g, 65.7%yield) as a black brown solid. LCMS calc. for C18H22BrN2O3 [M+H] +: m/z = 393.1; Found: 393.1.
Step 8: (3-bromo-2- ( (3-methoxy-2, 6-dimethylphenyl) amino) -5, 6-dimethylpyridin-4-yl) methanol
To a solution of methyl 3-bromo-2- ( (3-methoxy-2, 6-dimethylphenyl) amino) -5, 6-dimethylisonicotinate (3 g, 7.63 mmol) in DCM (21 mL) was added DIBAL-H (1 M, 21 mL) . The mixture was stirred at -70 ℃ for 2 h., then quenched by addition H2O (200 mL) at 0 ℃ in N2, and extracted with DCM (150 mL x 3) . The combined organic layers were washed with brine (80 mL x 2) , dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EA/PE (0-5%) to afford the title compound (3.0 g, 53.8%yield) as a yellow oil. 1H NMR: (400 MHz, CDCl3) δ 7.05 (d, J = 8.4 Hz, 1H) , 6.73 (d, J = 8.0 Hz, 1H) , 6.36 (s, 1H) , 4.85 (d, J = 6.4 Hz, 2H) , 3.85 (s, 3H) , 2.27 (s, 3H) . 2.25 (s, 3H) , 2.16 (s, 3H) , 2.09 (s, 3H) . LCMS calc. for C17H22BrN2O2 [M+H] +: m/z = 365.1; Found: 365.1.
Step 9: 2-amino-4- (hydroxymethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyr rolo [2, 3-b] pyridine-3-carbonitrile
This compound was prepared using procedures analogous to those described for Example 6 Step 10 using (3-bromo-2- ( (3-methoxy-2, 6-dimethylphenyl) amino) -5, 6-dimethylpyridin-4-yl) methanol and malononitrile to afford the title product as a yellow solid. 1H NMR: (400 MHz, CDCl3) δ 7.12 (d, J = 8.8 Hz, 1H) , 6.87 (d, J = 8.4 Hz, 1H) , 5.06 (s, 2H) , 4.47 (s, 3H) , 3.81 (s, 3H) , 2.32 (d, J = 14 Hz, 6H) , 1.84 (s, 3H) , 1.77 (s, 3H) . LCMS calc. for C20H23N4O2 [M+H] +: m/z = 351.2; Found: 351.2.
Step 10: methyl 2-amino-4- (hydroxymethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethyl -1H-pyrrolo [2, 3-b] pyridine-3-carboxylate
This compound was prepared using procedures analogous to those described for Example 6 Step 11 using 2-amino-4- (hydroxymethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H- pyrrolo [2, 3-b] pyridine-3-carbonitrile to afford the title product as a yellow solid. LCMS calc. for C21H26N3O4 [M+H] +: m/z = 384.2; Found: 384.2.
Step 11: methyl 2-amino-4- (azidomethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carboxylate
This compound was prepared using procedures analogous to those described for Example 6 Step 12 using methyl 2-amino-4- (hydroxymethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carboxylate and DPPA to afford the title product as a yellow solid. 1H NMR: (400 MHz, DMSO-d6) δ 7.25 (d, J = 8.4 Hz, 1H) , 7.09 (d, J = 8.4 Hz, 1H) , 6.78 (s, 2H) , 5.05-5.14 (m, 2H) , 3.83 (d, J = 14.8 Hz, 6H) , 2.29 (s, 3H) , 2.25 (s, 3H) , 1.77 (s, 3H) , 1.69 (s, 3H) . LCMS calc. for C21H25N6O3 [M+H] +: m/z = 409.2; Found: 409.2.
Step 12: methyl 2-amino-4- (aminomethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethy l-1H-pyrrolo [2, 3-b] pyridine-3-carboxylate
This compound was prepared using procedures analogous to those described for Example 6 Step 13 using methyl 2-amino-4- (azidomethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carboxylate and PPh3 to afford the title product as a white solid. 1H NMR: (400 MHz, DMSO-d6) δ 7.28 (d, J = 8.0 Hz, 1H) , 7.08 (d, J = 8.4 Hz, 1H) , 6.68 (s, 2H) , 4.20 (s, 2H) , 3.84 (s, 3H) , 3.79 (s, 3H) , 2.27 (d, J = 4.0 Hz, 6H) , 1.78 (s, 3H) , 1.68 (s, 3H) . LCMS calc. for C21H27N4O3 [M+H] +: m/z = 383.2; Found: 383.2.
Step 13: 2-amino-1- (3-methoxy-2, 6-dimethylphenyl) -6, 7-dimethyl-4, 5-dihydropyrrolo [4, 3, 2-de] [2, 6] naphthyridin-3 (1H) -one
This compound was prepared using procedures analogous to those described for Example 6 Step 14 using methyl 2-amino-4- (aminomethyl) -1- (3-methoxy-2, 6-dimethylphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carboxylate to afford the title product as a white solid. 1H NMR:  (400 MHz, DMSO-d6) δ 7.23 (d, J = 8.4 Hz, 1H) , 7.07 (d, J = 8.4 Hz, 1H) , 6.76 (s, 1H) , 5.84 (s, 2H) , 4.75 (s, 2H) , 3.85 (s, 3H) , 2.28 (s, 3H) , 2.06 (s, 3H) , 1.84 (s, 3H) , 1.73 (s, 3H) . LCMS calc. for C20H23N4O2 [M+H] +: m/z = 351.2; Found: 351.1.
Step 14: 2-amino-1- (3-hydroxy-2, 6-dimethylphenyl) -6, 7-dimethyl-4, 5-dihydropyrrolo [4, 3, 2-de] [2, 6] naphthyridin-3 (1H) -one
This compound was prepared using procedures analogous to those described for Example 6 Step 15 using 2-amino-1- (3-methoxy-2, 6-dimethylphenyl) -6, 7-dimethyl-4, 5-dihydropyr rolo [4, 3, 2-de] [2, 6] naphthyridin-3 (1H) -one to afford the title product as a white solid. 1H NMR: (400 MHz, DMSO-d6) δ 9.47 (s, 1H) , 7.04 (d, J = 8.4 Hz, 1H) , 6.90 (d, J = 8.0 Hz, 1H) , 6.75 (s, 1H) , 5.78 (s, 2H) , 4.75 (s, 2H) , 2.29 (s, 3H) , 2.06 (s, 3H) , 1.79 (s, 3H) , 1.69 (s, 3H) . LCMS calc. for C19H21N4O2 [M+H] +: m/z = 337.2; Found: 337.1.
Example 8: 6, 7-Dimethyl-9- (6-methylquinolin-5-yl) -9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-amine
Step 1: N- (3-bromo-5, 6-dimethylpyridin-2-yl) -6-methylquinolin-5-amine
A mixture of 2, 3-dibromo-5, 6-dimethylpyridine (10.0 g, 37.7 mmol, Example 3 Step 2) , 6-methylquinolin-5-amine (5.97 g, 37.7 mmol) , Xantphos (2.18 g, 3.77 mmol) , Cs2CO3 (30.7 g, 94.4 mmol) and Pd2 (dba) 3 (1.73 g, 1.89 mmol) in DME (60 mL) was degassed and purged with N2 for 3 cycles, and then stirred at 80 ℃ overnight under N2 atmosphere. The reaction mixture was cooled to r.t., diluted with water (250 mL) , extracted with EA (50 mL x 2) . The combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EA/PE (0～5%) to afford the title compound (7.50 g, 58.1%yield) as a yellow solid. 1H NMR : (400 MHz, MeOD) δ 8.75 (dd, J = 4.4, 1.6 Hz, 1H) , 8.33 (dd, J = 8.4, 0.4 Hz, 1H) , 7.91 (d, J = 8.8 Hz, 1H) , 7.72 (d, J = 8.8 Hz, 1H) , 7.61 (s, 1H) , 7.45 (dd, J = 8.4, 4.4 Hz, 1H) , 2.37 (s, 3H) , 2.13 (s, 3H) , 2.01 (d, J = 3.2 Hz, 3H) . LCMS calc. for C17H17BrN3 [M+H] +: m/z = 342.1; Found: 342.1.
Step 2: 2-amino-5, 6-dimethyl-1- (6-methylquinolin-5-yl) -1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile
To a solution of propanedinitrile (2.89 g, 43.8 mmol) in DME (45 mL) was added t-BuONa (4.2 g, 43.8 mmol) under N2 atmosphere and the mixture was stirred at 25 ℃ for 0.5 h. Then N- (3-bromo-5, 6-dimethylpyridin-2-yl) -6-methylquinolin-5-amine (7.5 g, 21.9 mmol) was added at 25 ℃, followed by the addition of Pd (dppf) Cl2. CH2Cl2 (1.79 g, 2.19 mmol) . The resulting mixture was stirred at 85 ℃ overnight under N2 atmosphere. The reaction mixture was quenched with water (50 mL) dropwise, extracted with EA (50 mL x 3) . The combined organic layers were washed with brine (20 mL) , dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with DCM (22 mL) . The solid was collected by filtration to afford the title compound (3.5 g, 50%yield) as a yellow solid. LCMS calc. for C20H18N5 [M+H] +: m/z = 328.2; Found: 328.2.
Step 3: 2-amino-5, 6-dimethyl-1- (6-methylquinolin-5-yl) -1H-pyrrolo [2, 3-b] pyridine-3-carboxamide
This compound was prepared using procedures analogous to those described for Example 1 Step 9 using 2-amino-5, 6-dimethyl-1- (6-methylquinolin-5-yl) -1H-pyrrolo [2, 3-b] pyridine -3-carbonitrile to afford the title product as a yellow solid. 1H NMR : (400 MHz, DMSO-d6) δ 8.90 (d, J = 2.8 Hz, 1H) , 8.16 (d, J = 8.8 Hz, 1H) , 7.87-7.92 (m, 2H) , 7.46 (dd, J = 8.4, 4.0 Hz, 1H) , 7.36-7.38 (m, 1H) , 6.90 (s, 2H) , 6.74 (s, 2H) , 2.27 (s, 3H) , 2.14 (d, J = 4.0 Hz, 6H) . LCMS calc. for C20H20N5O [M+H] +: m/z = 346.2; Found: 346.2.
Step 4: 6, 7-dimethyl-9- (6-methylquinolin-5-yl) -3, 9-dihydro-4H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-one
This compound was prepared using procedures analogous to those described for Example 1 Step 12 using 2-amino-5, 6-dimethyl-1- (6-methylquinolin-5-yl) -1H-pyrrolo [2, 3-b] pyridine-3-carboxamide and trimethoxymethane to afford the title product as a yellow solid. 1H NMR: (400 MHz, DMSO-d6) δ 12.6 (br s, 1H) , 8.90 (t, J = 4.0 Hz, 1H) , 8.25 (s, 1H) , 8.19 (d, J = 8.8 Hz, 1H) , 8.06 (s,  1H) , 7.90 (d, J = 8.8 Hz, 1H) , 7.35-7.40 (m, 2H) , 2.40 (s, 3H) , 2.33 (s, 3H) , 2.05 (s, 3H) . LCMS calc. for C21H18N5O [M+H] +: m/z = 356.1; Found: 356.2.
Step 5: 6, 7-dimethyl-9- (6-methylquinolin-5-yl) -9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-amine
This compound was prepared using procedures analogous to those described for Example 1 Step 13-14 using 6, 7-dimethyl-9- (6-methylquinolin-5-yl) -3, 9-dihydro-4H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-one in Step 13 to afford the title product as a white solid. 1H NMR: (400 MHz, CDCl3) δ 9.19 (d, J = 4.0 Hz, 1H) , 8.63 (d, J = 8.8 Hz, 1H) , 8.30-8.31 (m, 2H) , 8.05 (d, J = 8.8 Hz, 1H) , 7.72 (d, J = 8.4 Hz, 1H) , 7.60-7.63 (m, 1H) , 2.53 (s, 3H) , 2.49 (s, 3H) , 2.22 (s, 3H) . LCMS calc. for C21H19N6 [M+H] +: m/z = 355.2; Found: 355.1.
Example 9: 5- (4-Amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -4, 6-dichlorobenzene-1, 3-diol
Step 1: 3-bromo-N- (2, 6-dichloro-3, 5-dimethoxyphenyl) -5, 6-dimethylpyridin-2-amine
This compound was prepared using procedures analogous to those described for Example 8 Step 1 using 2, 3-dibromo-5, 6-dimethylpyridine (Example 3 Step 2) and 2, 6-difluoro-3, 5-dimethoxyaniline to afford the title product as a white solid. LCMS calc. for C15H16BrCl2N2O2 [M+H] : m/z = 407.2; Found: 407.2.
Step 2: 2-amino-1- (2, 6-dichloro-3, 5-dimethoxyphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile
This compound was prepared using procedures analogous to those described for Example 8 Step 2 using propanedinitrile and 3-bromo-N- (2, 6-dichloro-3, 5-dimethoxyphenyl) -5, 6- dimethylpyridin-2-amine to afford the title product as a brown solid. LCMS calc. for C18H17Cl2N4O2 [M+H] +: m/z = 391.1; Found: 391.1.
Step 3: 2-amino-1- (2, 6-dichloro-3, 5-dimethoxyphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carboxamide
This compound was prepared using procedures analogous to those described for Example 1 Step 9 using 2-amino-1- (2, 6-dichloro-3, 5-dimethoxyphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile to afford the title product. LCMS calc. for C18H19Cl2N4O3 [M+H] +: m/z = 409.2; Found: 409.2.
Step 4: 9- (2, 6-dichloro-3, 5-dimethoxyphenyl) -6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-amine
This compound was prepared using procedures analogous to those described for Example 1 Step 12-14 using 2-amino-1- (2, 6-dichloro-3, 5-dimethoxyphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carboxamide and trimethoxymethane in Step 12 to afford the title product. LCMS calc. for C19H18Cl2N5O2 [M+H] +: m/z = 418.1; Found: 418.1.
Step 5: 5- (4-amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -4, 6-dichlorobenzene-1, 3-diol
To a solution of 9- (2, 6-dichloro-3, 5-dimethoxyphenyl) -6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-amine (50 mg, 0.12 mmol) in DCM (5 mL) was added BBr3 (0.06 g, 0.24 mmol) dropwise at 0 ℃. The mixture was stirred at r.t. for 1 h., quenched with H2O (10 mL) and extracted with 2-MeTHF (10 mL x 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC eluting with MeCN/water (10-95%with 0.1%NH4HCO3) to afford the title  product (2.7 mg, yield: 5.8%) . 1H NMR (400 MHz, ) δ 10.60 (s, 2H) , 8.57 (s, 1H) , 8.20 (s, 1H) , 7.38 (s, 2H) , 6.92 (s, 1H) , 2.43 (s, 3H) , 2.38 (s, 3H) . LCMS calc. for C17H14Cl2N5O2 [M+H] +: m/z = 390.2; Found: 390.2.
Example 10: 5- (4-Amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -4, 6-difluorobenzene-1, 3-diol and
Example 11: 3- (4-Amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-difluoro-5-methoxyphenol
Step 1: 3-bromo-N- (2, 6-difluoro-3, 5-dimethoxyphenyl) -5, 6-dimethylpyridin-2-amine
This compound was prepared using procedures analogous to those described for Example 8 Step 1 using 2, 3-dibromo-5, 6-dimethylpyridine (Example 3 Step 2) and 2, 6-difluoro-3, 5-dimethoxyaniline to afford the title product as a white solid. LCMS calc. for C15H16BrF2N2O2 [M+H] : m/z = 373.2; Found: 373.2.
Step 2: 2-amino-1- (2, 6-difluoro-3, 5-dimethoxyphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile
This compound was prepared using procedures analogous to those described for Example 8 Step 2 using 2 3-bromo-N- (2, 6-difluoro-3, 5-dimethoxyphenyl) -5, 6-dimethylpyridin-2-amine to afford the title product as a brown solid. LCMS calc. for C18H17F2N4O2 [M+H] +: m/z = 359.2; Found: 359.2.
Step 3: 2-amino-1- (2, 6-difluoro-3, 5-dimethoxyphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carboxamide
This compound was prepared using procedures analogous to those described for Example 1 Step 9 using 2-amino-1- (2, 6-difluoro-3, 5-dimethoxyphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carbonitrile to afford the title product. LCMS calc. for C18H19F2N4O3 [M+H] +: m/z = 377.2; Found: 377.2.
Step 4: 9- (2, 6-difluoro-3, 5-dimethoxyphenyl) -6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-amine
This compound was prepared using procedures analogous to those described for Example 1 Step 12-14 using 2-amino-1- (2, 6-difluoro-3, 5-dimethoxyphenyl) -5, 6-dimethyl-1H-pyrrolo [2, 3-b] pyridine-3-carboxamide and trimethoxymethane in Step 12 to afford the title product. LCMS calc. for C19H17F2N4O3 [M+H] +: m/z = 387.2; Found: 387.2.
Step 5: 5- (4-amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -4, 6-difluorobenzene-1, 3-diol (Example 10) and 3- (4-amino-6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-9-yl) -2, 4-difluoro-5-methoxyphenol (Example 11)
To a solution of 9- (2, 6-difluoro-3, 5-dimethoxyphenyl) -6, 7-dimethyl-9H-pyrido [3', 2': 4, 5] pyrrolo [2, 3-d] pyrimidin-4-amine (90 mg, 0.23 mmol) in DCM (10 mL) was added BBr3 (0.115 g, 0.46 mmol) dropwise at 0 ℃. The mixture was stirred at r.t. for 1 h. The reaction mixture was quenched with H2O (10 mL) and extracted with 2-MeTHF (10 mL x 3) . The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure and purified by Prep-HPLC eluting with MeCN/water (10-95%with 0.1%NH4HCO3) to afford two products: P1 (the earlier eluted fraction: 5.46 mg, yield: 6.5%) and P2 (the latter eluted fraction: 3.35 mg, yield: 3.8%) . P1 was assigned to Example 10. 1H NMR (400 MHz, DMSO) δ 9.87 (s, 2H) , 8.60 (s, 1H) , 8.24 (s, 1H) , 7.44 (s, 2H) , 6.80 (t, J = 8.6 Hz, 1H) , 2.46 (s, 3H) , 2.39 (s, 3H) . LCMS calc. for C17H14F2N5O2 [M+H] +: m/z = 358.0; Found: 358.0. And P2 was assigned to Example 11. 1H NMR (400 MHz, DMSO) δ 10.18 (s, 1H) , 8.61 (s, 1H) , 8.24 (s, 1H) , 7.45 (s, 2H) , 6.97 (t, J = 8.3 Hz, 1H) , 3.87 (s, 3H) , 2.45 (s, 3H) , 2.39 (s, 3H) . LCMS calc. for C18H16F2N5O2 [M+H] +: m/z = 372.0; Found: 372.0.
Example A: PKMYT1 kinase assay
PKMYT1 kinase assay was initiated for evaluating potential inhibitory effect of candidate compounds. PKMYT1 was ordered from Carna, 05-176 and stored at -80℃ in aliquots. ADP quantity produced from ATP hydrolysis by PKMYT1 catalytic reaction was measured using a commercially available ADP-Glo Assay (ADP-GloTM Kinase Assay from Promega, 10 000 assays, #V9102) . Briefly, Compounds dissolved in DMSO (Sigma, D8418) were plated into a 384-well assay plate (Greiner, 784075) in duplicate using a dispenser (Labcyte, Echo 665) , and tested on a 10-point 3-fold serial dilution. Assay measurements were performed with 1× buffer comprising 1x kinase Buffer with 50uM DTT. Add 2.5 μl 2X PKMYT1 mix into the assay plates. After centrifuging at 1000g for 30s, the plates were covered and left to incubate for 10 minutes at RT before the addition of 2.5 μl 2X substrate mix [Unactive CDK1 (SignalChem, C22-14G-20) and ATP (Promega, V910B) ] to initiate reaction. The final PKMYT1 enzyme concentration was 2.5ng/ul; the final ATP concentration was 200uM and the final unactive CDK1 concentration was 0.01ug/ul. After incubating 2 hours at RT, 4 μL of ADP-Glo reagent was added and the plate was spun briefly and sealed and incubated in the dark for 40 minutes at RT. Following this, 8 μL of kinase detection reagent was added and the plate was spun briefly, sealed and incubated for 40 minutes at RT in the dark. Read on a multimode plate reader (Perkin Elmer, Envision 2104) in Luminescence mode. Average luminescence signal of high control (Wells with 1%DMSO) was calculated as High Control (HC) . Average luminescence signal of low control (Wells with 10000nM PD0166285) was calculated as Low control (LC) .
%inhibition = 100 -100* (Signalcmpd -SignalAve_LC) / (SignalAve_HC -SignalAve_LC) .
IC50 values were determined by fitting the data to the standard 4 parameters with Hill Slope using GraphPad Prism software. IC50 data is proved below in Table 1. +++<=0.1 μM, 0.1 μM< ++<=1 μM, +>1 μM.
Example B: Cell viability assay
Cell viability studies were conducted in HCC1569 cell line. Cells were cultured in RPMI 1640 (Hyclone, SH3080901B) with 10%FBS (AusGeneX, FBS500-S) and 1%penicillin-streptomycin (Gibco, 15140122) . Cells were seeded in 96-well cell culture plates (PerkinElmer, 6005680) at a density of 1500 cells/well. Compounds dissolved in DMSO were plated in duplicate using a multichannel pipette, and tested on a 9-point 3-fold serial dilution. DMSO final concentration was 0.2%for all wells. Cells were incubated for 7 days in a 37 ℃ active humidified incubator at 5%CO2. Cell viability was measured using the Cell Titer-Glo reagent (Promega, Catalog#: G7573) as manufacturer’s instructions. Luminescence signal was measured with a multimode plate reader (Perkin Elmer, Envision 2105 or BMG, ClarioStar Plus) . Average values of 0.2%DMSO treated wells in a plate was calculated as high control (HC) . Average values of only medium in a plate was calculated as low control (LC) .
%inhibition=100 -100* (Signalcmpd -SignalAve_LC) / (SignalAve_HC -SignalAve_LC) .
IC50 values were determined by fitting the data to the standard 4 parameters with Hill Slope using GraphPad Prism software. IC50 data is proved below in Table 2.
+++<=5 μM, 5 μM< ++<=50 μM, + >50 μM, ND: not determine.
Table 1
Although the present disclosure has been comprehensively described through its embodiments, it is worth noting that various changes and modifications are obvious to those skilled in the art. Such changes and modifications should be included in the scope of the appended claims of the present disclosure.

Claims (30)

  1. A compound of formula (IA) and (IB) , or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variants or prodrugs thereof, wherein:
    ring A is selected from:
    X is N or CR3;
    Y is N or CR9;
    L is (CR10R11) n, NR12 (CH2CH2) m, or O (CH2CH2) m;
    n is 1, 2 or 3; m is 0 or 1;
    R is selected from H, D or C1-C6 alkyl optionally substituted with F, OH or CN;
    R1, R2 and R3 are each independently selected from H, D, halo, CN, SF5, NRCRD, ORA, C (O) RB, C (O) NRCRD, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocyclalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb;
    or R1 and R2 together with the carbon atoms to which they are attached form a C3-C7 cycloalkyl, or 4-7 membered heterocycloalkyl, wherein, the C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, oxo, ORa, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb;
    or R2 and R3 together with the carbon atom to which they are attached form a C3-C7 cycloalkyl, or 4-7 membered heterocycloalkyl, wherein, the C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, oxo, ORa, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb;
    each R4 is independently selected from H, D, NH2, CN, C1-C3 alkyl optionally substituted with D, halogen or CN;
    each R5 is independently selected from H, D, halo, CN, C1-C6 alkyl optionally substituted with D, halogen or CN;
    each R6 is independently selected from H, D, halo, CN, ORB, SF5, C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl; wherein, the C1-C6 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl is optionally substituted with D, halo, CN, NH2, OH, -O-C1-C6 alkyl, -OC1-C6 haloalkyl;
    each R7 is independently selected from H, D, halogen, Me, CF3, OH, OMe, OCF3;
    each R8 is independently selected from H, D, CN, SF5, C1-C6 alkyl optionally substituted with D, halogen or CN;
    each R9 is independently selected from H, D, CN, halogen, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C3-C5 cycloalkyl;
    R10 and R11 are each independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, CN, halo, ORa, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, NRcS (O) 2Rb, or NRcS (O) 2NRcRd;
    or R10 and R11 together with the carbon atom (s) to which they are attached form a C3-C7 cycloalkyl, or 4-7 membered heterocycloalkyl, wherein, the C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, oxo, ORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, or NRcS (O) 2NRcRd;
    R12 is H, D, C1-C3 alkyl optionally substituted with D, OH, halogen, CN;
    each RA is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocyclalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1- C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb;
    each RB is independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, C (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) ;
    RC and RD are each independently selected from H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, SF5, OC (O) NRcRd, NRcRd, NRcC (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or B (ORc) (ORd) ;
    or RC and RD 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, or C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl;
    each Ra is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
    each Rb is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl;
    Rc and Rd are each independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, C6-C10 aryl-C6-C10 aryl, 5-10 membered heteroaryl-C3-C10 cycloalkyl, 5-10 membered heteroaryl-4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C6-C10 aryl, or 5-10 membered heteroaryl-5-10 membered heteroaryl; wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, 4-10 membered heterocycloalkyl-C1-C6 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, C6-C10 aryl-C6-C10 aryl, 5-10 membered heteroaryl-C3-C10 cycloalkyl, 5-10 membered heteroaryl-4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C6-C10 aryl, or 5-10 membered heteroaryl-5-10 membered heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C (O) ORa1, C (O) Rb1, S (O) 2Rb1, C1-C4 alkyl-O-C1-C4 alkyl, and C1-C4 alkyl-O-C1-C4 alkyl-O-;
    or Rc and Rd 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 hydroxyalkyl, C1-C4 cyanoalkyl, C6-C10 aryl, 5-10 membered heteroaryl, C (O) ORa1, C (O) Rb1, S (O) 2Rb1, C1-C4 alkoxy-C1-C4 alkyl, and C1-C4 alkoxy-C1-C4 alkoxy;
    each Re is independently selected from H, D, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, (C1-C4 alkoxy) -C1-C4 alkyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl;
    each Rf is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, or 4-10 membered heterocycloalkyl;
    each Ra1 is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 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, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or C1-C4 haloalkoxy;
    each Rb1 is independently selected from H, D, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alky; wherein the C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, phenyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, C6-C10 aryl-C1-C6 alkyl, 5-10 membered heteroaryl-C1-C6 alkyl, C3-C10 cycloalkyl-C1-C6 alkyl, or 4-10 membered heterocycloalkyl-C1-C6 alky is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.
  2. The compound of claim 1, wherein, X is N.
  3. The compound of claim 1, wherein, X is CR3.
  4. The compound of claim 3, wherein, R3 is independently selected from H, D, halo, CN, SF5, NRCRD, ORA, C (O) RB, C (O) NRCRD, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; wherein, the C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
  5. The compound of claim 3, wherein, R3 is independently selected from H, D, halo, CN, SF5, NH2, OH, NH2, OCH3, OCH2CH3, NHCH3, NHCH2CH3, NH (CH3) 2, CH3, CH2CH3, CF3, CH2CF3, C (O) RB, or C (O) NRCRD.
  6. The compound of anyone of claim 1-5, wherein, R is selected from H, D or C1-C6 alkyl optionally substituted with F, OH or CN.
  7. The compound of anyone of claim 1-6, wherein, R1 is independently selected from H, D, halo, CN, SF5, NRCRD, ORA, C (O) RB, C (O) NRCRD, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl; wherein, the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb; preferably, R1 is independently selected from H, D, halo, CN, SF5, OH, NH2, OCH3, OCH2CH3, NHCH3, NHCH2CH3, NH (CH3) 2, CH3, CH2CH3, CF3, CH2CF3, C (O) RB, C (O) NRCRD.
  8. The compound of anyone of claim 1-7, wherein, R2 is independently selected from H, D, halo, CN, SF5, NRCRD, ORA, C (O) RB, C (O) NRCRD, C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl; wherein, the C1-C6 alkyl, C3-C6 cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, OH, CN, halo, C1-C4 alkyl, NO2, oxo, ORa, SRa, SF5, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb; preferably, R2 is independently selected from H, D, halo, CN, SF5, OH, NH2, OCH3, OCH2CH3, NHCH3, NHCH2CH3, NH (CH3) 2, CH3, CH2CH3, CF3, CH2CF3, C (O) RB, C (O) NRCRD.
  9. The compound of anyone of claim 1-6, wherein, R1 and R2 together with the carbon atoms to which they are attached form a C3-C7 cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, oxo, ORa, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
  10. The compound of anyone of claim 1-6, wherein, R1 and R2 together with the carbon atoms 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, NO2, oxo, ORa, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
  11. The compound of anyone of claim 1-3, wherein, R2 and R3 together with the carbon atom to which they are attached form a C3-C7 cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, CN, NO2, oxo, ORa, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
  12. The compound of anyone of claim 1-3, wherein, R2 and R3 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, NO2, oxo, ORa, NHORa, C (O) Rb, C (O) NRcRd, C (O) ORa, OC (O) Rb, OC (O) NRcRd, NRcRd, NRcC (O) Rb, NRcC (O) NRcRd, NRcC (O) ORa, B (ORc) (ORd) , C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, P (O) ReRf, P (O) OReORf, OP (O) OReORf, S (O) Rb, S (O) NRcRd, S (O) 2Rb, NRcS (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2NRcRd, or NRcS (O) (=NRb) Rb.
  13. The compound of anyone of claim 1-12, wherein, R4 is selected from H, D, NH2, or CN, Me, CD3 or CF3.
  14. The compound of anyone of claim 1-13, wherein, R5 is selected from H, D, halo, CN, CH3, CD3, CH2CH3, CH2CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH2CH2OH.
  15. The compound of anyone of claim 1-15, wherein, R6 is selected from H, D, halo, CN, CH3, CD3, CH2CH3, CH2CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH2CH2OH.
  16. The compound of anyone of claim 1-15, wherein, R7 is H, D, F, Cl, Me, CF3, OH, OMe.
  17. The compound of anyone of claim 1-16, wherein, R8 is selected from H, D, CN, SF5, CH3, CD3, CH2CH3, CH2CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3.
  18. The compound of anyone of claim 1-17, wherein, the compound of formula (IA) and (IB) is represented by the compound of formula (IAa) , (IAb) , (IAc) , (IAd) , (IAe) , (IBa) , (IBb) , (IBc) , (IBd) , or (IBe) :

    or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variants or prodrugs thereof; wherein X, Y, L, R, R1, R2, R4, R5, R6, R7, R8 are defined with respect to Formula (IA) and (IB) .
  19. The compound of claim 18, wherein, the compound of formula (IA) and (IB) is represented by the compound of formula (IAa) , (IBa) :
    or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variants or prodrugs thereof; wherein X, Y, L, R, R1, R2, R4, R5, R6 and R7 are defined with respect to Formula (IA) and (IB) .
  20. The compound of anyone of claim 1-19, wherein, the compound of formula (IA) and (IB) is represented by the compound of formula (IIAa) , (IIAb) , (IIAc) , (IIAd) , (IIAe) , (IIBa) , (IIBb) , (IIBc) , (IIBd) , or (IIBe) :

    or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, Isotopic variants or prodrugs thereof; wherein X, Y, L, R, R1, R2, R4, R5, R6, R7, R8 are defined with respect to Formula (IA) and (IB) .
  21. The compound of anyone of claim 1-20, wherein, the compound of formula (IA) and (IB) is represented by the compound of formula (IIIAa) , (IIIAb) , (IIIAc) , (IIIAd) , (IIIAe) , (IIIBa) , (IIIBb) , (IIIBc) , (IIIBd) , or (IIIBe) :
    or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, Isotopic variants or prodrugs thereof; wherein X, Y, L, R, R1, R2, R4, R5, R6, R7, R8 are defined with respect to Formula (IA) and (IB) .
  22. The compound of anyone of claim 1-21, wherein, the compound of formula (IA) and (IB) is represented by the compound of formula (IIAa) , (IIBa) , (IIIAa) , (IIIBa) :
    or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, isotopic variants or prodrugs thereof; wherein X, Y, L, R, R1, R2, R4, R5, R6, R7 are defined with respect to Formula (IA) and (IB) .
  23. The compound of anyone of claim 1-22, wherein, the compound of formula (IB) is represented by the compound of formula (IVBa) , (IVBb) , or (IVBc) :
    or pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variant or prodrugs thereof; wherein Y, R1, R2, R5, R6, R7, R8, R10, R11 are defined with respect to Formula (IB) .
  24. The compound of anyone of claim 1-23, wherein, the compound of Formula (IA) and (IB) is:
    or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variants or prodrugs thereof.
  25. The compound of claim 24, wherein, the compound is:
    or a pharmaceutically acceptable salt, stereoisomer, atropisomer, solvate, N-oxide, isotopic variants or prodrugs thereof.
  26. A pharmaceutical composition comprising a compound of anyone of claim 1-25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  27. A method of treating a subject in need thereof comprising administering to the subject the compound of anyone of claim 1-25, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 26.
  28. The method of claim 27, wherein, the subject is suffering from, and is in need of a treatment for, a disease or condition having the symptom of cell hyperproliferation.
  29. The method of claim 28, wherein, the disease or condition is a cancer.
  30. The method of claim 29, wherein, the cancer is a cancer with CCNE1 amplification, FBXW7 loss-of-function mutations or other genetic alterations which depend on PKMYT1.
PCT/CN2023/113479 2022-08-24 2023-08-17 Tricyclic heterocyclic derivatives, compositions and uses thereof WO2024041440A1 (en)

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WO2008079965A1 (en) * 2006-12-22 2008-07-03 Incyte Corporation Substituted heterocycles as janus kinase inhibitors
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