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WO2024222866A1 - Cyclic derivatives, compositions and uses thereof - Google Patents

Cyclic derivatives, compositions and uses thereof Download PDF

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Publication number
WO2024222866A1
WO2024222866A1 PCT/CN2024/090050 CN2024090050W WO2024222866A1 WO 2024222866 A1 WO2024222866 A1 WO 2024222866A1 CN 2024090050 W CN2024090050 W CN 2024090050W WO 2024222866 A1 WO2024222866 A1 WO 2024222866A1
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Prior art keywords
alkyl
independently selected
cycloalkyl
membered heteroaryl
aryl
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French (fr)
Inventor
Wenlai Zhou
Jincong Zhuo
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Danatlas Pharmaceuticals Co Ltd
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Danatlas Pharmaceuticals Co Ltd
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Priority to CN202480027385.2A priority Critical patent/CN121039135A/en
Publication of WO2024222866A1 publication Critical patent/WO2024222866A1/en
Anticipated expiration legal-status Critical
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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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to cyclic derivatives as WRN inhibitors.
  • the present disclosure also relates to methods for preparing the cyclic derivatives, pharmaceutical compositions, and their uses in the treatment of WRN-mediated diseases, e.g., cancers and other diseases.
  • MMR DNA mismatch repair
  • MSS microsatellite-stable
  • MSI-H microsatellite instability-high
  • RNA interference RNA interference
  • WRN Werner Syndrome RecQ helicase
  • MSS microsatellite stable
  • Depletion of WRN leads to anti-proliferative effects and results in activation of multiple DNA damage signaling markers, induction of cell cycle arrest and apoptosis in MMR cancer models but not cancer cells with an intact MMR pathway.
  • WRN provides a DNA repair and maintenance function that is essential for MSI-H cell survival.
  • MSI-H cells there is an increase in non-canonical secondary DNA structures creating a requirement for WRN for their resolution (van Wietmarschen N, 2020) .
  • WRN or upon WRN helicase inhibition
  • the replication machinery runs into the unresolved structures eventually leading to an increase in double-stranded breaks and cell death.
  • inhibiting the WRN helicase is an attractive strategy for the treatment of dMMR/MSI-H cancers.
  • the present disclosure relates to, inter alia, compounds of Formula (I) ,
  • a pharmaceutical composition comprising a compound of formula (I) , or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof and at least one pharmaceutically acceptable carrier.
  • a method of inhibiting WRN comprising:
  • a method of treating cancers and other diseases comprising administering to a subject a therapeutically effective amount of a compound of formula (I) , or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof.
  • compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect.
  • the present disclosure provides, inter alia, a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof, wherein:
  • Cy is selected from 5-10 membered partially unsaturated heterocycloalkyl or 5-10 membered heteroaryl; wherein, the Cy is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R 3 ;
  • n 1, 2 or 3;
  • n 1 or 2;
  • each R is independently selected from H, D, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, OC 1 -C 6 alkyl, OC 1 -C 6 haloalkyl, -NH (C 1 -C 6 alkyl) , or -N (C 1 -C 6 alkyl) 2 ; wherein, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N 3 , NO 2 , SF 5 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloal
  • C 3 -C 5 cycloalkyl or 4-5 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, halo, OH, oxo, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, or OC 1 -C 4 haloalkyl;
  • R 1 is selected from H, D, halo, 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, OR A , SR A , or NR C R D ; 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, or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 ;
  • each R 2 is independently selected from H, D, CN, OH, C 1 -C 4 alkyl or OC 1 -C 4 alkyl; wherein, the C 1 -C 4 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from D, halo, CN, OH, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, NH 2 , -NH (C 1 -C 4 alkyl) , or -N (C 1 -C 4 alkyl) 2 ;
  • each R 3 is independently selected from H, D, halo, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl, OR A , SR A , or NR C R D ; wherein, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH,
  • Cy 1 is C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl; wherein, the C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl is optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R 5B ;
  • each R 5A is independently selected from D, halo, CN, N 3 , oxo, OR a , Si (C 1 -C 4 alkyl) 3 or OC 1 -C 6 alkyl-OH;
  • each R 5B is independently selected from H, D, halo, CN, NO 2 , N 3 , SF 5 , oxo, 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, OR a , SR a , 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 (OR c ) (OR d ) ,
  • 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
  • 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,
  • 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 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 heteroary
  • 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, 3, 4 or 5 substituents independently selected from D, halo, oxo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkyl-CN, OR a , SR a , C (O) R b , NR c R d ;
  • R a and R a1 are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl; wherein, the C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, C 3 -C 7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, halo, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 1 -C 4 halo
  • R b and R b1 are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 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, or 4-7 membered heterocycloalkyl
  • R c , R c1 , R d and R d1 are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C 3 -C 10 alkyl, C 3 -C 10 cycloalkyl-C 6 -C 10 alkyl, 4-10 membered heterocycloalkyl-C 1 -C 4 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, bi (C 6 -C 10 aryl) , 5-10 membered heteroaryl-
  • R c and R d or R c1 and R d1 together with the N atom to which they are attached form 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, O-C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, O-C 1 -C 4 haloalkyl, C 1 -C 4 alkyl-OH, C 1 -C 4 alkyl-CN, 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
  • R E and R e are each independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, (C 1 -C 4 alkoxy) -C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 alkyl;
  • R F and R f are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, or 4-10 membered heterocycloalkyl.
  • the compounds of Formula (I) are represented by compounds of Formula (Ia) or (Ib) :
  • the compounds of Formula (I) are represented by compounds of Formula (II) or (III) :
  • Cy is selected from 5-10 membered partially unsaturated heterocycloalkyl or 5-10 membered heteroaryl; wherein, the Cy is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R 3 .
  • Cy is 5-10 membered partially unsaturated heterocycloalkyl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R 3 ; and when n is 1 and L is -C (O) -, then Cy is not wherein, the position *is attached to L, the position **is attached to R 1 .
  • Cy is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R 3 .
  • the moiety is selected from:
  • X is N or CR 3A ;
  • X 1 is N or CR 3B ;
  • X 2 is N or CR 3C ;
  • X 3 , X 4 and X 5 are each independently selected from N or CR 3 ;
  • Y 1 and Y 2 are each independently selected from N, NR 3 , O, S or CR 3 ;
  • Y 3 is N or C
  • a 1 and A 2 are each independently selected from NR 3 , O, S or C (R 3 ) 2 ;
  • R 3A is H, D, halo, OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl;
  • R 3B is H, D, halo, OH
  • R 3C is H, D, halo, OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl, OC 1 -C 3 haloalkyl;
  • p 1 or 2;
  • R 1 and R 3 are defined with respect to Formula (I) ; in the moiety of one of R 3 at any position is replaced by R 1 .
  • Cy is selected from:
  • R 1 is attached to any possible position on the Cy;
  • the Cy is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R 3 ;
  • the compounds of Formula (I) are represented by compounds of Formula (IVa) , (IVb) , (IVc) , (IVd) , (IVe) or (IVf) :
  • X is N or CR 3A ;
  • X 1 is N or CR 3B ;
  • X 2 is N or CR 3C ;
  • X 3 , X 4 and X 5 are each independently selected from N or CR 3 ;
  • Y 1 and Y 2 are each independently selected from N, NR 3 , O, S or CR 3 ;
  • Y 3 is N or C
  • a 1 and A 2 are each independently selected from N, NR 3 , O, S or C (R 3 ) 2 ;
  • p 1 or 2;
  • R 3A is H, D, halo, OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl;
  • R 3B is H, D, halo, OH
  • R 3C is H, D, halo, OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl, OC 1 -C 3 haloalkyl;
  • the compounds of Formula (I) are represented by compounds of Formula (Va) , (Vb) , (Vc) , (Vd) , (Ve) or (Vf) :
  • X is N or CR 3A ;
  • X 1 is N or CR 3B ;
  • X 2 is N or CR 3C ;
  • X 3 , X 4 and X 5 are each independently selected from N or CR 3 ;
  • Y 1 and Y 2 are each independently selected from N, NR 3 , O, S or CR 3 ;
  • Y 3 is N or C
  • a 1 and A 2 are each independently selected from NR 3 , O, S or C (R 3 ) 2 ;
  • p 1 or 2;
  • R 3A is H, D, halo, OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl;
  • R 3B is H, D, halo, OH
  • R 3C is H, D, halo, OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl, OC 1 -C 3 haloalkyl;
  • L is -S (O) 2 -.
  • L is -C (O) -.
  • L is -S (O) 2 NHC (O) -.
  • L is -C (O) NHS (O) 2 -.
  • each R 2 is selected from H, D, CN, OH, C 1 -C 4 alkyl or OC 1 -C 4 alkyl; wherein, the C 1 -C 4 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from D, halo, CN, OH, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, NH 2 , -NH (C 1 -C 4 alkyl) , or -N (C 1 -C 4 alkyl) 2 .
  • each R 2 is selected from H. In some embodiments, each R 2 is selected from D. In some embodiments, each R 2 is selected from CN. In some embodiments, each R 2 is selected from OH.
  • each R 2 is selected from C 1 -C 4 alkyl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from D, halo, CN, OH, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, NH 2 , -NH (C 1 -C 4 alkyl) , or -N (C 1 -C 4 alkyl) 2 .
  • each R 2 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 F, CHF 2 , CF 3 .
  • each R 2 is selected from OC 1 -C 4 alkyl; wherein, the C 1 -C 4 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from D, halo, CN, OH, -O-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl, NH 2 , -NH (C 1 -C 4 alkyl) , or -N (C 1 -C 4 alkyl) 2 .
  • each R 2 is selected from OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH (CH 3 ) 2 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 OCH 3 .
  • the compounds of Formula (I) are represented by compounds of Formula (VIa) , (VIb) , (VIc) , (VId) , (VIe) or (VIf) :
  • the compounds of Formula (I) are represented by compounds of Formula (VIIa) , (VIIb) , (VIIc) , (VIId) , (VIIe) or (VIIf) :
  • the compounds of Formula (I) are represented by compounds of Formula (VIIIa) , (VIIIb) , (VIIIc) , (VIIId) , (VIIIe) or (VIIIf) :
  • the compounds of Formula (I) are represented by compounds of Formula (IXa) , (IXb) , (IXc) , (IXd) , (IXe) or (IXf) :
  • X is CR 3A
  • X 1 is CR 3B
  • X 2 is CR 3C .
  • X is CR 3A
  • X 1 is N
  • X 2 is CR 3C .
  • X is CR 3A
  • X 1 is CR 3B
  • X 2 is N.
  • X is N
  • X 1 is CR 3B
  • X 2 is CR 3C .
  • X is N
  • X 1 is CR 3B
  • X 2 is N
  • X 3 is CR 3
  • X 4 is N
  • X 5 is CR 3 .
  • X 3 is CR 3
  • X 4 is CR 3 .
  • Y 1 is NR 3 , O or S; Y 2 is N or CR 3 .
  • Cy is selected from:
  • R 3A is H, D, halo, OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl.
  • R 3A is H. In some embodiments, R 3A is D. In some embodiments, R 3A is F, Cl, Br, I. In some embodiments, R 3A is F. In some embodiments, R 3A is OH. In some embodiments, R 3A is CH 3 . In some embodiments, R 3A is CF 3 , CHF 2 , CH 2 F. In some embodiments, R 3A is OCF 3 .
  • R 3B is H, D, halo, OH.
  • R 3B is H. In some embodiments, R 3B is D. In some embodiments, R 3B is halo (such as F, Cl, Br, I) . In some embodiments, R 3B is OH.
  • R 3C is H, D, halo, OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl, OC 1 -C 3 haloalkyl.
  • R 3C is H. In some embodiments, R 3C is D. In some embodiments, R 3C is F, Cl, Br, I. In some embodiments, R 3C is OH.
  • R 3C is C 1 -C 3 alkyl. In some embodiments, R 3C is C 1 -C 3 haloalkyl. In some embodiments, R 3C is OC 1 -C 3 alkyl. In some embodiments, R 3C is OC 1 -C 3 haloalkyl.
  • each R 3 is independently selected from H, D, halo, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl, OR A , SR A , or NR C R D ; wherein, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alky
  • each R 3 is independently selected from H. In some embodiments, each R 3 is independently selected from D. In some embodiments, each R 3 is independently selected from halo (such as F, Cl, Br or I) . In some embodiments, each R 3 is independently selected from F. In some embodiments, each R 3 is independently selected from Cl. In some embodiments, each R 3 is independently selected from Br. In some embodiments, each R 3 is independently selected from I) . In some embodiments, each R 3 is independently selected from CN.
  • each R 3 is independently selected from OR A .
  • each R 3 is independently selected from OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH (CH 3 ) 2 , OCH 2 F, OCHF 2 , OCF 3 .
  • each R 3 is independently selected from SR A . In some embodiments, for example, included but not limited to, each R 3 is independently selected from SCH 3 , SCH 2 CH 3 , etc..
  • each R 3 is independently selected from NR C R D . In some embodiments, for example, each R 3 is independently selected from NH 2 , NHCH 3 , N (CH 3 ) 2 , NHCH 2 CH 3 , N (CH 2 CH 3 ) 2 , NHCH 2 CH 2 OH, N (CH 3 ) CH 2 CH 2 OH.
  • each R 3 is independently selected from C 1 -C 6 alkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, NR c R d , OR a , SR a , NHOR a , C (O) R b , C (O) OR a , OC (O) R b , C (O) NR c R d , NR c C (O) R b .
  • each R 3 is independently selected from CH 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 , CF 2 CH 3 , CF 2 CF 3 , CH 2 OH, CH 2 CH 2 OH, CH (OH) CH 3 , CH 2 CN, CH 2 CH 2 CN.
  • each R 3 is independently selected from C 2 -C 6 alkenyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, NR c R d , OR a , SR a , NHOR a , C (O) R b , C (O) OR a , OC (O) R b , C (O) NR c R d , NR c C (O) R b .
  • each R 3 is independently selected from C 2 -C 6 alkynyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, NR c R d , OR a , SR a , NHOR a , C (O) R b , C (O) OR a , OC (O) R b , C (O) NR c R d , NR c C (O) R b .
  • each R 3 is independently selected from C 3 -C 7 cycloalkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, NR c R d , OR a , SR a , NHOR a , C (O) R b , C (O) OR a , OC (O) R b , C (O) NR c R d , NR c C (O) R b .
  • each R 3 is independently selected from phenyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, NR c R d , OR a , SR a , NHOR a , C (O) R b , C (O) OR a , OC (O) R b , C (O) NR c R d , NR c C (O) R b .
  • each R 3 is independently selected from 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, NR c R d , OR a , SR a , NHOR a , C (O) R b , C (O) OR a , OC (O) R b , C (O) NR c R d , NR c C (O) R b .
  • each R 3 is independently selected from 5-7 membered heteroaryl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, NR c R d , OR a , SR a , NHOR a , C (O) R b , C (O) OR a , OC (O) R b , C (O) NR c R d , NR c C (O) R b .
  • each R 3 is independently selected from H, D, halo, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, OR A , SR A , or NR C R D ; wherein, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, NR c R d , OR a , SR a , NHOR a , C (O) R b ,
  • two R 3 together with the same ring carbon atom to which they are attached form oxo.
  • two R 3 together with the same ring carbon atom to which they are attached form C 3 -C 4 cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, or -OC 1 -C 6 haloalkyl.
  • two R 3 together with the same ring carbon atom to which they are attached form 4 membered heterocycloalkyl having a heteroatom selected from Si, N, O or S optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, or -OC 1 -C 6 haloalkyl.
  • two adjacent R 3 together with the atoms to which they are attached form C 3 -C 6 cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, or -OC 1 -C 6 haloalkyl.
  • two adjacent R 3 together with the atoms to which they are attached form 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms selected from Si, N, O or S optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, or -OC 1 -C 6 haloalkyl.
  • two adjacent R 3 together with the atoms to which they are attached form phenyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, or -OC 1 -C 6 haloalkyl.
  • two adjacent R 3 together with the atoms to which they are attached form 5-6 membered heteroarylene having 1, 2, 3 or 4 heteroatoms selected from N, O or S optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -O-C 1 -C 6 alkyl, or -OC 1 -C 6 haloalkyl.
  • m is 1, 2 or 3.
  • m is 1.
  • n is 2.
  • m is 3.
  • each R is independently selected from H, D, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, OC 1 -C 6 alkyl, OC 1 -C 6 haloalkyl, -NH (C 1 -C 6 alkyl) , or -N (C 1 -C 6 alkyl) 2 ; wherein, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N 3 , NO 2 , SF 5 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 alkyl,
  • each R is independently selected from H. In some embodiments, each R is independently selected from D. In some embodiments, each R is independently selected from halo (such as F, Cl, Br or I) .
  • each R is independently selected from C 1 -C 6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N 3 , NO 2 , SF 5 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl.
  • each R is independently selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 F, CHF 2 , CF 3 .
  • each R is independently selected from C 2 -C 6 alkenyl optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N 3 , NO 2 , SF 5 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl.
  • each R is independently selected from C 2 -C 6 alkynyl optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N 3 , NO 2 , SF 5 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl.
  • each R is independently selected from C 3 -C 6 cycloalkyl optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N 3 , NO 2 , SF 5 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl.
  • each R is independently selected from OC 1 -C 6 alkyl; wherein, the C 1 -C 6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N 3 , NO 2 , SF 5 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl.
  • each R is independently selected from OC 1 -C 6 haloalkyl.
  • each R is independently selected from -NH (C 1 -C 6 alkyl) ; wherein, the C 1 -C 6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N 3 , NO 2 , SF 5 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl.
  • each R is independently selected from -N (C 1 -C 6 alkyl) 2 ; wherein, the C 1 -C 6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N 3 , NO 2 , SF 5 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl.
  • two R groups together with the same ring carbon atom to which they are attached form C 3 -C 5 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, halo, OH, oxo, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, or OC 1 -C 4 haloalkyl.
  • two R groups together with the same ring carbon atom to which they are attached form 4-5 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, halo, OH, oxo, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, or OC 1 -C 4 haloalkyl.
  • R 1 is selected from H, D, halo, 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, or 5-10 membered heteroaryl; 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, or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents R 4 .
  • R 1 is H. In some embodiments, R 1 is D. In some embodiments, R 1 is halo (such as F, Cl, Br or I) .
  • R 1 is C 1 -C 6 alkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is C 2 -C 6 alkenyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is ethenyl, prop-1-en-1-yl, prop-1-en-2-yl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is C 2 -C 6 alkynyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is C 3 -C 10 cycloalkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is C 3 -C 10 saturated cycloalkyl or C 3 -C 10 partially unsaturated cycloalkyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is C 3 -C 10 saturated mono-cycloalkyl, C 6 -C 10 saturated bicycloalkyl, C 5 -C 10 saturated spiro-cycloalkyl, C 5 -C 10 saturated bridged cycloalkyl, C 8 -C 10 saturated fused cycloalkyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro [3.3] heptanyl, spiro [3.4] octanyl, spiro [3.5] nonanyl, spiro [3.6] decanyl, spiro [4.4] nonanyl, spiro [4.5] decanyl, spiro [4.6] undecanyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, bicyclo [5.2.0
  • R 1 is cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, or cyclohexenyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is 4-10 membered heterocycloalkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is 4-10 membered saturated heterocycloalkyl or 4-10 membered partially unsaturated heterocycloalkyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, dioxanyl tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, azepanyl, diazocanyl, diazepanyl, azepanyl, 2, 6-diazaspiro [3.3] heptanyl, 2-oxa-6-azaspiro [3.3] heptanyl, 2, 6-diazaspiro [3.4] octanyl, 2, 7-diazaspiro [3.5] nonanyl, 2, 7-diazaspiro [4.4] nonanyl, 3, 9-diazaspiro [5.5] undecanyl, 2-oxa-7-azaspiro [3.5] nonanyl, 2-
  • R 1 is 5-10 membered partially unsaturated mono-heterocycloalkyl, 6-10 membered partially unsaturated bicyclo heterocycloalkyl, 7-10 membered partially unsaturated spiro heterocycloalkyl, 7-10 membered partially unsaturated bridged heterocycloalkyl, or 8-10 membered partially unsaturated fused heterocycloalkyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is C 6 -C 10 aryl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is phenyl, naphthalenyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 4 .
  • R 1 is pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzo [b] thiophenyl, benzo [c] thiophenyl, indazolyl, benzo [d] imidazolyl, pyrrolo [3, 2-b] pyridinyl, pyrrolo [3, 2-c] pyridinyl, pyrrolo [2, 3-c] pyridinyl, pyrrolo [2, 3-b] pyridinyl, pyrrolo [3, 4-b] pyr
  • R 1 is selected from H, D, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, OR A , SR A , or NR C R D ; wherein, the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents R 4 .
  • each R 4 is independently selected from H. In some embodiments, each R 4 is independently selected from D. In some embodiments, each R 4 is independently selected from halo (such as F, Cl, Br or I) . In some embodiments, each R 4 is independently selected from F. In some embodiments, each R 4 is independently selected from Cl. In some embodiments, each R 4 is independently selected from Br. In some embodiments, each R 4 is independently selected from I.
  • each R 4 is independently selected from CN. In some embodiments, each R 4 is independently selected from NO 2 . In some embodiments, each R 4 is independently selected from N 3 . In some embodiments, each R 4 is independently selected from SF 5 . In some embodiments, each R 4 is independently selected from oxo.
  • each R 4 is independently selected from C 1 -C 6 alkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 5A .
  • each R 4 is independently selected from C 2 -C 6 alkenyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 5A .
  • each R 4 is independently selected from C 2 -C 6 alkynyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 5A .
  • each R 4 is independently selected from NR C R D . In some embodiments, each R 4 is independently selected from OR A . In some embodiments, each R 4 is independently selected from SR A .
  • each R 4 is independently selected from C (O) R B . In some embodiments, each R 4 is independently selected from C (O) OR A . In some embodiments, each R 4 is independently selected from OC (O) R B .
  • each R 4 is independently selected from B (OR C ) (OR D ) . In some embodiments, each R 4 is independently selected from P (O) R E R F . In some embodiments, each R 4 is independently selected from P (O) OR E OR F . In some embodiments, each R 4 is independently selected from OP (O) OR E OR F .
  • each R 4 is independently selected from Cy 1 .
  • each R 4 is independently selected from OCy 1 .
  • each R 4 is independently selected from C 1 -C 6 alkyl-Cy 1 ; wherein, the C 1 -C 6 alkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 5A .
  • each R 4 is independently selected from OC 1 -C 6 alkyl-Cy 1 ; wherein, the C 1 -C 6 alkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R 5A .
  • each R 5A is independently selected from D, halo, CN, N 3 , oxo, OR a , Si (C 1 -C 4 alkyl) 3 or OC 1 -C 6 alkyl-OH.
  • each R 5A is independently selected from D. In some embodiments, each R 5A is independently selected from halo (such as F, Cl, Br or I) . In some embodiments, each R 5A is independently selected from F. In some embodiments, each R 5A is independently selected from Cl. In some embodiments, each R 5A is independently selected from Br. In some embodiments, each R 5A is independently selected from I.
  • each R 5A is independently selected from CN. In some embodiments, each R 5A is independently selected from N 3 . In some embodiments, each R 5A is independently selected from oxo.
  • each R 5A is independently selected from OR a . In some embodiments, for example, included but not limited to, each R 5A is independently selected from OH, OCH 3 , OCH 2 F, OCHF 2 , OCF 3 .
  • each R 5A is independently selected from Si (C 1 -C 4 alkyl) 3 .
  • each R 5A is independently selected from OC 1 -C 6 alkyl-OH. In some embodiments, for example, included but not limited to, each R 5A is independently selected from OCH 2 CH 2 OH.
  • Cy 1 is C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl; wherein, the C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl is optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R 5B .
  • Cy 1 is C 3 -C 10 cycloalkyl optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R 5B .
  • Cy 1 is 4-10 membered heterocycloalkyl optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R 5B .
  • Cy 1 is C 6 -C 10 aryl optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R 5B .
  • Cy 1 is phenyl, naphthalenyl; each is optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R 5B .
  • Cy 1 is 5-10 membered heteroaryl optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R 5B .
  • R 5B is each independently selected from H, D, halo, CN, NO 2 , N 3 , SF 5 , oxo, 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, OR a , SR a , 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 (OR c ) (OR d
  • R 5B is independently selected from H. In some embodiments, R 5B is independently selected from D. In some embodiments, R 5B is independently selected from halo (such as F, Cl, Br or I) . In some embodiments, R 5B is independently selected from CN. In some embodiments, R 5B is independently selected from NO 2 . In some embodiments, R 5B is independently selected from N 3 . In some embodiments, R 5B is independently selected from SF 5 . In some embodiments, R 5B is independently selected from oxo.
  • R 5B is independently selected from C 1 -C 6 alkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO 2 , N 3 , SF 5 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, OR a1 , C (O) OR a1 , C (O) R b1 , NR c1 R d1 , C (O) NR c1 R d1 , S (O) 2 R b1 , or S (O) 2 NR c1 R d1 .
  • R 5B is independently selected from C 2 -C 6 alkenyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO 2 , N 3 , SF 5 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, OR a1 , C (O) OR a1 , C (O) R b1 , NR c1 R d1 , C (O) NR c1 R d1 , S (O) 2 R b1 , or S (O) 2 NR c1 R d1 .
  • R 5B is independently selected from C 2 -C 6 alkynyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO 2 , N 3 , SF 5 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, OR a1 , C (O) OR a1 , C (O) R b1 , NR c1 R d1 , C (O) NR c1 R d1 , S (O) 2 R b1 , or S (O) 2 NR c1 R d1 .
  • R 5B is independently selected from C 3 -C 10 cycloalkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO 2 , N 3 , SF 5 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, OR a1 , C (O) OR a1 , C (O) R b1 , NR c1 R d1 , C (O) NR c1 R d1 , S (O) 2 R b1 , or S (O) 2 NR c1 R d1 .
  • R 5B is independently selected from 4-10 membered heterocycloalkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO 2 , N 3 , SF 5 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, OR a1 , C (O) OR a1 , C (O) R b1 , NR c1 R d1 , C (O) NR c1 R d1 , S (O) 2 R b1 , or S (O) 2 NR c1 R d1 .
  • R 5B is independently selected from C 6 -C 10 aryl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO 2 , N 3 , SF 5 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, OR a1 , C (O) OR a1 , C (O) R b1 , NR c1 R d1 , C (O) NR c1 R d1 , S (O) 2 R b1 , or S (O) 2 NR c1 R d1 .
  • R 5B is independently selected from 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO 2 , N 3 , SF 5 , oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, OR a1 , C (O) OR a1 , C (O) R b1 , NR c1 R d1 , C (O) NR c1 R d1 , S (O) 2 R b1 , or S (O) 2 NR c1 R d1 .
  • R 5B is independently selected from OR a . In some embodiments, R 5B is independently selected from SR a . In some embodiments, R 5B is independently selected from NHOR a .
  • R 5B is independently selected from C (O) R b . In some embodiments, R 5B is independently selected from C (O) NR c R d . In some embodiments, R 5B is independently selected from C (O) OR a . In some embodiments, R 5B is independently selected from OC (O) R b . In some embodiments, R 5B is independently selected from OC (O) NR c R d .
  • R 5B is independently selected from P (O) R e R f . In some embodiments, R 5B is independently selected from P (O) OR e OR f . In some embodiments, R 5B is independently selected from OP (O) OR e OR f .
  • 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 heterocyclalkyl
  • each R A is independently selected from H. In some embodiments, each R A is independently selected from D.
  • each R A is independently selected from 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
  • 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 membere
  • each R B is independently selected from H, D. In some embodiments, each R B is independently selected from H. In some embodiments, each R B is independently selected from D.
  • each R B is independently selected from 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,
  • 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 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 heterocycl
  • each R C is independently selected from H, D. In some embodiments, 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, 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
  • each R D is independently selected from H, D. In some embodiments, 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, 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 together with the N atom to which they are attached form 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, oxo, CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkyl-CN, OR a , SR a , C (O) R b , NR c R d .
  • each R E is independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, (C 1 -C 4 alkoxy) -C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 alkyl.
  • each R E is independently selected from H, or D. In some embodiments, each R E is independently selected from H. In some embodiments, each R E is independently selected from D.
  • each R E is independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, (C 1 -C 4 alkoxy) -C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 alkyl.
  • each R F is independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, or 4-10 membered heterocycloalkyl.
  • each R F is independently selected from H. In some embodiments, each R F is independently selected from D.
  • each R F is independently selected from 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 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, 3, 4 or 5 substituents independently selected from D, OH, halo, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 1 -C 4 haloal
  • each R a is independently selected from H, or D. In some embodiments, each R a is independently selected from H. In some embodiments, each R a is independently selected from D.
  • each R a is independently selected from 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, 3, 4 or 5 substituents independently selected from D, OH, halo, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl,
  • each R b 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, C 6 -C 10 aryl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 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, or 4-7 membered heterocycloalkyl,
  • each R b is independently selected from H, D. In some embodiments, each R b is independently selected from H. In some embodiments, each R b is independently selected from D.
  • each R b is independently selected from 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, C 6 -C 10 aryl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl or 4-10 membered heterocycloalkyl-C 1 -C 4 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
  • each R c 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, 5-10 membered heteroaryl-C 3 -C 10 alkyl, C 3 -C 10 cycloalkyl-C 6 -C 10 alkyl, 4-10 membered heterocycloalkyl-C 1 -C 4 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, bi (C 6 -C 10 aryl) , 5-10 membered heteroaryl-C 3 -C 10 cycloalkyl
  • each R c is independently selected from H, D. In some embodiments, 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 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, 5-10 membered heteroaryl-C 3 -C 10 alkyl, C 3 -C 10 cycloalkyl-C 6 -C 10 alkyl, 4-10 membered heterocycloalkyl-C 1 -C 4 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, bi (C 6 -C 10 aryl) , 5-10 membered heteroaryl-C 3 -C 10 cycloalkyl, 5-10 membered heteroary
  • each R d is independently selected from H, D. In some embodiments, 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 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, 5-10 membered heteroaryl-C 3 -C 10 alkyl, C 3 -C 10 cycloalkyl-C 6 -C 10 alkyl, 4-10 membered heterocycloalkyl-C 1 -C 4 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, bi (C 6 -C 10 aryl) , 5-10 membered heteroaryl-C 3 -C 10 cycloalkyl, 5-10 membered heteroary
  • R c and R d together with the N atom to which they are attached form 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, O-C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, O-C 1 -C 4 haloalkyl, C 1 -C 4 alkyl-OH, C 1 -C 4 alkyl-CN, 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 al
  • each R e is independently selected from H, D, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, (C 1 -C 4 alkoxy) -C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 alkyl.
  • each R e is each independently selected from H, D. In some embodiments, each R e is each independently selected from H. In some embodiments, each R e is each independently selected from D.
  • each R e is each independently selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkenyl, (C 1 -C 4 alkoxy) -C 1 -C 4 alkyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 alkyl.
  • each R f is independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, or 4-10 membered heterocycloalkyl.
  • each R f is independently selected from H. In some embodiments, each R f is independently selected from D.
  • each R f is independently selected from 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, 3, 4 or 5 substituents independently selected from D, OH, halo, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 1 -C 4 halo
  • each R a1 is independently selected from H, D. In some embodiments, each R a1 is independently selected from H. In some embodiments, each R a1 is independently selected from D.
  • each R a1 is independently selected from 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, 3, 4 or 5 substituents independently selected from D, OH, halo, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl,
  • each R b1 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, C 6 -C 10 aryl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 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, or 4-7 membered heterocycloalkyl
  • each R b1 is independently selected from H, D. In some embodiments, each R b1 is independently selected from H. In some embodiments, each R b1 is independently selected from D.
  • each R b1 is independently selected from 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, C 6 -C 10 aryl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, or 4-10 membered heterocycloalkyl-C 1 -C 4 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, or 4-7 membered heterocycloalkyl, C 6
  • R c1 and R d1 are each independently selected from H, D, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl-C 1 -C 4 alkyl, 4-10 membered heterocycloalkyl-C 1 -C 4 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, bi (C 6 -C 10 -C 10
  • each R c1 is independently selected from H. In some embodiments, each R c1 is independently selected from D.
  • each R c1 is independently selected from 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, C 6 -C 10 aryl-C 1 -C 4 alkyl, 5-10 membered heteroaryl-C 3 -C 10 alkyl, C 3 -C 10 cycloalkyl-C 6 -C 10 alkyl, 4-10 membered heterocycloalkyl-C 1 -C 4 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, bi (C 6 -C 10 aryl) , 5-10 membere
  • each R d1 is independently selected from H. In some embodiments, each R c1 is independently selected from D.
  • each R d1 is independently selected from 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, 5-10 membered heteroaryl-C 3 -C 10 alkyl, C 3 -C 10 cycloalkyl-C 6 -C 10 alkyl, 4-10 membered heterocycloalkyl-C 1 -C 4 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, bi (C 6 -C 10 aryl) , 5-10 membered heteroaryl-C 3 -C 10 cycloalkyl, 5-10
  • R c1 and R d1 together with the N atom to which they are attached form 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH 2 , -NH (C 1 -C 4 alkyl) , -N (C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, O-C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, O-C 1 -C 4 haloalkyl, C 1 -C 4 alkyl-OH, C 1 -C 4 alkyl-CN, 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
  • Stereoisomers of the compounds of Formula I, and the pharmaceutical salts and solvates thereof, are also contemplated, described, and encompassed herein. Methods of using compounds of Formula I are described, as well as pharmaceutical compositions including the compounds of Formula I.
  • the compounds of Formula I may have multiple stereogenic centers.
  • the present disclosure contemplates and encompasses each stereoisomer of any compound of Formula I (and subgenera described herein) , as well as mixtures of said stereoisomers.
  • the present disclosure further provides compounds described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.
  • the present disclosure further provides uses of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention provides a method of inhibiting WRN in a cell expressing WRN, the method comprising contacting the cell with the compound disclosed herein.
  • the cell is associated with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) . In some embodiments, the cell is in a subject.
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • 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 dMMR/MSI-H.
  • the disease or condition is a cancer.
  • the cancer is a cancer with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) .
  • a method of inhibiting WRN in a subject comprising administering to the subject a therapeutically effective amount of the present invention, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention.
  • a method of treating a disease which can be treated by WRN inhibition in a subject comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention.
  • the disease is cancer.
  • the cancer is characterized as MSI-H or dMMR.
  • the cancer characterized as MSI-H or dMMR is selected from colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney and ovarian cancer.
  • the cancer characterized as MSI-H or dMMR is selected from colorectal, gastric and endometrial cancer.
  • the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from prostate cancer, uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal carcinoma, breast carcinoma, kidney renal clear cell carcinoma and ovarian serous cystadenocarcinoma.
  • MSI-H microsatellite instability-high
  • dMMR mismatch repair deficient
  • the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) .
  • 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 cycloalkyl 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.
  • 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, H, D, halogen, CN, NO 2 , SF 5 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, NR c R d , OR a , SR a , NHOR a , C (O) R b , C (O) OR a , OC (O) R b , C (O) NR c R d , NR c C (O) R b , OC (O) NR c R d , OC (O) OR a , NR c C (O) OR a , NR c C (O) OR a
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters) . All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone–enol pairs, amide-imidic acid pairs, lactam–lactim pairs, amide-imidic acid pairs, enamine –imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H-and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H-and 2H-isoindole, and 1H-and 2H-pyrazole, Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • the compounds of the present disclosure may exist as rotational isomers. Descriptions of a compound of the invention that do not indicate a particular rotational isomer are intended to encompass any individual rotational isomers, as well as mixtures of rotational isomers in any proportion. Depiction of a particular rotational isomer is meant to refer to the depicted rotational isomer, substantially free of other rotational isomers.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • the compounds of the invention, and salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99%by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • the present disclosure also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977) , each of which is incorporated herein by reference in its entirety.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • a “solvate” refers to a physical association of a compound of Formula I with one or more solvent molecules.
  • Subject includes humans.
  • the terms “human, ” “patient, ” and “subject” are used interchangeably herein.
  • Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
  • “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
  • “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • isotopic variant refers to a compound that contains proportions of isotopes at one or more of the atoms that constitute such compound that is greater than natural abundance.
  • an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non-radioactive isotopes such as for example, deuterium ( 2 H or D) , carbon-13 ( 13 C) , nitrogen-15 ( 15 N) , or the like.
  • any hydrogen may be 2 H/D
  • any carbon may be 13 C
  • any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • isomers compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers. ” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers, ” for example, diastereomers, enantiomers, and atropisomers.
  • the compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R) -or (S) -stereoisomers at each asymmetric center, or as mixtures thereof.
  • the term “inhibit” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • cancer refers to a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to colorectal, gastric, endometrial, prostate, adrenocortical, uterine, cervical, esophageal, breast, kidney, ovarian cancer and the like.
  • tumor and “cancer” are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating, tumors.
  • cancer or “tumor” includes premalignant, as well as malignant cancers and tumors.
  • WRN inhibitor or ‘WRN helicase inhibitor’ as used herein means a compound that inhibits Werner Syndrome RecQ DNA helicase (WRN) .
  • WRN refers to the protein of Werner Syndrome RecQ DNA helicase.
  • WRN includes mutants, fragments, variants, isoforms, and homologs of full-length wild-type WRN.
  • the protein is encoded by the WRN gene (Entrez gene ID 7486; Ensembl ID ENSG00000165392) .
  • Exemplary WRN sequences are available at the Uniprot database under accession number Q14191.
  • Disease or condition mediated by WRN includes a disease or condition, such as cancer, which is treated by WRN inhibition.
  • this can include cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) .
  • ‘Microsatellite unstable cancer’ , microsatellite instability-high cancer’ , ‘microsatellite high cancer’ and ‘MSI-high cancer’ ‘MSIhi’ and ‘MSI-H’ when used herein, are used interchangeably, and describe cancers that have a high number of alterations in the length of simple repetitive genomic sequences within microsatellites.
  • the determination of MSI-H or dMMR tumor status for patients can be performed using, e.g., polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR.
  • PCR polymerase chain reaction
  • IHC immunohistochemistry
  • synthetic lethality and “synthetic lethal” are used to refer to reduced cell viability and/or a reduced rate of cell proliferation caused by a combination of mutations or approaches to cause loss of function (e.g., RNA interference or protein function inhibition) in two or more genes but not by the loss of function of only one of these genes.
  • loss of function e.g., RNA interference or protein function inhibition
  • compositions comprising compounds of Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound 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 (I) or a pharmaceutically salt thereof for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.1 mg to 1000 mg of Formula (I) or a pharmaceutically salt thereof with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • compositions and methods for preparing the same are non-limiting exemplary pharmaceutical compositions and methods for preparing the same.
  • the compounds of Formula (I) or a pharmaceutically salt thereof or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action) .
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion) ; buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc. ) ; transmucosal (including, e.g., by a patch, plaster, etc.
  • intranasal e.g., by nasal spray
  • ocular e.g., by eye drops
  • pulmonary e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose
  • rectal e.g., by suppository or enema
  • vaginal e.g., by pessary
  • parenteral for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, 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 WRN inhibitor with an IC 50 value of about or less than a predetermined value, as ascertained in an in vitro assay.
  • the WRN inhibitor inhibits WRN with an IC 50 value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM
  • WRN is a synthetic lethal target in the cancers with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) .
  • the subject methods are useful for treating disease conditions associated with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) .
  • a cancer that has “defective mismatch repair” (dMMR) or “dMMR character” includes cancer types associated with documented MLH1, PMS2, MSH2, MSH3, MSH4, MSH5, MSH6, MLH3, PMS1, and EXO1 mutations or epigenetic silencing, microsatellite fragile sites, or other gene inactivation mechanisms.
  • a cell or cancer with “defective” mismatch repair has a significantly reduced (e.g., at least about 25%, 30%, 40%, 50%, 60%, 70%, 80%or 90%decrease) amount of mismatch repair. In some cases, a cell or cancer which is defective in mismatch repair will perform no mismatch repair.
  • 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 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, 8th Ed. (Wiley, 2019) ; Peturssion et al, "Protecting Groups in Carbohydrate Chemistry, " J Chem. Educ., 1997, 74 (11) , 1297; and Wuts et al., Protective Groups in Organic Synthesis, 5th Ed., (Wiley, 2014) .
  • 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 amide derivatives of formula 1-4 can be prepared as the methods outlined in Scheme 1.
  • Carboxylic acids 1-1 can couple with amines 1-2 to provide the amide derivatives 1-4 under standard amide coupling conditions (e.g., in the presence of a coupling reagent such as EDCI, HATU, HBTU, BOP, or PyBOP with a base such as DIPEA, DMAP or pyridine) .
  • the amides 1-4 can be prepared by reaction of the amines 1-2 with acyl chlorides 1-3 which can be obtained by treatment of the corresponding carboxylic acids 1-1 with a suitable reagent such as thionyl chloride or oxalyl chloride.
  • a series of carboxylic acids of formula 2-4 and 2-8 can be prepared as the methods outlined in Scheme 2.
  • Suzuki coupling of carboxylates 2-1 where W is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., SMe, OTf or OMs) with a suitable boronic acid or boronate ester 2-2 R 1 B (OR) 2 where R is selected from H or alkyl can afford compounds 2-3 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 ) .
  • Hydrolysis of the esters 2-3 can provide the carboxylic acids 2-4 in the presence of basic conditions (e.g., such as aqueous LiOH or other inorganic bases) .
  • R 1 can be directly introduced to the N-atom of Cy ring in carboxylate esters 2-5 to provide the corresponding carboxylate esters 2-7 by alkylation with R 1 -W 1 2-6 where W 1 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base such as NaH, KOH, KOt-Bu or through Buchwald reaction 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 ) .
  • Hydrolysis of the esters 2-7 can provide the carboxylic acids 2-8 under basic conditions (e.g., such as aqueous LiOH or other inorganic bases) .
  • a series of 1, 2, 4-triazine-6-carboxylic acids of formula 3-5 can be prepared as the methods outlined in Scheme 3. Condensation of the hydrazine carboxamides 3-1 with diethyl 2-oxomalonate 3-2 in methanol in the presence of HCl can provide the cyclized compounds 3-3. Alkylation of the NH of 3-3 can be achieved by treatment with R 1 -W 1 where W 1 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base such NaH or KOtBu to afford 1, 2, 4-triazine-6-carboxylate esters 3-4.
  • W 1 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base such NaH or KOtBu to afford 1, 2, 4-triazine-6-carboxylate esters 3-4.
  • alkylation of the NH of 3-3 can be achieved by Buchwald reactions 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 .
  • Hydrolysis of the triazine-6-carboxylate esters 3-4 can provide the carboxylic acids 3-5 under basic conditions (e.g., such as aqueous LiOH or other inorganic bases) .
  • a series of 1, 2, 4-triazine-6-carboxylic acids of formula 4-5 can be prepared as the methods outlined in Scheme 4. 1, 2, 4-triazine-6-carboxylate ester 4-1 is treated with NBS to yield the corresponding bromo compounds 4-2.
  • Suzuki coupling of the bromo compounds 4-2 with suitable boronic acids R 1 (OH) 2 or boronates R 1 (OR) 2 R where R is selected from H or alkyl under standard Suzuki coupling conditions e.g., in the presence of a palladium catalyst, such as Xanphos Pd, or [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K 3 PO 4
  • a palladium catalyst such as Xanphos Pd
  • [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base such as K 3 PO 4
  • Alkylation of the NH of 4-3 can be achieved by treatment with R 3 -W 2 where W 2 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base such NaH or KOtBu to afford 1, 2, 4-triazine-6-carboxylate esters 4-4.
  • Hydrolysis of the triazine-6-carboxylate esters 4-4 can provide the carboxylic acids 4-5 under basic conditions (e.g., such as aqueous LiOH or other inorganic bases) .
  • a series of oxo-2, 3-dihydropyridazine-4-carboxylic acids of formula 5-8 can be prepared as the methods outlined in Scheme 5.
  • Condensation of ⁇ -keto esters 5-1 with ethyl 3-hydrazineyl-3-oxopropanoate 5-2 can provide 5-3 which can be cyclized to provide compounds 5-4 in the presence of a base such as KOtBu, NaOMe or NaOEt.
  • the hydroxyl group of 5-4 can be protected by treatment with tert-butydimethylsilyl chloride in the presence of a base such as TEA or imidazole.
  • Alkylation of the OH protected compounds 5-5 can provide the corresponding compounds 5-6 by reactions of R 3 -W 2 where W 2 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base such NaH or KOtBu.
  • W 2 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base such NaH or KOtBu.
  • Removal of the protecting group on 5-6 can be carried out in the presence of an acid such as TFA or fluoride reagent such as FH in pyridine.
  • Hydrolysis of compounds 5-7 in the presence of a base such as LiOH or other inorganic bases can provide the carboxylic acids 5-8.
  • a series of uracil acids of formula 6-4 can be prepared as the methods outlined in Scheme 6.
  • Compounds 6-1 can be selectively alkylated by R 3 -W 2 where W 2 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a mild base such as KOH.
  • Introduction of R 1 on 6-2 can be carried out by using R 1 -W 1 where W 1 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base such as NaH or KOtBu.
  • 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.
  • Hydrolysis of 6-3 in the presence of an inorganic base such as LiOH can provide the uracil acids 6-4.
  • a series of hydroxythiazolo-pyridine carboxylic acids of formula 7-9 can be prepared as the methods outlined in Scheme 7.
  • Reduction of nitro compound 7-1 can provide the corresponding amines 7-2 under various reduction conditions such as Fe/HCl, hydrogenation or Zn/NH 4 Cl.
  • Treatment of the amines 7-2 with potassium thiocyanate can yield the aminothiazolo-pyridines 7-3 which can be transformed into bromide compounds 7-4 in the presence of a bromination reagent such as bromine in acetic acid.
  • Carboxylation of the bromides 7-4 to provide the methyl ester 7-5 can be carried out under CO (gas) in the presence of palladium catalyst such as Pd (dppf) Cl 2 .
  • Sandmeyer-type reactions of the amines 7-5 to the bromo compounds 7-6 can be achieved by using sodium nitrate followed by reacting with CuBr.
  • Suzuki coupling of the bromo compounds 7-6 with suitable boronic acids or boronates R 1 (OR) 2 (where R is selected from H or alkyl) under standard Suzuki coupling 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
  • the hydroxythiazolo-pyridine carboxylic acids 7-9 can be prepared by treating 7-7 with BBr 3 in dichloromethane or other suitable conditions to provide 7-8 followed by hydrolysis of 7-8 in the presence of an inorganic base such as LiOH in a suitable solvent such as THF.
  • a series of hydroxythiazolo-pyridine carboxylic acids of formula 8-7 can be prepared as the methods outlined in Scheme 8. Condensation of amino thiozole 8-1 with 2- (alkoxymethylene) malonate ester (where R is Me or Et) can provide the intermediate enimo-ester 8-3 which can be cyclized into hydroxythiazolo-pyridine carboxylate 8-4 by enhancing temperature in a suitable solvent such as Ph 2 O. Bromination of the 8-4 with a bromination reagent such as NBS can produce the corresponding bromide 8-5.
  • Suzuki coupling of the OH compounds 8-5 with suitable boronic acids or boronates R 1 (OR’) 2 (where R’ is selected from H or alkyl) under standard Suzuki coupling 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 base such as K 3 PO 4
  • a series of aza-indone carboxylic acids of formula 9-8 can be prepared as the methods outlined in Scheme 9.
  • Replacement of the chlorine in aza-indone chloride 9-1 with methoxyl group can be performed under NaOMe/MeOH conditions with heating.
  • Protection of NH in 9-2 can be carried out using a suitable protecting reagent such as BOC anhydride or Tosyl chloride to provide the protected compound 9-3 which can be transformed into the corresponding bromide 9-4 by lithiation of 9-3 using butyllium in a suitable solvent such THF followed by addition of bromine at low temperatures.
  • Removal of phenolic methyl group on 9-4 can provide the corresponding OH compounds 9-5 in the presence of a demethylation reagent such as BBr 3 .
  • Suzuki coupling of the OH compounds 9-5 with suitable boronic acids or boronates R 1 (OR) 2 (where R is selected from H or alkyl) under standard Suzuki coupling 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 ) can afford the compounds 9-6.
  • a palladium catalyst such as [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K 3 PO 4
  • a series of bicyclic-pyridine carboxylic acids of formula 10-4 can be prepared as the methods outlined in Scheme 10. Condensation of suitable heterocyclic amino-aldehydes 10-1 with dialkyl malonates 10-2 where R a is C 1 -C 6 alkyl such as Me, Et, or tert-Bu can afford the bicyclic-pyridine carboxylates 10-3 under basic conditions such as NaOMe, NaOEt, t-BuOK with a piperidine in alcohol solvent. Hydrolysis of 10-3 using basic conditions such as aqueous LiOH or NaOH can provide the desired hydroxythiazolo-pyridine carboxylic acids 10-4.
  • a series of sulfonylurea of formula 11-5 can be prepared as the methods outlined in Scheme 11.
  • Treatment of the amines 11-1 with chlorosulfonic acid can provide the sulfamic acids 11-2 which can be transformed into the corresponding sulfamoyl chlorides 11-3 with a suitable chlorination agent such as SOCl 2 , PCl 5 , or COCl 2 with or without solvent, e.g. CCl 4 or CHCl 3 , optionally in the presence of a base, e.g. pyridine or ⁇ -picoline, and catalytic amounts of DMF.
  • the sulfonylurea 11-5 can be achieved by coupling of the sulfamoyl chlorides 11-3 with primary amides 11-4 in the presence of a base such as Hunig’s base.
  • Step 1 tert-butyl (3-bromothiophen-2-yl) carbamate
  • Step 2 tert-butyl (3-formylthiophen-2-yl) carbamate
  • Step 3 ethyl 6-oxo-6, 7-dihydrothieno [2, 3-b] pyridine-5-carboxylate
  • Step 4 ethyl 2-bromo-6-hydroxythieno [2, 3-b] pyridine-5-carboxylate
  • Step 5 ethyl 6-hydroxy-2-phenylthieno [2, 3-b] pyridine-5-carboxylate
  • Step 6 6-hydroxy-2-phenylthieno [2, 3-b] pyridine-5-carboxylic acid
  • Step 7 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -6-hydroxy-2-phenylthieno [2, 3-b] pyridine-5-carboxamide
  • Step 1 6-hydroxy-2- (m-tolyl) thieno [2, 3-b] pyridine-5-carboxylic acid
  • Step 2 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -6-hydroxy-2- (m-tolyl) thieno [2, 3-b] pyridine-5-carboxamide
  • This compound was prepared by the procedure analogous to that described for Example 1 Step 7 using 6-hydroxy-2- (m-tolyl) thieno [2, 3-b] pyridine-5-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford title product as a white solid.
  • Step 1 2- (3, 4-dimethylphenyl) -6-hydroxythieno [2, 3-b] pyridine-5-carboxylic acid
  • Step 2 2- (3, 4-dimethylphenyl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -6-hydroxythieno [2, 3-b] pyridine-5-carboxamide
  • This compound was prepared by the procedure analogous to that described for Example 1 Step 7 using 2- (3, 4-dimethylphenyl) -6-hydroxythieno [2, 3-b] pyridine-5-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford title product as a white solid.
  • Step 1 ethyl 6-hydroxy-2-vinylthieno [2, 3-b] pyridine-5-carboxylate
  • Step 2 ethyl 2-ethyl-6-hydroxythieno [2, 3-b] pyridine-5-carboxylate
  • Step 4 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-ethyl-6-hydroxythieno [2, 3-b] pyridine-5-carboxamide
  • Step 1 tert-butyl (2-formylthiophen-3-yl) carbamate
  • Step 2 ethyl 5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate and 5-oxo-4, 5-dihydro thieno [3, 2-b] pyridine-6-carboxylic acid
  • Step 3 ethyl 2-bromo-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate
  • Step 4 ethyl 2- (3, 4-dimethylphenyl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate
  • Step 5 2- (3, 4-dimethylphenyl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
  • Step 6 2- (3, 4-dimethylphenyl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
  • Example 6 7- (3, 4-Dimethylphenyl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
  • Step 1 tert-butyl (6-chloro-3-formylpyridin-2-yl) carbamate
  • Step 2 2-amino-6- (3, 4-dimethylphenyl) nicotinaldehyde
  • Step 3 ethyl 7- (3, 4-dimethylphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxylate
  • Step 4 7- (3, 4-dimethylphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxylic acid
  • Step 5 7- (3, 4-dimethylphenyl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
  • This compound was prepared by the procedure analogous to that described for Example 1 Step 7 using 7- (3, 4-dimethylphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxylic acid and 3-amino-2,3-dihydrothiophene 1, 1-dioxide hydrochloride to afford title product as a yellow solid.
  • Step 1 ethyl 5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate
  • Step 2 5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
  • Step 3 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
  • Step 2 2- (cyclohex-1-en-1-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
  • This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 2- (cyclohex-1-en-1-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title product as a white solid.
  • Step 1 2-cyclohexyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
  • Step 2 2-cyclohexyl-N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
  • This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 2-cyclohexyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title product as a white solid.
  • Step 1 5-oxo-2- (prop-1-en-2-yl) -4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
  • Step 2 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-2- (prop-1-en-2-yl) -4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
  • Step 1 2-isopropyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
  • Step 2 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-isopropyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
  • Example 12 N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-2-vinyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
  • Step 1 5-oxo-2-vinyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
  • Step 2 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-2-vinyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
  • Example 13 N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -2-ethyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
  • Step 1 2-ethyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
  • Step 2 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-ethyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
  • Step 1 methyl 3- ( (tert-butoxycarbonyl) amino) -4-methylthiophene-2-carboxylate
  • Step 2 tert-butyl (2- (hydroxymethyl) -4-methylthiophen-3-yl) carbamate
  • Step 4 ethyl 3-methyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate
  • Step 5 ethyl 2-bromo-3-methyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate
  • Step 6 ethyl 3-methyl-5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate
  • Step 7 3-methyl-5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
  • Step 8 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -3-methyl-5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
  • This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 3-methyl-5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title product as a yellow solid.
  • This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride and 4-hydroxyquinoline-3-carboxylic acid to afford the title compound (8.5 mg, 27.93%yield) as a white solid.
  • Example 16 N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-7- (prop-1-en-2-yl) -1, 2-dihydro quinoline-3-carboxamide
  • Step 2 ethyl 7-bromo-2-hydroxyquinoline-3-carboxylate
  • Step 3 ethyl 2-hydroxy-7- (prop-1-en-2-yl) quinoline-3-carboxylate
  • Step 4 2-hydroxy-7- (prop-1-en-2-yl) quinoline-3-carboxylic acid
  • Step 5 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-7- (prop-1-en-2-yl) -1, 2-dihydroquinoline-3-carboxamide
  • This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 2-hydroxy-7- (prop-1-en-2-yl) quinoline-3-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to obtain the title product as a white solid.
  • Example 17 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -7-isopropyl-2-oxo-1, 2-dihydroquinoline-3-carboxamide
  • Step 1 ethyl 2-hydroxy-7-isopropylquinoline-3-carboxylate
  • Step 3 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -7-isopropyl-2-oxo-1, 2-dihydroquinoline-3-carboxamide
  • This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 2-hydroxy-7-isopropylquinoline-3-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title product as a white solid.
  • Step 1 4-oxo-1, 4-dihydropyrrolo [1, 2-b] pyridazine-3-carboxylic acid
  • Step 2 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -4-oxo-1, 4-dihydropyrrolo [1, 2-b] pyridazine-3-carboxamide
  • This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 4-oxo-1, 4-dihydropyrrolo [1, 2-b] pyridazine-3-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title product as a yellow solid.
  • Step 1 ethyl (2, 4-dimethoxybenzyl) glycinate
  • Step 2 ethyl 2-bromo-4- (bromomethyl) thiazole-5-carboxylate
  • Step 3 ethyl 2-bromo-4- ( ( (2, 4-dimethoxybenzyl) (2-ethoxy-2-oxoethyl) amino) methyl) thiazole-5-carboxylate
  • Step 4 ethyl 4- ( ( (2, 4-dimethoxybenzyl) (2-ethoxy-2-oxoethyl) amino) methyl) -2- (3, 4-dimethylphenyl) thiazole-5-carboxylate
  • Step 5 ethyl 5- (2, 4-dimethoxybenzyl) -2- (3, 4-dimethylphenyl) -7-oxo-4, 5, 6, 7-tetrahydrothiazolo [4, 5-c] pyridine-6-carboxylate
  • Step 6 ethyl 2- (3, 4-dimethylphenyl) -7-oxo-6, 7-dihydrothiazolo [4, 5-c] pyridine-6-carboxylate
  • Step 7 2- (3, 4-dimethylphenyl) -7-oxo-6, 7-dihydrothiazolo [4, 5-c] pyridine-6-carboxylic acid
  • Step 8 2- (3, 4-dimethylphenyl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -7-hydroxythiazolo [4, 5-c] pyridine-6-carboxamide
  • Step 1 ethyl 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylate
  • Step 3 7- (cyclopent-1-en-1-yl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-hydroxyquinoline-3-carboxamide
  • Step 1 ethyl 7-cyclopentyl-2-hydroxyquinoline-3-carboxylate
  • Step 2 7-cyclopentyl-N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-hydroxyquinoline-3-carboxamide
  • This compound was prepared by procedures analogous to those described for Example 21 Step 2-3 using ethyl 7-cyclopentyl-2-hydroxyquinoline-3-carboxylate to replace ethyl 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylate in Step 2 to afford the title product as a white solid.
  • Step 1 ethyl 7-bromo-2-chloroquinoline-3-carboxylate
  • Step 3 methyl 7- (dimethylamino) -2-methoxyquinoline-3-carboxylate
  • Step 4 7- (dimethylamino) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-methoxyquinoline-3-carboxamide
  • Step 2 7-bromo-N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-methoxyquinoline-3-carboxamide
  • Step 4 2-methoxy-6- (prop-1-en-2-yl) quinoline-3-carboxylic acid
  • Step 6 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -6-isopropyl-2-methoxyquinoline-3-carboxamide
  • Step 5 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2, 6-dimethoxyquinoline-3-carboxamide
  • Step 1 methyl 2-hydroxy-6- (prop-1-en-2-yl) quinoline-3-carboxylate
  • Step 2 2-hydroxy-6- (prop-1-en-2-yl) quinoline-3-carboxylic acid
  • This compound was prepared by procedures analogous to those described for Example 21 Step 3 using 2-hydroxy-6- (prop-1-en-2-yl) quinoline-3-carboxylic acid to replace 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylic acid to afford the title product as a white solid.
  • Example 26 Step 4 This compound was prepared by procedures analogous to those described for Example 21 Step 3 using 2-methoxy-6- (prop-1-en-2-yl) quinoline-3-carboxylic acid (Example 26 Step 4) to replace 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylic acid to afford the title product as a white solid.
  • Step 1 ethyl 7- (2-fluorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylate
  • Step 2 7- (2-fluorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid
  • Step 3 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -7- (2-fluorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxamide
  • Step 2 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-7-phenyl-1, 2-dihydroquinoline-3-carboxamide
  • Step 1 7- (1-methyl-1H-pyrazol-4-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid
  • Step 2 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxamide
  • Step 2 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-7- (thiophen-2-yl) -1, 2-dihydroquinoline-3-carboxamide
  • Example 36 7- (3, 6-Dihydro-2H-pyran-4-yl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxamide
  • Step 1 ethyl 7- (3, 6-dihydro-2H-pyran-4-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxylate
  • Step 2 7- (3, 6-dihydro-2H-pyran-4-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid
  • Step 3 7- (3, 6-dihydro-2H-pyran-4-yl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxamide
  • Step 1 ethyl 2-oxo-7- (tetrahydro-2H-pyran-4-yl) -1, 2-dihydroquinoline-3-carboxylate
  • Step 2 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-7- (tetrahydro-2H-pyran-4-yl) -1, 2-dihydroquinoline-3-carboxamide
  • Step 2 methyl 6- ( (tert-butoxycarbonyl) (ethyl) amino) -2-methoxyquinoline-3-carboxylate
  • Step 3 6- ( (tert-butoxycarbonyl) (ethyl) amino) -2-methoxyquinoline-3-carboxylic acid
  • Step 4 tert-butyl (3- ( (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) carbamoyl) -2-methoxyquinolin-6-yl) (ethyl) carbamate
  • Step 5 N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -6- (ethylamino) -2-hydroxyquinoline-3-carboxamide
  • WRN ATPase assay was initiated to evaluate potential inhibitory effect of compounds for ATP hydrolysis activity of WRN protein.
  • WRN [UniPro: Q14191 (WRN_HUMAN) , N500-C946] was expressed and purified in insect system and stored at -80°C in aliquots.
  • FORKF DNA was annealed with equal amounts of OLIGOA-BHQ2 (TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCGTACCC-GATGTGTTCGTTC-BHQ2) and OLIGOB-TAMRA (TAMRAGAACGAACACATCGGGTACG-TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT
  • the assay buffer was comprised of 30 mM HEPES pH7.4 (Gibco, 15630-080) , 40 mM KCl (Sigma, P9541-500G) , 5%Glycerol (sigma, G7757-1L) , 8 mM MgCl 2 (Invitrogen, AM9530G) , 0.1 mg/ml BSA (PerkinElmer, CR84-100) .
  • Luminescence output was recorded using BMG CLARIO star plus reader. Each concentration of compound was tested in duplicates in the assay plate. Average luminescence signal of high control (Wells with 1 %DMSO) was calculated as High Control (HC) . Average luminescence signal of low control (Wells with no WRN protein) was calculated as Low control (LC) .
  • %inhibition 100 -100* (Signal cmpd -Signal Ave_LC ) / (Signal Ave_HC -Signal Ave_LC ) .
  • WRN unwinding assay was initiated to evaluate potential inhibitory effect of compounds for WEN helicase activity.
  • WRN [UniPro: Q14191 (WRN_HUMAN) , N500-C946] was expressed and purified in insect system and stored at -80°C in aliquots.
  • FORKF DNA was annealed with equal amounts of OLIGOA-BHQ2 (TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT
  • the assay buffer was comprised of 30 mM HEPES pH7.4 (Gibco, 15630-080) , 40 mM KCl (Sigma, P9541-500G) , 5%Glycerol (sigma, G7757-1L) , 8 mM MgCl 2 (Invitrogen, AM9530G) , 0.1 mg/ml BSA (PerkinElmer, CR84-100) .
  • %inhibition 100 -100* (Signal cmpd -Signal Ave_LC ) / (Signal Ave_HC -Signal Ave_LC ) .
  • MSS cell line SW620 was included for viability assay.
  • 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 1000 cells/well for SW48 cell and 500 cells/well for SW620 cell.
  • 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 6 days in a 37 °C active humidified incubator at 5%CO 2 .
  • 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 (BMG CLARIO star 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* (Signal cmpd -Signal Ave_LC ) / (Signal Ave_HC -Signal Ave_LC ) .

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Abstract

The disclosure relates to cyclic derivatives as shown in Formula (I), to pharmaceutical compositions comprising them, to a process for their preparation, and their use as therapeutic agents.

Description

CYCLIC DERIVATIVES, COMPOSITIONS AND USES THEREOF
CROSS REFERENCES TO RELATED APPLICATIONS
This application claims the benefit of the priority of International Application No. PCT/CN2023/091064, filed April 27, 2023, International Application No. PCT/CN2023/124321, filed October 12, 2023, International Application No. PCT/CN2023/131288, filed November 13, 2023, each of which is hereby incorporated in its entirety.
TECHNICAL FIELD
The present disclosure relates to cyclic derivatives as WRN inhibitors. The present disclosure also relates to methods for preparing the cyclic derivatives, pharmaceutical compositions, and their uses in the treatment of WRN-mediated diseases, e.g., cancers and other diseases.
BACKGROUND
Numerous microsatellites are distributed prevalently in the genome of eukaryote. When DNA polymerase initiates replication at microsatellite sequences, base addition or deletion happens due to DNA polymerase slippage during replication. If DNA mismatch repair (MMR) is intact, the replication error is repaired and microsatellite-stable (MSS) is maintained. However, in the cell of mismatch repair deficiency (dMMR) , these replication errors will be accumulated and finally lead to microsatellite instability-high (MSI-H) (Yuji Eso, 2019) . dMMR/MSI-H is ubiquitous in many cancers (Bonneville R, 2017) , such as colorectal, gastric, endometrial and adrenocortical cancers, etc.
Through large-scale CRISPR/Cas9 knockout in 517 cell lines and RNA interference (RNAi) silencing screens in 389 cell lines, Chan, E.M. et al. has identified the Werner Syndrome RecQ helicase (WRN) as being selectively required in vitro and in vivo, for the survival of cell lines with defective mismatch repair that have become MSI-H, yet dispensable in microsatellite stable (MSS) models (Chan, E.M., 2019) . WRN is synthetic lethal with MSI-H cancers (Chan, E.M., 2019; Kategaya, L., 2019) . Depletion of WRN leads to anti-proliferative effects and results in activation of multiple DNA damage signaling markers, induction of cell cycle arrest and apoptosis in MMR cancer models but not cancer cells with an intact MMR pathway.
Recently, the mechanism of WRN dependence in MSI-H cancers has been elucidated. WRN provides a DNA repair and maintenance function that is essential for MSI-H cell survival. In MSI-H cells, there is an increase in non-canonical secondary DNA structures creating a requirement for WRN for their resolution (van Wietmarschen N, 2020) . In the absence of WRN (or upon WRN helicase inhibition) in MSI-H cancers, the replication machinery runs into the unresolved structures eventually leading to an increase in double-stranded breaks and cell death.
Therefore, inhibiting the WRN helicase is an attractive strategy for the treatment of dMMR/MSI-H cancers. There is a need to provide small molecule inhibitors for inhibiting the WRN helicase that are useful for treating cancer.
SUMMARY
The present disclosure relates to, inter alia, compounds of Formula (I) ,
or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof; wherein the variables are as defined below.
In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I) , or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof and at least one pharmaceutically acceptable carrier.
In another aspect, provided herein is a method of inhibiting WRN comprising:
contacting WRN with a compound of formula (I) , or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof.
In another aspect, provided herein is a method of treating cancers and other diseases comprising administering to a subject a therapeutically effective amount of a compound of formula (I) , or pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound 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 (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof, wherein:
L is -S (O) 2-, -S (O) (=NR2) -, -C (O) -, -S (O) 2NHC (O) -, -C (O) NHS (O) 2-, or -C (O) NHS (O) (=NR2) -;
Cy is selected from 5-10 membered partially unsaturated heterocycloalkyl or 5-10 membered heteroaryl; wherein, the Cy is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R3;
when n is 1 and L is -C (O) -, then Cy is notwherein, the position *is attached to L, the position **is attached to R1;
m is 1, 2 or 3;
n is 1 or 2;
each R is independently selected from H, D, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, OC1-C6 alkyl, OC1-C6 haloalkyl, -NH (C1-C6 alkyl) , or -N (C1-C6 alkyl) 2; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N3, NO2, SF5, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl;
or two R groups together with the same ring carbon atom to which they are attached form C3-C5 cycloalkyl or 4-5 membered heterocycloalkyl; wherein, the C3-C5 cycloalkyl or 4-5 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, halo, OH, oxo, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl;
R1 is selected from H, D, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, ORA, SRA, or NRCRD; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4;
each R2 is independently selected from H, D, CN, OH, C1-C4 alkyl or OC1-C4 alkyl; wherein, the C1-C4 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from D, halo, CN, OH, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, NH2, -NH (C1-C4 alkyl) , or -N (C1-C4 alkyl) 2;
each R3 is independently selected from H, D, halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl, ORA, SRA, or  NRCRD; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb;
wherein, two R3 together with the same ring carbon atom to which they are attached form oxo, C3-C4 cycloalkyl, 4 membered heterocycloalkyl; wherein, the C3-C4 cycloalkyl, 4 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, or -OC1-C6 haloalkyl;
wherein, two adjacent R3 together with the atoms to which they are attached form C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; wherein, the C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, or -OC1-C6 haloalkyl;
each R4 is independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NRCRD, ORA, SRA, C (O) RB, C (O) ORA, OC (O) RB, C (O) NRCRD, NRCC (O) RB, OC (O) NRCRD, OC (O) ORA, NRCC (O) NRCRD, NRCC (O) ORA, C (=NRC) NRCRD, NRDC (=NRC) NRCRD, NRDC (=NRC) RB, S (O) RB, S (O) NRCRD, S (O) 2RB, S (O) 2NRCRD, NRCS (O) 2RB, S (O) (=NRB) RB, NRCS (O) 2NRCRD, NRCS (O) (=NRB) RB, B (ORC) (ORD) , P (O) RERF, P (O) OREORF, OP (O) OREORF, Cy1, OCy1, C1-C6 alkyl-Cy1, or OC1-C6 alkyl-Cy1; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R5A;
Cy1 is C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl; wherein, the C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl is optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R5B;
each R5A is independently selected from D, halo, CN, N3, oxo, ORa, Si (C1-C4 alkyl) 3 or OC1-C6 alkyl-OH;
each R5B is independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, ORa, SRa, 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; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently  selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, ORa1, C (O) ORa1, C (O) Rb1, NRc1Rd1, C (O) NRc1Rd1, S (O) 2Rb1, or S (O) 2NRc1Rd1;
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, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, NO2, oxo, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, ORa, SRa, 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, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, OC2-C4 alkylOH, OC2-C4 alkyl-O-C1-C4 alkyl, OC2-C4 alkyl-O-C1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, ORa, SRa, 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-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, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4  alkyl, OC1-C4 haloalkyl, OC2-C4 alkylOH, OC2-C4 alkyl-O-C1-C4 alkyl, OC2-C4 alkyl-O-C1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, ORa, SRa, C (O) Rb, 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, 3, 4 or 5 substituents independently selected from D, halo, oxo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-CN, ORa, SRa, C (O) Rb, NRcRd;
Ra and Ra1 are each 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, 3, 4 or 5 substituents independently selected from D, OH, halo, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl;
Rb and Rb1 are each 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, C6-C10 aryl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl; 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-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, , C1-C4 haloalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl;
Rc, Rc1, Rd and Rd1 are each 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, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (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-C4 alkyl, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, 4 or 5  substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, O-C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, 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-;
Rc and Rd or Rc1 and Rd1 together with the N atom to which they are attached form 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, O-C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, 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;
RE and Re are 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, 4-10 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;
RF and Rf are each 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.
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (Ia) or (Ib) :
or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
wherein, Cy, L, R, R1, m and n are defined with respect to Formula (I) .
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (II) or (III) :
or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
wherein, Cy, L, R, R1 and m are defined with respect to Formula (I) .
In some embodiments, Cy is selected from 5-10 membered partially unsaturated heterocycloalkyl or 5-10 membered heteroaryl; wherein, the Cy is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R3.
In some embodiments, Cy is 5-10 membered partially unsaturated heterocycloalkyl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R3; and when n is 1 and L is -C (O) -, then Cy is notwherein, the position *is attached to L, the position **is attached to R1.
In some embodiments, Cy is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R3.
In some embodiments, the moietyis selected from
wherein, is a single bond or double bond;
X is N or CR3A;
X1 is N or CR3B;
X2 is N or CR3C;
X3, X4 and X5 are each independently selected from N or CR3;
Y1 and Y2 are each independently selected from N, NR3, O, S or CR3;
Y3 is N or C;
A1 and A2 are each independently selected from NR3, O, S or C (R3) 2;
R3A is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl;
R3B is H, D, halo, OH;
R3C is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, OC1-C3 haloalkyl;
p is 1 or 2;
R1 and R3 are defined with respect to Formula (I) ; in the moiety ofone of R3 at any position is replaced by R1.
In other embodiments, Cy is selected from:

wherein, the position *is attached to L, R1 is attached to any possible position on the Cy; the Cy is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R3;
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (IVa) , (IVb) , (IVc) , (IVd) , (IVe) or (IVf) :
or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
wherein, is a single bond or double bond;
X is N or CR3A;
X1 is N or CR3B;
X2 is N or CR3C;
X3, X4 and X5 are each independently selected from N or CR3;
Y1 and Y2 are each independently selected from N, NR3, O, S or CR3;
Y3 is N or C;
A1 and A2 are each independently selected from N, NR3, O, S or C (R3) 2;
p is 1 or 2;
R3A is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl;
R3B is H, D, halo, OH;
R3C is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, OC1-C3 haloalkyl;
wherein, L, R, R1, R3 and m are defined with respect to Formula (I) ; in the formula (Ive) , one of R3 at any position is replaced by R1.
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (Va) , (Vb) , (Vc) , (Vd) , (Ve) or (Vf) :
or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
wherein, is a single bond or double bond;
X is N or CR3A;
X1 is N or CR3B;
X2 is N or CR3C;
X3, X4 and X5 are each independently selected from N or CR3;
Y1 and Y2 are each independently selected from N, NR3, O, S or CR3;
Y3 is N or C;
A1 and A2 are each independently selected from NR3, O, S or C (R3) 2;
p is 1 or 2;
R3A is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl;
R3B is H, D, halo, OH;
R3C is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, OC1-C3 haloalkyl;
wherein, L, R, R1, R3 and m are defined with respect to Formula (I) ; in the formula (Ve) , one of R3 at any position is replaced by R1.
In some embodiments, L is -S (O) 2-, -S (O) (=NR2) -, -C (O) -, -S (O) 2NHC (O) -, -C (O) NHS (O) 2-, or -C (O) NHS (O) (=NR2) -.
In some embodiments, L is -S (O) 2-.
In some embodiments, L is -S (O) (=NR2) -.
In some embodiments, L is -C (O) -.
In some embodiments, L is -S (O) 2NHC (O) -.
In some embodiments, L is -C (O) NHS (O) 2-.
In some embodiments, L is -C (O) NHS (O) (=NR2) -.
In some embodiments, each R2 is selected from H, D, CN, OH, C1-C4 alkyl or OC1-C4 alkyl; wherein, the C1-C4 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from D, halo, CN, OH, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, NH2, -NH (C1-C4 alkyl) , or -N (C1-C4 alkyl) 2.
In some embodiments, each R2 is selected from H. In some embodiments, each R2 is selected from D. In some embodiments, each R2 is selected from CN. In some embodiments, each R2 is selected from OH.
In some embodiments, each R2 is selected from C1-C4 alkyl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from D, halo, CN, OH, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, NH2, -NH (C1-C4 alkyl) , or -N (C1-C4 alkyl) 2. In some embodiments, for example, included but not limited to, each R2 is selected from CH3, CH2CH3, CH2CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3.
In some embodiments, each R2 is selected from OC1-C4 alkyl; wherein, the C1-C4 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from D, halo, CN, OH, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, NH2, -NH (C1-C4 alkyl) , or -N (C1-C4 alkyl) 2. In some embodiments, for example, included but not limited to, each R2 is selected from OCH3, OCH2CH3, OCH2CH2CH3, OCH (CH3) 2, OCH2F, OCHF2, OCF3, OCH2OCH3.
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (VIa) , (VIb) , (VIc) , (VId) , (VIe) or (VIf) :

or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
wherein, X, X1, X2, X3, X4, X5, Y1, Y2, Y3, A1, A2, L, R, R1, R3, m and p are defined with respect to Formula (I) ; in the formula (VIe) , one of R3 at any position is replaced by R1.
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (VIIa) , (VIIb) , (VIIc) , (VIId) , (VIIe) or (VIIf) :
or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
wherein, X, X1, X2, X3, X4, X5, Y1, Y2, Y3, A1, A2, L, R, R1, R3, m and p are defined with respect to Formula (I) ; in the formula (VIIe) , one of R3 at any position is replaced by R1.
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (VIIIa) , (VIIIb) , (VIIIc) , (VIIId) , (VIIIe) or (VIIIf) :

or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
wherein, X, X1, X2, X3, X4, X5, Y1, Y2, Y3, A1, A2, L, R, R1, R3, m and p are defined with respect to Formula (I) ; in the formula (VIIIe) , one of R3 at any position is replaced by R1.
In some embodiments, the compounds of Formula (I) are represented by compounds of Formula (IXa) , (IXb) , (IXc) , (IXd) , (IXe) or (IXf) :
or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
wherein, X, X1, X2, X3, X4, X5, Y1, Y2, Y3, A1, A2, L, R, R1, R3, m and p are defined with respect to Formula (I) ; in the formula (IXe) , one of R3 at any position is replaced by R1.
In some embodiments, X is CR3A, X1 is CR3B, X2 is CR3C.
In some embodiments, X is CR3A, X1 is N, X2 is CR3C.
In some embodiments, X is CR3A, X1 is CR3B, X2 is N.
In some embodiments, X is N, X1 is CR3B, X2 is CR3C.
In some embodiments, X is N, X1 is CR3B, X2 is N.
In some embodiments, in the compound of formula (IVa) , (Va) , (VIa) , (VIIa) , (VIIIa) , (IXa) , (IVf) , (Vf) , (VIf) , (VIIf) , (VIIIf) , (IXf) , all of X3, X4 and X5 are CR3.
In some embodiments, in the compound of formula (IVa) , (Va) , (VIa) , (VIIa) , (VIIIa) , (IXa) , (IVf) , (Vf) , (VIf) , (VIIf) , (VIIIf) , (IXf) , X3 is CR3, X4 is N, and X5 is CR3.
In some embodiments, in the compound of formula (IVa) , (Va) , (VIa) , (VIIa) , (VIIIa) , (IXa) , (IVf) , (Vf) , (VIf) , (VIIf) , (VIIIf) , (IXf) , X3 is CR3, X4 is CR3, and X5 is N.
In some embodiments, in the compound of formula (IVa) , (Va) , (VIa) , (VIIa) , (VIIIa) , (IXa) , (IVf) , (Vf) , (VIf) , (VIIf) , (VIIIf) , (IXf) , X3 is CR3, X4 is N, and X5 is N.
In some embodiments, in the compound of formula (IVa) , (Va) , (VIa) , (VIIa) , (VIIIa) , (IXa) , (IVf) , (Vf) , (VIf) , (VIIf) , (VIIIf) , (IXf) , X3 is N, X4 is CR3, and X5 is CR3.
In some embodiments, in the compound of formula (IVa) , (Va) , (VIa) , (VIIa) , (VIIIa) , (IXa) , (IVf) , (Vf) , (VIf) , (VIIf) , (VIIIf) , (IXf) , X3 is N, X4 is N, and X5 is CR3.
In some embodiments, in the compound of formula (IVa) , (Va) , (VIa) , (VIIa) , (VIIIa) , (IXa) , (IVf) , (Vf) , (VIf) , (VIIf) , (VIIIf) , (IXf) , X3 is N, X4 is CR3, and X5 is N.
In some embodiments, in the compound of formula (IVc) , (IVd) , (Vc) , (Vd) , (VIc) , (VId) , (VIIc) , (VIId) , (VIIIc) , (VIIId) , (IXc) , (IXd) , X3 is CR3, X4 is CR3.
In some embodiments, in the compound of formula (IVc) , (IVd) , (Vc) , (Vd) , (VIc) , (VId) , (VIIc) , (VIId) , (VIIIc) , (VIIId) , (IXc) , (IXd) , X3 is N, X4 is CR3.
In some embodiments, in the compound of formula (IVc) , (IVd) , (Vc) , (Vd) , (VIc) , (VId) , (VIIc) , (VIId) , (VIIIc) , (VIIId) , (IXc) , (IXd) , X3 is CR3, X4 is N.
In some embodiments, in the compound of formula (IVb) , (Vb) , (VIb) , (VIIb) , (VIIIb) , (IXb) , isand Y1 is N or CR3; Y2 is NR3, O or S.
In some embodiments, in the compound of formula (IVb) , (Vb) , (VIb) , (VIIb) , (VIIIb) , (IXb) , isand Y1 is NR3, O or S; Y2 is N or CR3.
In some embodiments, in the compound of formula (IVb) , (Vb) , (VIb) , (VIIb) , (VIIIb) , (IXb) , isand Y1 is N or CR3; Y2 is N or CR3.
In other embodiments, Cy is selected from:
wherein, the position *is attached to L, the position **is attached to R1.
In some embodiments, R3A is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl.
In some embodiments, R3A is H. In some embodiments, R3A is D. In some embodiments, R3A is F, Cl, Br, I. In some embodiments, R3A is F. In some embodiments, R3A is OH. In some embodiments, R3A is CH3. In some embodiments, R3A is CF3, CHF2, CH2F. In some embodiments, R3A is OCF3.
In some embodiments, R3B is H, D, halo, OH.
In some embodiments, R3B is H. In some embodiments, R3B is D. In some embodiments, R3B is halo (such as F, Cl, Br, I) . In some embodiments, R3B is OH.
In some embodiments, R3C is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, OC1-C3 haloalkyl.
In some embodiments, R3C is H. In some embodiments, R3C is D. In some embodiments, R3C is F, Cl, Br, I. In some embodiments, R3C is OH.
In some embodiments, R3C is C1-C3 alkyl. In some embodiments, R3C is C1-C3 haloalkyl. In some embodiments, R3C is OC1-C3 alkyl. In some embodiments, R3C is OC1-C3 haloalkyl.
In some embodiments, when X1 is CR3B, X2 is N and R3B is OH, then the tautomer ofis
In some embodiments, each R3 is independently selected from H, D, halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl, ORA, SRA, or NRCRD; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb.
In some embodiments, each R3 is independently selected from H. In some embodiments, each R3 is independently selected from D. In some embodiments, each R3 is independently selected from halo (such as F, Cl, Br or I) . In some embodiments, each R3 is independently selected from F. In some embodiments, each R3 is independently selected from Cl. In some embodiments, each R3 is independently selected from Br. In some embodiments, each R3 is independently selected from I) . In some embodiments, each R3 is independently selected from CN.
In some embodiments, each R3 is independently selected from ORA. In some embodiments, for example, each R3 is independently selected from OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH (CH3) 2, OCH2F, OCHF2, OCF3.
In some embodiments, each R3 is independently selected from SRA. In some embodiments, for example, included but not limited to, each R3 is independently selected from SCH3, SCH2CH3, etc..
In some embodiments, each R3 is independently selected from NRCRD. In some embodiments, for example, each R3 is independently selected from NH2, NHCH3, N (CH3) 2, NHCH2CH3, N (CH2CH3) 2, NHCH2CH2OH, N (CH3) CH2CH2OH.
In some embodiments, each R3 is independently selected from C1-C6 alkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb. In some embodiments, each R3 is independently selected from CH3, CH2CH3, CH2CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CF2CH3, CF2CF3, CH2OH, CH2CH2OH, CH (OH) CH3, CH2CN, CH2CH2CN.
In some embodiments, each R3 is independently selected from C2-C6 alkenyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb.
In some embodiments, each R3 is independently selected from C2-C6 alkynyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb.
In some embodiments, each R3 is independently selected from C3-C7 cycloalkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb.
In some embodiments, each R3 is independently selected from phenyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb.
In some embodiments, each R3 is independently selected from 4-7 membered heterocycloalkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb.
In some embodiments, each R3 is independently selected from 5-7 membered heteroaryl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb.
In some embodiments, each R3 is independently selected from H, D, halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, ORA, SRA, or NRCRD; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb.
In some embodiments, each R3 is independently selected from H, D, halo, CN, CH3, CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CF2CH3, -CH=CH2, -C (CH3) =CH2, OH, OCH3, OCH2CH3, NH2, NHCH3, N (CH3) 2.
In some embodiments, two R3 together with the same ring carbon atom to which they are attached form oxo.
In some embodiments, two R3 together with the same ring carbon atom to which they are attached form C3-C4 cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, or -OC1-C6 haloalkyl.
In some embodiments, two R3 together with the same ring carbon atom to which they are attached form 4 membered heterocycloalkyl having a heteroatom selected from Si, N, O or S optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, or -OC1-C6 haloalkyl.
In some embodiments, two adjacent R3 together with the atoms to which they are attached form C3-C6 cycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, or -OC1-C6 haloalkyl.
In some embodiments, two adjacent R3 together with the atoms to which they are attached form 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms selected from Si, N, O or S optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, or -OC1-C6 haloalkyl.
In some embodiments, two adjacent R3 together with the atoms to which they are attached form phenyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, or -OC1-C6 haloalkyl.
In some embodiments, two adjacent R3 together with the atoms to which they are attached form 5-6 membered heteroarylene having 1, 2, 3 or 4 heteroatoms selected from N, O or S optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, or -OC1-C6 haloalkyl.
In some embodiments, m is 1, 2 or 3.
In some embodiments, m is 1.
In some embodiments, m is 2.
In some embodiments, m is 3.
In some embodiments, each R is independently selected from H, D, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, OC1-C6 alkyl, OC1-C6 haloalkyl, -NH (C1-C6 alkyl) , or -N (C1-C6 alkyl) 2; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N3, NO2, SF5, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl.
In some embodiments, each R is independently selected from H. In some embodiments, each R is independently selected from D. In some embodiments, each R is independently selected from halo (such as F, Cl, Br or I) .
In some embodiments, each R is independently selected from C1-C6 alkyl optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N3, NO2, SF5, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl. In some embodiments, each R is independently selected from CH3, CH2CH3, CH2CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3.
In some embodiments, each R is independently selected from C2-C6 alkenyl optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N3, NO2, SF5, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl.
In some embodiments, each R is independently selected from C2-C6 alkynyl optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N3, NO2, SF5, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl.
In some embodiments, each R is independently selected from C3-C6 cycloalkyl optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N3, NO2, SF5, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl.
In some embodiments, each R is independently selected from OC1-C6 alkyl; wherein, the C1-C6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N3, NO2, SF5, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl.
In some embodiments, each R is independently selected from OC1-C6 haloalkyl.
In some embodiments, each R is independently selected from -NH (C1-C6 alkyl) ; wherein, the C1-C6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N3, NO2, SF5, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl.
In some embodiments, each R is independently selected from -N (C1-C6 alkyl) 2; wherein, the C1-C6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N3, NO2, SF5, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl.
In some embodiments, two R groups together with the same ring carbon atom to which they are attached form C3-C5 cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, halo, OH, oxo, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl.
In some embodiments, two R groups together with the same ring carbon atom to which they are attached form 4-5 membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from D, halo, OH, oxo, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl.
In some embodiments, R1 is selected from H, D, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl;  wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents R4.
In some embodiments, R1 is H. In some embodiments, R1 is D. In some embodiments, R1 is halo (such as F, Cl, Br or I) .
In some embodiments, R1 is C1-C6 alkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4. In some embodiments, R1 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is C2-C6 alkenyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4. In some embodiments, R1 is ethenyl, prop-1-en-1-yl, prop-1-en-2-yl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is C2-C6 alkynyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is C3-C10 cycloalkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is C3-C10 saturated cycloalkyl or C3-C10 partially unsaturated cycloalkyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is C3-C10 saturated mono-cycloalkyl, C6-C10 saturated bicycloalkyl, C5-C10 saturated spiro-cycloalkyl, C5-C10 saturated bridged cycloalkyl, C8-C10 saturated fused cycloalkyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro [3.3] heptanyl, spiro [3.4] octanyl, spiro [3.5] nonanyl, spiro [3.6] decanyl, spiro [4.4] nonanyl, spiro [4.5] decanyl, spiro [4.6] undecanyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, bicyclo [5.2.0] nonanyl, octahydropentalenyl, octahydro-1H-indenyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is C5-C10 partially unsaturated mono-cycloalkyl, C6-C10 partially unsaturated bicycloalkyl, C7-C10 partially unsaturated spiro-cycloalkyl, C7-C10 partially unsaturated bridged cycloalkyl, C8-C10 partially unsaturated fused cycloalkyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, or cyclohexenyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is 4-10 membered heterocycloalkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is 4-10 membered saturated heterocycloalkyl or 4-10 membered partially unsaturated heterocycloalkyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, dioxanyl tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, azepanyl, diazocanyl, diazepanyl, azepanyl, 2, 6-diazaspiro [3.3] heptanyl, 2-oxa-6-azaspiro [3.3] heptanyl, 2, 6-diazaspiro [3.4] octanyl, 2, 7-diazaspiro [3.5] nonanyl, 2, 7-diazaspiro [4.4] nonanyl, 3, 9-diazaspiro [5.5] undecanyl, 2-oxa-7-azaspiro [3.5] nonanyl, 2-oxa-6-azaspiro [3.4] octanyl, 7-oxa-2-azaspiro [3.5] nonanyl, 6-oxa-2-azaspiro [3.4] octanyl, octahydropyrrolo [3, 4-c] pyrrolyl, hexahydrofuro [3, 4-c] pyrrolyl, hexahydrothieno [3, 4-c] pyrrolyl, octahydrocyclopenta [b] pyrrolyl, octahydropyrrolo [3, 2-b] pyrrolyl, hexahydrofuro [3, 2-b] pyrrolyl, octahydropyrano [3, 2-b] pyrrolyl, octahydropyrrolo [3, 2-b] pyridinyl, hexahydropyrrolo [1, 2-a] imidazolyl, octahydropyrrolo [2, 3-c] pyridinyl, octahydropyrrolo [3, 2-c] pyridinyl, octahydroimidazo [1, 2-a] pyridinyl, octahydropyrrolo [3, 4-c] pyridinyl, decahydroquinolinyl, octahydrochromenyl, decahydroquinoxalinyl, octahydropyrido [1, 2-a] pyrazinyl, octahydropyrazino [2, 1-c] [1, 4] oxazinyl, octahydropyrido [2, 1-c] [1, 4] oxazineyl, octahydropyrano [3, 2-c] pyridinyl, decahydro-2, 6-naphthyridinyl, hexahydro-1H-furo [3, 4-c] pyrrolyl, octahydro-1H-pyrano [3, 4-c] pyridinyl, octahydro-2H-pyrido [1, 2-a] pyrazinyl, octahydropyrrolo [1, 2-a] pyrazinyl, hexahydro-3H-oxazolo [3, 4-a] pyrazinyl, hexahydro-5H-cyclopenta [b] [1, 4] dioxinyl, benzo [d] [1, 3] dioxolyl, 2-azabicyclo [1.1.1] pentanyl, 5-azabicyclo [2.1.1] hexanyl, 2-azabicyclo [2.2.1] heptanyl, 2-azabicyclo [2.2.2] octanyl, 6-azabicyclo [3.1.1] heptanyl, 3-azabicyclo [3.2.1] octanyl, 3-azabicyclo [3.3.1] nonanyl, 3-azabicyclo [3.3.2] decanyl, 1, 2, 3, 6-tetrahydropyrrolo [2, 3-b] pyrrolyl, 1, 2, 3, 5-tetrahydropyrrolo [3, 4-b] pyrrolyl, 4, 5, 6, 7-tetrahydropyrrolo [2, 3-b] pyridinyl, 2, 3, 4, 5-tetrahydropyrrolo [2, 3-b] pyrazinyl, 2, 3, 4, 5-tetrahydropyrrolo [3, 2-b] [1, 4] oxazinyl, 2, 3-dihydropyrrolo [1, 2-a] imidazolyl, 1, 2, 3, 4-tetrahydropyrrolo [1, 2-a] pyrimidinyl, 2, 3, 4, 6-tetrahydropyrrolo [3, 4-b] pyrazinyl, 2, 3, 4, 6-tetrahydropyrrolo [3, 4-b] [1, 4] oxazinyl, 5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazinyl, 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a] pyrazinyl, 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyrazinyl, indolinyl, 1, 2, 3, 4-tetrahydroquinolinyl, 1, 2, 3, 4-tetrahydroquinoxalinyl, 3, 4-dihydrobenzo [b] [1, 4] oxazinyl, 2, 3-dihydropyrrolo [2, 3-b] pyridinyl, 1, 2, 3, 4-tetrahydro-1, 7-naphthyridinyl, 1, 2, 3, 4-tetrahydropyrido [3, 4-b] pyrazinyl, 3, 4-dihydropyrido [4, 3-b] [1, 4] oxazinyl,  5, 6, 7, 8-tetrahydro-1, 7-naphthyridinyl, 5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidinyl, 5, 6, 7, 8-tetrahydro-1, 6-naphthyridinyl, 5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidinyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is 5-10 membered partially unsaturated mono-heterocycloalkyl, 6-10 membered partially unsaturated bicyclo heterocycloalkyl, 7-10 membered partially unsaturated spiro heterocycloalkyl, 7-10 membered partially unsaturated bridged heterocycloalkyl, or 8-10 membered partially unsaturated fused heterocycloalkyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is C6-C10 aryl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is phenyl, naphthalenyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzo [b] thiophenyl, benzo [c] thiophenyl, indazolyl, benzo [d] imidazolyl, pyrrolo [3, 2-b] pyridinyl, pyrrolo [3, 2-c] pyridinyl, pyrrolo [2, 3-c] pyridinyl, pyrrolo [2, 3-b] pyridinyl, pyrrolo [3, 4-b] pyridinyl, pyrrolo [3, 4-c] pyridinyl, benzo [d] isoxazolyl, benzo [d] oxazolyl, furo [3, 2-b] pyridinyl, furo [3, 2-c] pyridinyl, furo [2, 3-c] pyridinyl, furo [2, 3-b] pyridinyl, benzo [c] isoxazolyl, furo [3, 4-b] pyridinyl, furo [3, 4-c] pyridinyl, benzo [d] isothiazolyl, benzo [d] thiazolyl, thieno [3, 2-b] pyridinyl, thieno [3, 4-c] pyridinyl, benzo [d] [1, 2, 3] triazolyl, pyrazolo [4, 3-b] pyridinyl, pyrazolo [4, 3-c] pyridinyl, pyrazolo [3, 4-c] pyridinyl, pyrazolo [3, 4-b] pyridinyl, imidazo [4, 5-b] pyridinyl, imidazo [4, 5-c] pyridinyl, imidazo [4, 5-c] pyridinyl, imidazo [4, 5-b] pyridinyl, pyrrolo [3, 2-c] pyridazinyl, pyrrolo [3, 2-d] pyrimidinyl, pyrrolo [2, 3-b] pyrazinyl, pyrrolo [2, 3-d] pyridazinyl, pyrrolo [2, 3-d] pyrimidinyl, pyrrolo [2, 3-c] pyridazinyl, pyrrolo [3, 4-c] pyridazinyl, pyrrolo [3, 4-d] pyrimidinyl, pyrrolo [3, 4-b] pyrazinyl, pyrrolo [3, 4-d] pyridazinyl, pyrrolo [3, 4-d] pyrimidinyl, 6H-pyrrolo [3, 4-c] pyridazinyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
In some embodiments, R1 is selected from H, D, halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, ORA, SRA, or NRCRD; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents R4.
In some embodiments, R1 is selected from H, D, halo, CN, CH3, CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CF2CH3, -CH=CH2, -C (CH3) =CH2, OH, OCH3, OCH2CH3, NH2,  NHCH3, N (CH3) 2, phenyl, 
In some embodiments, each R4 is independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NRCRD, ORA, SRA, C (O) RB, C (O) ORA, OC (O) RB, C (O) NRCRD, NRCC (O) RB, OC (O) NRCRD, OC (O) ORA, NRCC (O) NRCRD, NRCC (O) ORA, C (=NRC) NRCRD, NRDC (=NRC) NRCRD, NRDC (=NRC) RB, S (O) RB, S (O) NRCRD, S (O) 2RB, S (O) 2NRCRD, NRCS (O) 2RB, S (O) (=NRB) RB, NRCS (O) 2NRCRD, NRCS (O) (=NRB) RB, B (ORC) (ORD) , P (O) RERF, P (O) OREORF, OP (O) OREORF, Cy1, OCy1, C1-C6 alkyl-Cy1, or OC1-C6 alkyl-Cy1; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R5A.
In some embodiments, each R4 is independently selected from H. In some embodiments, each R4 is independently selected from D. In some embodiments, each R4 is independently selected from halo (such as F, Cl, Br or I) . In some embodiments, each R4 is independently selected from F. In some embodiments, each R4 is independently selected from Cl. In some embodiments, each R4 is independently selected from Br. In some embodiments, each R4 is independently selected from I.
In some embodiments, each R4 is independently selected from CN. In some embodiments, each R4 is independently selected from NO2. In some embodiments, each R4 is independently selected from N3. In some embodiments, each R4 is independently selected from SF5. In some embodiments, each R4 is independently selected from oxo.
In some embodiments, each R4 is independently selected from C1-C6 alkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R5A.
In some embodiments, each R4 is independently selected from C2-C6 alkenyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R5A.
In some embodiments, each R4 is independently selected from C2-C6 alkynyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R5A.
In some embodiments, each R4 is independently selected from NRCRD. In some embodiments, each R4 is independently selected from ORA. In some embodiments, each R4 is independently selected from SRA.
In some embodiments, each R4 is independently selected from C (O) RB. In some embodiments, each R4 is independently selected from C (O) ORA. In some embodiments, each R4 is independently selected from OC (O) RB.
In some embodiments, each R4 is independently selected from C (O) NRCRD. In some embodiments, each R4 is independently selected from NRCC (O) RB. In some embodiments, each R4 is independently selected from OC (O) NRCRD. In some embodiments, each R4 is independently selected from OC (O) ORA. In some embodiments, each R4 is independently selected from NRCC (O) NRCRD. In some embodiments, each R4 is independently selected from NRCC (O) ORA. In some embodiments, each R4 is independently selected from C (=NRC) NRCRD. In some embodiments, each R4 is independently selected from NRDC (=NRC) NRCRD. In some embodiments, each R4 is independently selected from NRDC (=NRC) RB.
In some embodiments, each R4 is independently selected from S (O) RB. In some embodiments, each R4 is independently selected from S (O) NRCRD. In some embodiments, each R4 is independently selected from S (O) 2RB. In some embodiments, each R4 is independently selected from S (O) 2NRCRD. In some embodiments, each R4 is independently selected from NRCS (O) 2RB. In some embodiments, each R4 is independently selected from S (O) (=NRB) RB. In some embodiments, each R4 is independently selected from NRCS (O) 2NRCRD. In some embodiments, each R4 is independently selected from NRCS (O) (=NRB) RB.
In some embodiments, each R4 is independently selected from B (ORC) (ORD) . In some embodiments, each R4 is independently selected from P (O) RERF. In some embodiments, each R4 is independently selected from P (O) OREORF. In some embodiments, each R4 is independently selected from OP (O) OREORF.
In some embodiments, each R4 is independently selected from Cy1.
In some embodiments, each R4 is independently selected from OCy1.
In some embodiments, each R4 is independently selected from C1-C6 alkyl-Cy1; wherein, the C1-C6 alkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R5A.
In some embodiments, each R4 is independently selected from OC1-C6 alkyl-Cy1; wherein, the C1-C6 alkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R5A.
In some embodiments, each R5A is independently selected from D, halo, CN, N3, oxo, ORa, Si (C1-C4 alkyl) 3 or OC1-C6 alkyl-OH.
In some embodiments, each R5A is independently selected from D. In some embodiments, each R5A is independently selected from halo (such as F, Cl, Br or I) . In some embodiments, each R5A is independently selected from F. In some embodiments, each R5A is independently selected from Cl. In some embodiments, each R5A is independently selected from Br. In some embodiments, each R5A is independently selected from I.
In some embodiments, each R5A is independently selected from CN. In some embodiments, each R5A is independently selected from N3. In some embodiments, each R5A is independently selected from oxo.
In some embodiments, each R5A is independently selected from ORa. In some embodiments, for example, included but not limited to, each R5A is independently selected from OH, OCH3, OCH2F, OCHF2, OCF3.
In some embodiments, each R5A is independently selected from Si (C1-C4 alkyl) 3.
In some embodiments, each R5A is independently selected from OC1-C6 alkyl-OH. In some embodiments, for example, included but not limited to, each R5A is independently selected from OCH2 CH2OH.
In some embodiments, Cy1 is C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl; wherein, the C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl is optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R5B.
In some embodiments, Cy1 is C3-C10 cycloalkyl optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R5B.
In some embodiments, Cy1 is 4-10 membered heterocycloalkyl optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R5B.
In some embodiments, Cy1 is C6-C10 aryl optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R5B. In some embodiments, Cy1 is phenyl, naphthalenyl; each is optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R5B.
In some embodiments, Cy1 is 5-10 membered heteroaryl optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R5B.
In some embodiments, R5B is each independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, ORa, SRa, 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; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, ORa1, C (O) ORa1, C (O) Rb1, NRc1Rd1, C (O) NRc1Rd1, S (O) 2Rb1, or S (O) 2NRc1Rd1.
In some embodiments, R5B is independently selected from H. In some embodiments, R5B is independently selected from D. In some embodiments, R5B is independently selected from halo (such as F, Cl, Br or I) . In some embodiments, R5B is independently selected from CN. In some embodiments, R5B is independently selected from NO2. In some embodiments, R5B is independently selected from  N3. In some embodiments, R5B is independently selected from SF5. In some embodiments, R5B is independently selected from oxo.
In some embodiments, R5B is independently selected from C1-C6 alkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, ORa1, C (O) ORa1, C (O) Rb1, NRc1Rd1, C (O) NRc1Rd1, S (O) 2Rb1, or S (O) 2NRc1Rd1.
In some embodiments, R5B is independently selected from C2-C6 alkenyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, ORa1, C (O) ORa1, C (O) Rb1, NRc1Rd1, C (O) NRc1Rd1, S (O) 2Rb1, or S (O) 2NRc1Rd1.
In some embodiments, R5B is independently selected from C2-C6 alkynyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, ORa1, C (O) ORa1, C (O) Rb1, NRc1Rd1, C (O) NRc1Rd1, S (O) 2Rb1, or S (O) 2NRc1Rd1.
In some embodiments, R5B is independently selected from C3-C10 cycloalkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, ORa1, C (O) ORa1, C (O) Rb1, NRc1Rd1, C (O) NRc1Rd1, S (O) 2Rb1, or S (O) 2NRc1Rd1.
In some embodiments, R5B is independently selected from 4-10 membered heterocycloalkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, ORa1, C (O) ORa1, C (O) Rb1, NRc1Rd1, C (O) NRc1Rd1, S (O) 2Rb1, or S (O) 2NRc1Rd1.
In some embodiments, R5B is independently selected from C6-C10 aryl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, ORa1, C (O) ORa1, C (O) Rb1, NRc1Rd1, C (O) NRc1Rd1, S (O) 2Rb1, or S (O) 2NRc1Rd1.
In some embodiments, R5B is independently selected from 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-7 membered  heterocycloalkyl, 5-6 membered heteroaryl, ORa1, C (O) ORa1, C (O) Rb1, NRc1Rd1, C (O) NRc1Rd1, S (O) 2Rb1, or S (O) 2NRc1Rd1.
In some embodiments, R5B is independently selected from ORa. In some embodiments, R5B is independently selected from SRa. In some embodiments, R5B is independently selected from NHORa.
In some embodiments, R5B is independently selected from C (O) Rb. In some embodiments, R5B is independently selected from C (O) NRcRd. In some embodiments, R5B is independently selected from C (O) ORa. In some embodiments, R5B is independently selected from OC (O) Rb. In some embodiments, R5B is independently selected from OC (O) NRcRd.
In some embodiments, R5B is independently selected from NRcRd. In some embodiments, R5B is independently selected from NRcC (O) Rb. In some embodiments, R5B is independently selected from NRcC (O) NRcRd. In some embodiments, R5B is independently selected from NRcC (O) ORa. In some embodiments, R5B is independently selected from B (ORc) (ORd) . In some embodiments, R5B is independently selected from C (=NRc) NRcRd. In some embodiments, R5B is independently selected from NRdC (=NRc) NRcRd. In some embodiments, R5B is independently selected from NRdC (=NRc) Rb.
In some embodiments, R5B is independently selected from P (O) ReRf. In some embodiments, R5B is independently selected from P (O) OReORf. In some embodiments, R5B is independently selected from OP (O) OReORf.
In some embodiments, R5B is independently selected from S (O) Rb. In some embodiments, R5B is independently selected from S (O) NRcRd. In some embodiments, R5B is independently selected from S (O) 2Rb. In some embodiments, R5B is independently selected from NRcS (O) 2Rb. In some embodiments, R5B is independently selected from S (O) 2NRcRd. In some embodiments, R5B is independently selected from NRcS (O) 2NRcRd. In some embodiments, R5B is independently selected from NRcS (O) (=NRb) Rb.
In some embodiments, 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, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, NO2, oxo, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, ORa, SRa, 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 RA is independently selected from H. In some embodiments, each RA is independently selected from D.
In some embodiments, each RA is independently selected from 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, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, NO2, oxo, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, ORa, SRa, 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 compounds of Formula I, 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, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, OC2-C4 alkylOH, OC2-C4 alkyl-O-C1-C4 alkyl, OC2-C4 alkyl-O-C1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, ORa, SRa, 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 RB is independently selected from H, D. In some embodiments, each RB is independently selected from H. In some embodiments, each RB is independently selected from D.
In some embodiments, each RB is independently selected from 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, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, OC2-C4 alkylOH, OC2-C4 alkyl-O-C1-C4 alkyl, OC2-C4 alkyl-O-C1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, ORa, SRa, 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, RC and RD are each 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, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, OC2-C4 alkylOH, OC2-C4 alkyl-O-C1-C4 alkyl, OC2-C4 alkyl-O-C1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, ORa, SRa, C (O) Rb, 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, D. 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, 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, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, OC2-C4 alkylOH, OC2-C4 alkyl-O-C1-C4 alkyl, OC2-C4 alkyl-O-C1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, ORa, SRa, C (O) Rb, 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. 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, 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, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, OC2-C4 alkylOH, OC2-C4 alkyl-O-C1-C4 alkyl, OC2-C4 alkyl-O-C1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, ORa, SRa, C (O) Rb, 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 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, oxo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-CN, ORa, SRa, C (O) Rb, NRcRd.
In some embodiments, 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, 4-10 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 RE is independently selected from H, or D. In some embodiments, each RE is independently selected from H. In some embodiments, each RE is independently selected from D.
In some embodiments, each RE is independently selected from 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, 4-10 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, or 4-10 membered heterocycloalkyl.
In some embodiments, each RF is independently selected from H. In some embodiments, each RF is independently selected from D.
In some embodiments, each RF is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, or 4-10 membered heterocycloalkyl.
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, 3, 4 or 5 substituents independently selected from D, OH, halo, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl.
In some embodiments, each Ra is independently selected from H, or D. In some embodiments, each Ra is independently selected from H. In some embodiments, each Ra is independently selected from D.
In some embodiments, each Ra is independently selected from 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, 3, 4 or 5 substituents independently selected from D, OH, halo, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl.
In some embodiments, each Rb 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, C6-C10 aryl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl; 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-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, , C1-C4 haloalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.
In some embodiments, each Rb is independently selected from H, D. In some embodiments, each Rb is independently selected from H. In some embodiments, each Rb is independently selected from D.
In some embodiments, each Rb is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl or 4-10 membered heterocycloalkyl-C1-C4 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-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, , C1-C4  haloalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.
In some embodiments, each Rc 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, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (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-C4 alkyl, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, O-C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, 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, each Rc is independently selected from H, D. 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-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (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-C4 alkyl, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2,  C1-C4 alkyl, O-C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, 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, each Rd is independently selected from H, D. 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-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (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-C4 alkyl, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, O-C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, 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 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, O-C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, 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 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, 4-10 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 Re is each independently selected from H, D. In some embodiments, each Re is each independently selected from H. In some embodiments, each Re is each independently selected from D.
In some embodiments, each Re is each independently selected from 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, 4-10 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, or 4-10 membered heterocycloalkyl.
In some embodiments, each Rf is independently selected from H. In some embodiments, each Rf is independently selected from D.
In some embodiments, each Rf is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, or 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, 3, 4 or 5 substituents independently selected from D, OH, halo, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl.
In some embodiments, each Ra1 is independently selected from H, D. In some embodiments, each Ra1 is independently selected from H. In some embodiments, each Ra1 is independently selected from D.
In some embodiments, each Ra1 is independently selected from 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, 3, 4 or 5 substituents independently selected from D, OH, halo, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl.
In some embodiments, each Rb1 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, C6-C10 aryl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl; 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-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, ,  C1-C4 haloalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.
In some embodiments, each Rb1 is independently selected from H, D. In some embodiments, each Rb1 is independently selected from H. In some embodiments, each Rb1 is independently selected from D.
In some embodiments, each Rb1 is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl; 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-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, , C1-C4 haloalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl.
In some embodiments, Rc1 and Rd1 are each 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, C6-C10 aryl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (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-C4 alkyl, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, O-C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, 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, each Rc1 is independently selected from H. In some embodiments, each Rc1 is independently selected from D.
In some embodiments, each Rc1 is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered  heterocycloalkyl, C6-C10 aryl-C1-C4 alkyl, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (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-C4 alkyl, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, O-C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, 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, each Rd1 is independently selected from H. In some embodiments, each Rc1 is independently selected from D.
In some embodiments, each Rd1 is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (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-C4 alkyl, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, O-C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, 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, Rc1 and Rd1 together with the N atom to which they are attached form 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently  selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, O-C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, 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, the compound of Formula (I) is:

or a pharmaceutically acceptable salt thereof.
Stereoisomers of the compounds of Formula I, and the pharmaceutical salts and solvates thereof, are also contemplated, described, and encompassed herein. Methods of using compounds of Formula I are described, as well as pharmaceutical compositions including the compounds of Formula I.
It will be apparent that the compounds of Formula I, 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 I (and subgenera described herein) . The present disclosure contemplates and encompasses each stereoisomer of any compound of Formula I (and subgenera described herein) , as well as mixtures of said stereoisomers.
Pharmaceutically acceptable salts and solvates of the compounds of Formula I (including all subgenera described herein) are also within the scope of the disclosure.
Isotopic variants of the compounds of Formula I (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 WRN in a cell expressing WRN, the method comprising contacting the cell with the compound disclosed herein.
In some embodiments, the cell is associated with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) . 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 dMMR/MSI-H. In some embodiments, the disease or condition is a cancer. In some embodiments, the cancer is a cancer with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) .
A method of inhibiting WRN in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the present invention, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention.
A method of treating a disease which can be treated by WRN inhibition in a subject, comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention.
In some embodiments, the disease is cancer.
In some embodiments, the cancer is characterized as MSI-H or dMMR.
In some embodiments, the cancer characterized as MSI-H or dMMR is selected from colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney and ovarian cancer.
In some embodiments, the cancer characterized as MSI-H or dMMR is selected from colorectal, gastric and endometrial cancer.
In some embodiments, the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from prostate cancer, uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal carcinoma, breast carcinoma, kidney renal clear cell carcinoma and ovarian serous cystadenocarcinoma.
Use of the compound of the present invention or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention, in the manufacture of a medicament for the treatment of cancer.
In some embodiments, the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) .
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. Similarly, 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 cycloalkyl 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, “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, H, D, halogen, CN, NO2, SF5, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb, OC (O) NRcRd, OC (O) ORa, NRcC (O) NRcRd, NRcC (O) ORa, C (=NRc) NRcRd, NRdC (=NRc) NRcRd, NRdC (=NRc) Rb, S (O) Rb, S (O) NRcRd, S (O) 2Rb, S (O) 2NRcRd, NRcS (O) 2Rb, S (O) (=NRb) Rb, NRcS (O) 2NRcRd, NRcS (O) (=NRb) Rb, B (ORc) (ORd) , P (O) ReRf, P (O) OReORf, or OP (O) OReORf; wherein, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl is optionally substituted by 1-6 substituents independently selected from D, halogen, CN, NO2, SF5, OH, oxo, C1-C6 alkyl, -O-C1-C6 alkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, -OC1-C6 haloalkyl, NRc1Rd1, ORa1, SRa1, NHORa1, C (O) Rb1, C (O) ORa1, OC (O) Rb1, C (O) NRc1Rd1, NRcC (O) Rb1.
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 I with one or more solvent molecules.
“Subject” includes humans. The terms “human, ” “patient, ” and “subject” are used interchangeably herein.
“Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) . 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 I 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 I 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.
As used herein, the term “inhibit” , "inhibition" or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
The term “cancer” refers to a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to colorectal, gastric, endometrial, prostate, adrenocortical, uterine, cervical, esophageal, breast, kidney, ovarian cancer and the like.
The terms “tumor” and “cancer” are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating, tumors. As used herein, the term “cancer” or “tumor” includes premalignant, as well as malignant cancers and tumors. ‘WRN inhibitor’ or ‘WRN helicase inhibitor’ as used herein means a compound that inhibits Werner Syndrome RecQ DNA helicase (WRN) .
The term "WRN" as used herein refers to the protein of Werner Syndrome RecQ DNA helicase. The term “WRN” includes mutants, fragments, variants, isoforms, and homologs of full-length wild-type WRN. In one embodiment, the protein is encoded by the WRN gene (Entrez gene ID 7486; Ensembl ID ENSG00000165392) . Exemplary WRN sequences are available at the Uniprot database under accession number Q14191.
‘Disease or condition mediated by WRN’ includes a disease or condition, such as cancer, which is treated by WRN inhibition. In particular this can include cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) .
‘Microsatellite unstable cancer’ , microsatellite instability-high cancer’ , ‘microsatellite high cancer’ and ‘MSI-high cancer’ ‘MSIhi’ and ‘MSI-H’ when used herein, are used interchangeably, and describe cancers that have a high number of alterations in the length of simple repetitive genomic sequences within microsatellites.
The determination of MSI-H or dMMR tumor status for patients can be performed using, e.g., polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR.
The terms “synthetic lethality, ” and “synthetic lethal” are used to refer to reduced cell viability and/or a reduced rate of cell proliferation caused by a combination of mutations or approaches to cause loss of function (e.g., RNA interference or protein function inhibition) in two or more genes but not by the loss of function of only one of these genes.
Pharmaceutical Compositions
Also provided are pharmaceutical compositions comprising compounds of Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide thereof, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound 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 (I) or a pharmaceutically salt thereof for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
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 (I) or a pharmaceutically salt thereof with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
Described below are non-limiting exemplary pharmaceutical compositions and methods for preparing the same.
Methods of Administration
The compounds of Formula (I) or a pharmaceutically salt thereof or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action) .
Routes of administration include, but are not limited to, oral (e.g., by ingestion) ; buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc. ) ; transmucosal (including, e.g., by a patch, plaster, etc. ) ; intranasal (e.g., by nasal spray) ; ocular (e.g., by eye drops) ; pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose) ; rectal (e.g., by suppository or enema) ; vaginal (e.g., by pessary) ; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, 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 WRN inhibitor with an IC50 value of about or less than a predetermined value, as ascertained in an in vitro assay. In some embodiments, the WRN inhibitor inhibits WRN 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 μΜor less, 1.6 μΜ or less, 1.7 μΜ or less, 1.8 μΜ or less, 1.9 μΜ or less, 2 μΜ or 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) .
WRN is a synthetic lethal target in the cancers with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) . The subject methods are useful for treating disease conditions associated with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) .
A cancer that has “defective mismatch repair” (dMMR) or “dMMR character” includes cancer types associated with documented MLH1, PMS2, MSH2, MSH3, MSH4, MSH5, MSH6, MLH3, PMS1, and EXO1 mutations or epigenetic silencing, microsatellite fragile sites, or other gene inactivation mechanisms. A cell or cancer with “defective” mismatch repair has a significantly reduced (e.g., at least about 25%, 30%, 40%, 50%, 60%, 70%, 80%or 90%decrease) amount of mismatch repair. In some cases, a cell or cancer which is defective in mismatch repair will perform no mismatch repair.
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.
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, 8th Ed. (Wiley, 2019) ; Peturssion et al, "Protecting Groups in Carbohydrate Chemistry, " J Chem. Educ., 1997, 74 (11) , 1297; and Wuts et al., Protective Groups in Organic Synthesis, 5th Ed., (Wiley, 2014) .
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.
Abbreviations


General Synthetic Procedures
A series of amide derivatives of formula 1-4 can be prepared as the methods outlined in Scheme 1. Carboxylic acids 1-1 can couple with amines 1-2 to provide the amide derivatives 1-4 under standard amide coupling conditions (e.g., in the presence of a coupling reagent such as EDCI, HATU, HBTU, BOP, or PyBOP with a base such as DIPEA, DMAP or pyridine) . Alternatively, the amides 1-4 can be prepared by reaction of the amines 1-2 with acyl chlorides 1-3 which can be obtained by treatment of the corresponding carboxylic acids 1-1 with a suitable reagent such as thionyl chloride or oxalyl chloride.
Scheme 1
A series of carboxylic acids of formula 2-4 and 2-8 can be prepared as the methods outlined in Scheme 2. Suzuki coupling of carboxylates 2-1 where W is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., SMe, OTf or OMs) with a suitable boronic acid or boronate ester 2-2 R1B (OR) 2 where R is selected from H or alkyl can afford compounds 2-3 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) . Hydrolysis of the esters 2-3 can provide the carboxylic acids 2-4 in the presence of basic conditions (e.g., such as aqueous LiOH or other inorganic bases) .
Alternatively, R1 can be directly introduced to the N-atom of Cy ring in carboxylate esters 2-5 to provide the corresponding carboxylate esters 2-7 by alkylation with R1-W1 2-6 where W1 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base such as NaH, KOH, KOt-Bu or through Buchwald reaction 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) . Hydrolysis of the esters 2-7 can provide the carboxylic acids 2-8 under basic conditions (e.g., such as aqueous LiOH or other inorganic bases) .
Scheme 2
A series of 1, 2, 4-triazine-6-carboxylic acids of formula 3-5 can be prepared as the methods outlined in Scheme 3. Condensation of the hydrazine carboxamides 3-1 with diethyl 2-oxomalonate 3-2 in methanol in the presence of HCl can provide the cyclized compounds 3-3. Alkylation of the NH of 3-3 can be achieved by treatment with R1-W1 where W1 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base such NaH or KOtBu to afford 1, 2, 4-triazine-6-carboxylate esters 3-4. Alternatively, alkylation of the NH of 3-3 can be achieved by Buchwald reactions 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. Hydrolysis of the triazine-6-carboxylate esters 3-4 can provide the carboxylic acids 3-5 under basic conditions (e.g., such as aqueous LiOH or other inorganic bases) .
Scheme 3
A series of 1, 2, 4-triazine-6-carboxylic acids of formula 4-5 can be prepared as the methods outlined in Scheme 4. 1, 2, 4-triazine-6-carboxylate ester 4-1 is treated with NBS to yield the corresponding bromo compounds 4-2. Suzuki coupling of the bromo compounds 4-2 with suitable boronic acids R1 (OH) 2 or boronates R1 (OR) 2R where R is selected from H or alkyl under standard Suzuki coupling conditions (e.g., in the presence of a palladium catalyst, such as Xanphos Pd, or [1, 1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and a base, such as K3PO4) can afford the compounds 4-3. Alkylation of the NH of 4-3 can be achieved by treatment with R3-W2 where W2 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base such NaH or KOtBu to afford 1, 2, 4-triazine-6-carboxylate esters 4-4. Hydrolysis of the triazine-6-carboxylate esters 4-4 can provide the carboxylic acids 4-5 under basic conditions (e.g., such as aqueous LiOH or other inorganic bases) .
Scheme 4
A series of oxo-2, 3-dihydropyridazine-4-carboxylic acids of formula 5-8 can be prepared as the methods outlined in Scheme 5. Condensation of α-keto esters 5-1 with ethyl 3-hydrazineyl-3-oxopropanoate 5-2 can provide 5-3 which can be cyclized to provide compounds 5-4 in the presence of a base such as KOtBu, NaOMe or NaOEt. The hydroxyl group of 5-4 can be protected by treatment with tert-butydimethylsilyl chloride in the presence of a base such as TEA or imidazole. Alkylation of the OH protected compounds 5-5 can provide the corresponding compounds 5-6 by reactions of R3-W2 where W2 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base such NaH or KOtBu. Removal of the protecting group on 5-6 can be carried out in the presence of an acid such as TFA or fluoride reagent such as FH in pyridine. Hydrolysis of compounds 5-7 in the presence of a base such as LiOH or other inorganic bases can provide the carboxylic acids 5-8.
Scheme 5
A series of uracil acids of formula 6-4 can be prepared as the methods outlined in Scheme 6. Compounds 6-1 can be selectively alkylated by R3-W2 where W2 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a mild base such as KOH. Introduction of R1 on 6-2 can be carried out by using R1-W1 where W1 is halogen (e.g., Cl, Br or I) or pseudohalogen (e.g., OTf or OMs) in the presence of a base such as NaH or KOtBu. Alternatively, it can also be carried out under Buchwald conditions 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. Hydrolysis of 6-3 in the presence of an inorganic base such as LiOH can provide the uracil acids 6-4.
Scheme 6
A series of hydroxythiazolo-pyridine carboxylic acids of formula 7-9 can be prepared as the methods outlined in Scheme 7. Reduction of nitro compound 7-1 can provide the corresponding amines 7-2 under various reduction conditions such as Fe/HCl, hydrogenation or Zn/NH4Cl. Treatment of the amines 7-2 with potassium thiocyanate can yield the aminothiazolo-pyridines 7-3 which can be transformed into bromide compounds 7-4 in the presence of a bromination reagent such as bromine in acetic acid. Carboxylation of the bromides 7-4 to provide the methyl ester 7-5 can be carried out under CO (gas) in the presence of palladium catalyst such as Pd (dppf) Cl2. Sandmeyer-type reactions of the amines 7-5 to the bromo compounds 7-6 can be achieved by using sodium nitrate followed by reacting with CuBr. Suzuki coupling of the bromo compounds 7-6 with suitable boronic acids or boronates R1 (OR) 2 (where R is selected from H or alkyl) under standard Suzuki coupling 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) can afford the compounds 7-7. The hydroxythiazolo-pyridine carboxylic acids 7-9 can be prepared by treating 7-7  with BBr3 in dichloromethane or other suitable conditions to provide 7-8 followed by hydrolysis of 7-8 in the presence of an inorganic base such as LiOH in a suitable solvent such as THF.
Scheme 7
A series of hydroxythiazolo-pyridine carboxylic acids of formula 8-7 can be prepared as the methods outlined in Scheme 8. Condensation of amino thiozole 8-1 with 2- (alkoxymethylene) malonate ester (where R is Me or Et) can provide the intermediate enimo-ester 8-3 which can be cyclized into hydroxythiazolo-pyridine carboxylate 8-4 by enhancing temperature in a suitable solvent such as Ph2O. Bromination of the 8-4 with a bromination reagent such as NBS can produce the corresponding bromide 8-5. Suzuki coupling of the OH compounds 8-5 with suitable boronic acids or boronates R1 (OR’) 2 (where R’ is selected from H or alkyl) under standard Suzuki coupling 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) can afford the compounds 8-6. Hydrolysis of 8-6 in the presence of a base such as aqueous LiOH or NaOH can provide the desired hydroxythiazolo-pyridine carboxylic acids 8-7.
Scheme 8
A series of aza-indone carboxylic acids of formula 9-8 can be prepared as the methods outlined in Scheme 9. Replacement of the chlorine in aza-indone chloride 9-1 with methoxyl group can be performed under NaOMe/MeOH conditions with heating. Protection of NH in 9-2 can be carried out using a suitable protecting reagent such as BOC anhydride or Tosyl chloride to provide the protected compound 9-3 which can be transformed into the corresponding bromide 9-4 by lithiation of 9-3 using butyllium in a suitable solvent such THF followed by addition of bromine at low temperatures. Removal of phenolic methyl group on 9-4 can provide the corresponding OH compounds 9-5 in the presence of a demethylation reagent such as BBr3. Suzuki coupling of the OH compounds 9-5 with suitable boronic acids or boronates R1 (OR) 2 (where R is selected from H or alkyl) under standard Suzuki coupling 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) can afford the compounds 9-6. Removal of protecting group on 9-6 in the presence of a suitable reagent such TFA (when P is Boc group) or base such as NaOH aqueous solution (when P is Tosyl group) followed by hydrolysis of 9-7 in the presence of an inorganic base such as LiOH in a suitable solvent such as THF can provide the acids 9-8.
Scheme 9
A series of bicyclic-pyridine carboxylic acids of formula 10-4 can be prepared as the methods outlined in Scheme 10. Condensation of suitable heterocyclic amino-aldehydes 10-1 with dialkyl malonates 10-2 where Ra is C1-C6 alkyl such as Me, Et, or tert-Bu can afford the bicyclic-pyridine carboxylates 10-3 under basic conditions such as NaOMe, NaOEt, t-BuOK with a piperidine in alcohol solvent. Hydrolysis of 10-3 using basic conditions such as aqueous LiOH or NaOH can provide the desired hydroxythiazolo-pyridine carboxylic acids 10-4.
Scheme 10
A series of sulfonylurea of formula 11-5 can be prepared as the methods outlined in Scheme 11. Treatment of the amines 11-1 with chlorosulfonic acid can provide the sulfamic acids 11-2 which can  be transformed into the corresponding sulfamoyl chlorides 11-3 with a suitable chlorination agent such as SOCl2, PCl5, or COCl2 with or without solvent, e.g. CCl4 or CHCl3, optionally in the presence of a base, e.g. pyridine or γ-picoline, and catalytic amounts of DMF. The sulfonylurea 11-5 can be achieved by coupling of the sulfamoyl chlorides 11-3 with primary amides 11-4 in the presence of a base such as Hunig’s base.
Scheme 11
Examples
Example 1: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -6-hydroxy-2-phenylthieno [2, 3-b] pyridine-5-carboxamide
Step 1: tert-butyl (3-bromothiophen-2-yl) carbamate
A mixture of 3-bromothiophene-2-carboxylic acid (10.0 g, 48.78 mmol) , DPPA (14.75g, 53. mmol) and TEA (4.9 g, 48.78 mmol) in t-BuOH (90 mL) was stirred at 65 ℃ overnight. The reaction mixture was cooled to r.t. and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -5%) to afford the title compound (9 g, 66%yield) as a colorless oil. LCMS calc. for C9H13BrNO2S [M+H] +: m/z = 277.9; Found: 222.0 [M+H-56] +.
Step 2: tert-butyl (3-formylthiophen-2-yl) carbamate
To a solution of tert-butyl (3-bromothiophen-2-yl) carbamate (2 g, 7.2 mmol) in THF (20 mL) was added n-BuLi (8.6 mL) at -78 ℃ under nitrogen atmosphere. After stirring for 45 min., morpholine-4-carbaldehyde (4.1 g, 36 mmol) was added at -78 ℃. The mixture was stirred for 16 h.,  quenched with sat. aq. NH4Cl (20 mL) and extracted with EtOAc (10 mL x 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue purified by flash chromatography on a silica gel column eluting with EtOAc /PE (0 -10%) to afford the title compound (450 mg, 29%yield) as a yellow oil. LCMS calc. for C10H14NO3S [M+H] +: m/z = 228.1; Found: 172.2 [M+H-56] +.
Step 3: ethyl 6-oxo-6, 7-dihydrothieno [2, 3-b] pyridine-5-carboxylate
A mixture of tert-butyl (3-formylthiophen-2-yl) carbamate (490 mg, 2.16 mmol) , diethyl malonate (1.73 g, 10.79 mmol) and piperidine (92 mg, 1.08 mmol) in EtOH (20 mL) was stirred at 90 ℃ for 1 h. under N2. To the mixture above was addedNaOMe (1.17 g, 21.59 mmol) , and the mixture was stirred at for 5 h. under N2. EtOH was removed under vaccum and EtOAc (20 mL) was added. The mixture was adjusted pH to 5-6 with aq. HCl (1 N) and extracted with EtOAc (20 mL x 3) . The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -20%) to afford the title compound (385 mg, 80%yield) as a white solid. LCMS calc. for C10H10NO3S [M+H] +: m/z = 224.0; Found: 224.2.
Step 4: ethyl 2-bromo-6-hydroxythieno [2, 3-b] pyridine-5-carboxylate
To a solution of ethyl 6-oxo-6, 7-dihydrothieno [2, 3-b] pyridine-5-carboxylate (385 mg, 1.73 mmol) in AcOH (10 mL) was added NBS (307 mg, 1.73 mmol) . The mixture was stirred at r.t. for 0.5 h. under N2. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -20%) to afford the title compound (390 mg, 75%yield) as a white solid. LCMS calc. for C10H9BrNO3S [M+H] +: m/z = 301.9; Found: 302.1.
Step 5: ethyl 6-hydroxy-2-phenylthieno [2, 3-b] pyridine-5-carboxylate
A mixture of ethyl 2-bromo-6-hydroxythieno [2, 3-b] pyridine-5-carboxylate (100 mg, 0.33 mmol) , phenylboronic acid (81 mg, 0.66 mmol) , Pd (dppf) Cl2 (48 mg, 0.07 mmol) and K2CO3 (137 mg, 0.99 mmol) in 1, 4-dioxane (5 mL) and H2O (0.5 mL) was stirred at 90 ℃ for 4 h. under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3) . The combined organic  layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -20%) to afford the title compound (65 mg, 66%yield) as a light yellow solid. LCMS calc. for C16H14NO3S [M+H] +: m/z = 300.1; Found: 300.3.
Step 6: 6-hydroxy-2-phenylthieno [2, 3-b] pyridine-5-carboxylic acid
To a solution of ethyl 6-hydroxy-2-phenylthieno [2, 3-b] pyridine-5-carboxylate (65 mg, 0.22 mmol) in THF (3 mL) , MeOH (1 mL) and H2O (1 mL) was added LiOH (52 mg, 2.2 mmol) at r.t. The reaction mixture was stirred for 2 h. at 60 ℃. The reaction mixture was adjusted pH to 5-6 with aq. HCl (1 N) . The solid was filtered. The filter cake was washed with H2O and dried in vacuo to afford the title compound (31 mg, 53%yield) as a light brown solid. LCMS calc. for C14H10NO3S [M+H] +: m/z = 272.0; Found: 272.2.
Step 7: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -6-hydroxy-2-phenylthieno [2, 3-b] pyridine-5-carboxamide
To a mixture of 6-hydroxy-2-phenylthieno [2, 3-b] pyridine-5-carboxylic acid (26 mg, 96 μmol) , 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride (16 mg, 96 μmol) and DIPEA (62 mg, 480 μmol) in DMF (5 mL) was added HATU (55 mg, 144 μmol) at r.t. The reaction mixture was stirred at r.t. for 2 h., and concentrated under reduced pressure. The residue was purified by Prep-HPLC on a C18 column eluting with MeCN/H2O (5%-50%, with 0.1%FA) to afford the title compound (5.2 mg, 14%yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H) , 10.11 (s, 1H) , 8.75 (s, 1H) , 7.78 (s, 1H) , 7.67 (d, J = 7.2 Hz, 2H) , 7.47 (dd, J = 10.4, 4.8 Hz, 2H) , 7.41 –7.33 (m, 1H) , 7.28 (dd, J = 6.4, 2.0 Hz, 1H) , 7.00 (dd, J = 6.4, 3.2 Hz, 1H) , 5.45 –5.34 (m, 1H) , 3.75 (dd, J = 13.6, 8.0 Hz, 1H) , 3.30 –3.25 (m, 1H) . LCMS calc. for C18H15N2O4S2 [M+H] +: m/z = 387.0; Found: 387.2.
Example 2: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -6-hydroxy-2- (m-tolyl) thieno [2, 3-b] pyridine-5-carboxamide
Step 1: 6-hydroxy-2- (m-tolyl) thieno [2, 3-b] pyridine-5-carboxylic acid
This compound was prepared by the procedure analogous to that described for Example 1 Step 5-6 using m-tolylboronic acid to replace phenylboronic acid in Step 5 to afford the title product as a light brown solid. LCMS calc. for C15H12NO3S [M+H] +: m/z = 286.0; Found: 286.2.
Step 2: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -6-hydroxy-2- (m-tolyl) thieno [2, 3-b] pyridine-5-carboxamide
This compound was prepared by the procedure analogous to that described for Example 1 Step 7 using 6-hydroxy-2- (m-tolyl) thieno [2, 3-b] pyridine-5-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford title product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1H) , 10.30 (s, 1H) , 8.69 (s, 1H) , 7.72 (s, 1H) , 7.52 –7.41 (m, 2H) , 7.34 (t, J = 7.6 Hz, 1H) , 7.27 (dd, J = 6.4, 2.0 Hz, 1H) , 7.17 (d, J = 7.6 Hz, 1H) , 6.99 (dd, J = 6.4, 3.2 Hz, 1H) , 5.44 –5.33 (m, 1H) , 3.75 (dd, J = 13.6, 8.0 Hz, 1H) , 3.27 (dd, J = 13.6, 4.0 Hz, 1H) , 2.36 (s, 3H) . LCMS calc. for C19H17N2O4S2 [M+H] +: m/z = 401.1; Found: 401.3.
Example 3: 2- (3, 4-Dimethylphenyl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -6-hydroxythieno [2, 3-b] pyridine-5-carboxamide
Step 1: 2- (3, 4-dimethylphenyl) -6-hydroxythieno [2, 3-b] pyridine-5-carboxylic acid
This compound was prepared by the procedure analogous to that described for Example 1 Step 5-6 using (3, 4-dimethylphenyl) boronic acid to replace phenylboronic acid in Step 5 to afford the title product as a white solid. LCMS calc. for C16H14NO3S [M+H] +: m/z = 300.1; Found: 300.1.
Step 2: 2- (3, 4-dimethylphenyl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -6-hydroxythieno [2, 3-b] pyridine-5-carboxamide
This compound was prepared by the procedure analogous to that described for Example 1 Step 7 using 2- (3, 4-dimethylphenyl) -6-hydroxythieno [2, 3-b] pyridine-5-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford title product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1H) , 10.14 (s, 1H) , 8.72 (s, 1H) , 7.68 (s, 1H) , 7.44 (s, 1H) , 7.39 (d, J = 7.6 Hz, 1H) , 7.27 (dd, J = 6.6, 2.0 Hz, 1H) , 7.22 (d, J = 8.0 Hz, 1H) , 6.99 (dd, J = 6.6, 3.0 Hz, 1H) , 5.39 (s, 1H) , 3.75 (dd, J = 13.8, 7.9 Hz, 1H) , 3.26 (d, J = 4.1 Hz, 1H) , 2.26 (d, J = 13.0 Hz, 6H) . LCMS calc. for C20H19N2O4S2 [M+H] +: m/z = 415.1; Found: 415.0.
Example 4: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -2-ethyl-6-hydroxythieno [2, 3-b] pyridine-5-carboxamide
Step 1: ethyl 6-hydroxy-2-vinylthieno [2, 3-b] pyridine-5-carboxylate
A mixture of ethyl 2-bromo-6-hydroxythieno [2, 3-b] pyridine-5-carboxylate (160 mg, 0.53 mmol, Example 1 Step 4) , 4, 4, 5, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolane (163 mg, 1.06 mmol) , Pd (dppf) Cl2 (77 mg, 0.11 mmol) and K2CO3 (219 mg, 1.59 mmol) in 1, 4-dioxane (10 mL) and H2O (1 mL) was stirred at 90 ℃ for 4 h. under N2. The reaction mixture was diluted with water (20 mL) , and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -20%) to afford the title compound (85 mg, 64%yield) as a light yellow solid. LCMS calc. for C12H12NO3S [M+H] +: m/z = 250.0; Found: 250.2.
Step 2: ethyl 2-ethyl-6-hydroxythieno [2, 3-b] pyridine-5-carboxylate
To a solution of ethyl 6-hydroxy-2-vinylthieno [2, 3-b] pyridine-5-carboxylate (50 mg, 0.2 mmol) in MeOH (5 mL) was added Pd/C (43 mg, 0.04 mmol, 10%wet) at r.t. The reaction mixture was stirred at r.t. for 4 h. under H2. The mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford the title compound (41 mg, 81%yield) as a white solid. LCMS calc. for C12H14NO3S [M+H] +: m/z = 252.1; Found: 252.2.
Step 3: 2-ethyl-6-hydroxythieno [2, 3-b] pyridine-5-carboxylic acid
A mixture of ethyl 2-ethyl-6-hydroxythieno [2, 3-b] pyridine-5-carboxylate (41 mg, 0.16 mmol) and LiOH (39 mg, 1.6 mmol) in THF (3 mL) , MeOH (1 mL) and H2O (1 mL) was stirred for 2 h. at 60 ℃. The reaction mixture was adjusted pH to 5-6 with aq. HCl (1 N) . The solid was filtered, washed with H2O (5 mL) , and dried in vacuo to afford the title compound (24 mg, 67%yield) as a white solid. LCMS calc. for C10H10NO3S [M+H] +: m/z = 224.0; Found: 224.2.
Step 4: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-ethyl-6-hydroxythieno [2, 3-b] pyridine-5-carboxamide
To a mixture of 2-ethyl-6-hydroxythieno [2, 3-b] pyridine-5-carboxylic acid (24 mg, 0.11 mmol) , 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride (18 mg, 0.11 mmol) and DIPEA (69 mg, 0.54 mmol) in DMF (5 mL) was added HATU (61 mg, 0.16 mmol) at r.t. The reaction mixture was stirred at r.t. for 2 h., and concentrated under reduced pressure. The residue was purified by Prep-HPLC on a C18 column eluting with MeCN/H2O (5%-50%, with 0.1%NH4HCO3) to afford the title  product (12 mg, 33%yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.42 (s, 1H) , 10.19 (s, 1H) , 8.66 (s, 1H) , 7.27 (dd, J = 6.4, 1.6 Hz, 1H) , 7.06 (s, 1H) , 6.98 (dd, J = 6.4, 2.8 Hz, 1H) , 5.43 –5.33 (m, 1H) , 3.74 (dd, J = 13.6, 8.0 Hz, 1H) , 3.26 (dd, J = 13.6, 3.6 Hz, 1H) , 2.81 (q, J = 7.6 Hz, 2H) , 1.25 (t, J = 7.2 Hz, 3H) . LCMS calc. for C14H15N2O4S2 [M+H] +: m/z = 339.0; Found: 339.0.
Example 5: 2- (3, 4-Dimethylphenyl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
Step 1: tert-butyl (2-formylthiophen-3-yl) carbamate
To a solution of tert-butyl thiophen-3-ylcarbamate (5.0 g, 20.00 mmol) in THF (100 mL) was added n-butyl lithium (2.5 M in hexanes, 20 mL, 50 mmol) dropwise at -78 ℃ under nitrogen. After completion of addition, the reaction mixture was stirred at -78 ℃ for 1 h, and then DMF (2.8 g, 40 mmol) was added. The reaction mixture was stirred at ambient temperature until completion (～1 h. ) , and quenched with MeOH. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EA/PE (5%) to afford the title compound (4.5 g, 79%yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H) , 9.94 (d, J = 0.9 Hz, 1H) , 8.01 (dt, J = 5.4, 0.6 Hz, 1H) , 7.60 (d, J = 5.4 Hz, 1H) , 1.49 (s, 9H) . LCMS calc. for C10H14NO3S [M+H] +: m/z = 228.1; Found: 172.2 [M+H-56] +.
Step 2: ethyl 5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate and 5-oxo-4, 5-dihydro thieno [3, 2-b] pyridine-6-carboxylic acid
A mixture of tert-butyl (2-formylthiophen-3-yl) carbamate (4.5 g, 20 mmol) , diethyl malonate (6.4 g, 40 mmol) , EtONa (13.6 g, 200 mmol) and piperidine (1.7 g, 20 mmol) in EtOH (100 mL) was stirred at 85 ℃ for 2 h. under N2 atmosphere. The mixture was concentrated under reduced pressure. The residue was diluted with water and washed with DCM (100 mL x 3) . The organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with MeOH/DCM (5%) to afford ethyl 5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate (300 mg, 8%yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H) ,  8.65 (d, J = 0.7 Hz, 1H) , 8.12 (d, J = 5.4 Hz, 1H) , 7.04 –7.00 (m, 1H) , 4.23 (q, J = 7.1 Hz, 2H) , 1.28 (t, J = 7.1 Hz, 3H) . LCMS calc. for C10H10NO3S [M+H] +: m/z = 224.0; Found: 224.2.
The aqueous layer was adjusted pH to 4-5 with aq. HCl (6 N) . The precipitate was filtered and dried in vacuo to afford 5-oxo-4, 5-dihydro thieno [3, 2-b] pyridine-6-carboxylic acid (1.6 g) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 15.15 (s, 1H) , 9.05 (s, 1H) , 8.33 (d, J = 5.5 Hz, 1H) , 7.21 (d, J = 5.4 Hz, 1H) . LCMS calc. for C8H6NO3S [M+H] +: m/z = 196.0; Found: 196.1.
Step 3: ethyl 2-bromo-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate
A mixture of ethyl 5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate (150 mg, 0.67 mmol) and NBS (178 mg, 1.00 mmol) in MeCN (5 mL) was stirred at r.t. 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/PE (5%) to afford the title compound (40 mg, 20%yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H) , 8.84 (s, 1H) , 8.40 (s, 1H) , 4.31 (q, J = 7.1 Hz, 2H) , 1.31 (t, J = 7.1 Hz, 3H) . LCMS calc. for C10H9BrNO3S [M+H] +: m/z = 301.9; Found: 302.1.
Step 4: ethyl 2- (3, 4-dimethylphenyl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate
A mixture of ethyl 2-bromo-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate (35 mg, 0.2 mmol) , (3, 4-dimethylphenyl) boronic acid (60 mg, 0.4 mmol) , K3PO4 (127 mg, 0.6 mmol) and Pd (Ph3P) 4 (46 mg, 0.04 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred at 90 ℃ for 2 h.. The mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC eluting with PE/EA (35%) to afford the title compound (30 mg, 69%yield) as a yellow solid. LCMS calc. for C18H18NO3S [M+H] +: m/z = 328.1; Found: 328.3.
Step 5: 2- (3, 4-dimethylphenyl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
A mixture of ethyl 2- (3, 4-dimethylphenyl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate (30 mg, 0.1 mmol) and aq. NaOH (8 N, 2 mL) in EtOH (4 mL) was stirred at 80 ℃ for 1 h. under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (5 mL) , and adjusted to pH ～2 with aq. HCl (2 N) . The solid was collected by  filtration and dried in vacuo to afford the title compound (20 mg, 73%yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H) , 8.27 (s, 1H) , 7.35 (s, 1H) , 7.29 –7.23 (m, 2H) , 2.29 (d, J = 3.0 Hz, 6H) . LCMS calc. for C16H14NO3S [M+H] +: m/z = 300.1; Found: 300.2.
Step 6: 2- (3, 4-dimethylphenyl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
A mixture of 2- (3, 4-dimethylphenyl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid (20 mg, 0.10 mmol) , 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride (20 mg, 0.12 mmol) , HATU (76 mg, 0.20 mmol) and DIEA (39 mg, 0.30 mmol) in DMF (2 mL) was stirred at r.t. for 2 h. under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC on a C18 column eluting with MeCN/H2O (60%-65%, with 0.1%FA) to afford the title compound (4.82 mg, 22%yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H) , 10.26 (s, 1H) , 8.97 (s, 1H) , 8.12 (s, 1H) , 7.28 (d, J = 22.9 Hz, 4H) , 7.00 (s, 1H) , 5.39 (s, 1H) , 3.76 (d, J = 12.8 Hz, 1H) , 3.08 (s, 1H) , 2.28 (s, 6H) . LCMS calc. for C20H19N2O4S2 [M+H] +: m/z = 415.1; Found: 415.2.
Example 6: 7- (3, 4-Dimethylphenyl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
Step 1: tert-butyl (6-chloro-3-formylpyridin-2-yl) carbamate
To a cooled (-78 ℃) solution of tert-butyl (6-chloropyridin-2-yl) carbamate (5.0 g, 21.86 mmol) and 1, 2-bis (di-ethylamino) ethane (9.4 g, 54.66 mmol) in THF (80 mL) was added n-butyl lithium (2.5 M in hexane, 22 mL, 55.0 mmol) dropwise under nitrogen. After completion of addition of n-BuLi, the reaction mixture was slowly warmed to -10 ℃ and stirred at -10 ℃. for 2 h.. Then the mixture was re-cooled to -78 ℃. and DMF (3.2 g, 43.7 mmol) was added. The reaction mixture was warmed to ambient temperature and stirred until it was completed. The mixture was adjusted to pH 2-3 with aq. HCl (1N, 6 mL) at -10 ℃, and extracted with EtOAc (100 mL x 2) . The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (5%) to afford the title compound (1.3 g, 20%yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H) , 9.83 (s, 1H) , 8.20 (d, J = 8.0 Hz, 1H) , 7.43 (d, J = 8.0 Hz, 1H) , 1.46 (s, 9H) . LCMS calc. for C11H14ClN2O3 [M+H] +: m/z = 257.1; Found: 201.1 [M+H-56] +, 279.1 [M+Na] +.
Step 2: 2-amino-6- (3, 4-dimethylphenyl) nicotinaldehyde
A mixture of tert-butyl (6-chloro-3-formylpyridin-2-yl) carbamate (1 g, 4.0 mmol) , (3, 4-dimethylphenyl) boronic acid (1.2 g, 8.0 mmol) , K3PO4 (2.5 g, 12.0 mmol) and Pd (Ph3P) 4 (924 mg, 0.8 mmol) in dioxane (20 mL) and H2O (4 mL) was stirred at 90 ℃ overnight under N2. The reaction mixture was concentrated under reduced pressure. The residue was extracted with EtOAc (30 mL x 3) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (5%) to afford the title compound (800 mg, 82%yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H) , 8.05 (d, J = 8.0 Hz, 1H) , 7.92 (d, J = 1.9 Hz, 1H) , 7.83 (dd, J = 7.9, 2.0 Hz, 1H) , 7.61 (s, 2H) , 7.31 (d, J = 8.0 Hz, 1H) , 7.26 (d, J = 7.9 Hz, 1H) , 2.29 (d, J = 8.7 Hz, 6H) . LCMS calc. for C14H15N2O [M+H] +: m/z = 227.1; Found: 227.0.
Step 3: ethyl 7- (3, 4-dimethylphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxylate
A mixture of 2-amino-6- (3, 4-dimethylphenyl) nicotinaldehyde (700 mg, 3.10 mmol) , diethyl malonate (992 mg, 6.20 mmol) and piperidine (2.6 g, 31.0 mmol) in EtOH (25 mL) was stirred at 85 ℃ 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 EtOAc/PE (50%) to afford the title compound (600 mg, 60%yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H) , 8.51 (s, 1H) , 8.30 (d, J = 8.2 Hz, 1H) , 8.00 (d, J = 2.0 Hz, 1H) , 7.93 (dd, J = 7.9, 2.0 Hz, 1H) , 7.86 (d, J = 8.2 Hz, 1H) , 7.30 (d, J = 7.9 Hz, 1H) , 4.28 (q, J = 7.1 Hz, 2H) , 2.31 (d, J = 9.8 Hz, 6H) , 1.31 (t, J = 7.1 Hz, 3H) . LCMS calc. for C19H19N2O3 [M+H] +: m/z = 323.1; Found: 323.1.
Step 4: 7- (3, 4-dimethylphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxylic acid
A mixture of ethyl 7- (3, 4-dimethylphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (600 mg, 1.86 mmol) and aq. NaOH (8 N, 6 mL) in EtOH (20 mL) was stirred at 80 ℃ overnight under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) , and adjusted to pH ～6 with aq. HCl (2 N) . The solid was filtered and dried in vacuo to afford the title compound (530 mg, 97%yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 14.49 (s, 1H) , 13.48 (s, 1H) , 8.96 (s, 1H) , 8.51 (d, J = 8.4 Hz, 1H) , 8.07 –8.02 (m,  2H) , 7.98 (dd, J = 7.9, 2.0 Hz, 1H) , 7.33 (d, J = 7.9 Hz, 1H) , 2.32 (d, J = 9.8 Hz, 6H) . LCMS calc. for C17H15N2O3 [M+H] +: m/z = 295.1; Found: 295.3.
Step 5: 7- (3, 4-dimethylphenyl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxamide
This compound was prepared by the procedure analogous to that described for Example 1 Step 7 using 7- (3, 4-dimethylphenyl) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxylic acid and 3-amino-2,3-dihydrothiophene 1, 1-dioxide hydrochloride to afford title product as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H) , 10.10 (d, J = 7.9 Hz, 1H) , 8.88 (s, 1H) , 8.45 (d, J = 8.3 Hz, 1H) , 8.06 –8.02 (m, 1H) , 7.96 (dd, J = 8.2, 2.8 Hz, 2H) , 7.35 –7.27 (m, 2H) , 7.00 (dd, J = 6.6, 3.0 Hz, 1H) , 5.49 –5.36 (m, 1H) , 3.76 (dd, J = 13.8, 7.9 Hz, 1H) , 3.30 (d, J = 4.1 Hz, 1H) , 2.33 (s, 3H) , 2.30 (s, 3H) . LCMS calc. for C21H20N3O4S [M+H] +: m/z = 410.1; Found: 410.1.
Example 7: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
Step 1: ethyl 5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate
A mixture of ethyl 2-bromo-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate (90 mg, 0.299 mmol, Example 5 Step 3) , phenylboronic acid (55 mg, 0.449 mmol) , Cs2CO3 (292 mg, 0.897 mmol) , Pd (PPh3) 4 (17 mg, 0.015 mmol) in toluene (1 mL) and H2O (0.2 mL) was stirred at 85 ℃overnight under N2. Then the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc. 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 (0-50%) afford the title product (33 mg, 36.9 %yield) as a yellow solid. LCMS calc. for C16H14NO3S [M+H] +: m/z =300.1; Found: 300.0.
Step 2: 5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
A mixture of ethyl 5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate (33 mg, 0.11 mmol) , LiOH (13 mg, 0.33 mmol) in THF (2 mL) and H2O (0.2 mL) was stirred at 40 ℃ for 2 h.. The reaction mixture was diluted with H2O (1 mL) and adjusted to pH～2 with aq. HCl (1 M) . The  precipitate was filtered and dried in vacuo to afford the title product (25 mg, 83.6%yield) as a white solid. LCMS calc. for C14H10NO3S [M+H] +: m/z =272.0; Found: 272.2.
Step 3: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H) , 10.55 (s, 1H) , 8.93 (s, 1H) , 8.18 (s, 1H) , 7.61 (d, J = 6.8 Hz, 2H) , 7.51-7.47 (m, 2H) , 7.44-7.40 (m, 1H) , 7.27-7.25 (m, 1H) , 7.01-6.98 (m, 1H) , 5.40-5.38 (m, 1H) , 3.78-3.73 (m, 1H) , 3.29 –3.24 (m, 1H) . LCMS calc. for C18H15N2O4S2 [M+H] +: m/z = 387.0; Found: 387.2.
Example 8: 2- (Cyclohex-1-en-1-yl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
Step 1. ethyl 2- (cyclohex-1-en-1-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate
A mixture of ethyl 2-bromo-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate (100 mg, 0.33 mmol, Example 5 Step 3) , 2- (cyclohex-1-en-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (89.54 mg, 0.43 mmol) , K2CO3 (114.0 mg, 0.83 mmol) and Pd (dppf) Cl2 (24.15 mg, 0.033 mmol) in 1, 4-dioxane (9 mL) and H2O (1 mL) was stirred at 90 ℃ for 2 h. under N2. The reaction mixture was quenched with H2O and extracted with EtOAc (15 mL x 3) . The combined organic layers were washed with sat. aq. NH4Cl and brine, 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 (0-25%) to afford the title product (100 mg, 80 %yield) as a yellow solid. LCMS calc. for C16H18NO3S [M+H] +: m/z = 304.1; Found: 304.1.
Step 2: 2- (cyclohex-1-en-1-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
A mixture of ethyl 2- (cyclohex-1-en-1-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate (80 mg, 0.26 mmol) and NaOH (31.2 mg, 0.78 mmol) in MeOH (0.8 mL) , THF (0.4 mL) and H2O (0.2 mL) was stirred at r.t. overnight. The reaction mixture was concentrated under reduced pressure, then ice water (1 mL) was added. The mixture was adjusted to pH ～1 with aq. HCl (1 N) .  The precipitate formed was collected and washed with water (2 mL) , cold diethyl ether (2 mL) and hexane (5 mL) to afford the title product (52 mg, 72.2%yield) as a yellow solid. LCMS calc. for C14H14NO3S [M+H] +: m/z = 276.1; Found: 276.2.
Step 3. 2- (cyclohex-1-en-1-yl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 2- (cyclohex-1-en-1-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title product as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.20 (d, J = 7.6 Hz, 1H) , 9.54 (s, 1H) , 8.92 (s, 1H) , 7.57 (s, 1H) , 6.81-6.79 (m, 2H) , 6.00-5.98 (m, 1H) , 5.59-5.57 (m, 1H) , 3.80 (dd, J = 13.8, 8.0 Hz, 1H) , 3.24 (dd, J = 13.8, 4.7 Hz, 1H) , 2.35-2.33 (m, 2H) , 2.29 –2.27 (m, 2H) , 1.84-1.82 (m, 2H) , 1.74-1.72 (m, 2H) . LCMS calc. for C18H19N2O4S2 [M+H] +: m/z = 391.1; Found: 391.2.
Example 9: 2-Cyclohexyl-N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
Step 1: 2-cyclohexyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
To a solution of 2- (cyclohex-1-en-1-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid (27 mg, 0.098 mmol, Example 8 Step 2) in MeOH (2 mL) was added Pd/C (31.1 mg, 10 %wet) . The mixture was stirred at r.t. for 1 h. under H2 atmosphere. Then the reaction mixture was filtered and concentrated under reduced pressure to afford the crude product (20 mg) which was used in the next step without further purification. LCMS calc. for C14H16NO3S [M+H] +: m/z = 278.1; Found: 278.2.
Step 2: 2-cyclohexyl-N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 2-cyclohexyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title product as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.15 (d, J = 7.2 Hz, 1H) , 9.94 (s, 1H) , 8.94 (s, 1H) , 7.51 (s, 1H) , 6.81-6.79 (m, 2H) , 5.59-5.57 (m, 1H) , 3.81-3.79 (m, 1H) , 3.25-3.23 (m, 1H) , 2.68-2.65 (m, 1H) , 2.01-1.99 (m, 2H) , 1.91- 1.89 (m, 2H) , 1.83-1.81 (m, 2H) , 1.50-1.38 (m, 4H) . LCMS calc. for C18H21N2O4S2 [M+H] +: m/z =393.1; Found: 393.3.
Example 10: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-2- (prop-1-en-2-yl) -4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
Step 1: 5-oxo-2- (prop-1-en-2-yl) -4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
This compound was prepared by procedures analogous to those described for Example 8 Step 1-2 using 2-bromo-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate (Example 5 Step 3) and 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane in Step 1 to afford the title product as a yellow solid. LCMS calc. for C11H10NO3S [M+H] +: m/z = 236.0; Found: 236.2.
Step 2: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-2- (prop-1-en-2-yl) -4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 5-oxo-2- (prop-1-en-2-yl) -4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H) , 10.32 (s, 1H) , 8.93 (s, 1H) , 8.07 (s, 1H) , 7.28-7.25 (m, 1H) , 7.00-6.98 (m, 1H) , 5.39 –5.31 (m, 2H) , 3.77-3.72 (m, 1H) , 3.28-3.26 (m, 1H) , 2.10 (s, 3H) . LCMS calc. for C15H15N2O4S2 [M+H] +: m/z = 351.0; Found: 351.2.
Example 11: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -2-isopropyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
Step 1: 2-isopropyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
This compound was prepared by procedures analogous to those described for Example 9 Step 1 using 5-oxo-2- (prop-1-en-2-yl) -4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid (Example 10  Step 1) to afford the title product as a yellow solid. LCMS calc. for C11H12NO3S [M+H] +: m/z = 238.0; Found: 238.2.
Step 2: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-isopropyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 2-isopropyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H) , 10.33 (d, J = 7.6 Hz, 1H) , 8.91 (s, 1H) , 7.91 (s, 1H) , 7.27 (dd, J = 6.6, 2.0 Hz, 1H) , 7.00 (dd, J = 6.6, 3.0 Hz, 1H) , 5.39-5.36 (m, 1H) , 3.78-3.71 (m, 1H) , 3.20-3.08 (m, 1H) , 2.03-1.99 (m, 1H) , 1.28-1.21 (m, 6H) . LCMS calc. for C15H17N2O4S2 [M+H] +: m/z = 353.1; Found: 353.2.
Example 12: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-2-vinyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
Step 1: 5-oxo-2-vinyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
This compound was prepared by procedures analogous to those described for Example 8 Step 1-2 using 2-bromo-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate (Example 5 Step 3) and 4, 4, 5, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolane in Step 1 to afford the title compound as a yellow solid. LCMS calc. for C10H8NO3S [M+H] +: m/z = 222.0; Found: 222.2.
Step 2: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -5-oxo-2-vinyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 5-oxo-2-vinyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H) , 10.27 (d, J = 6.8 Hz, 1H) , 8.95 (s, 1H) , 8.41 (s, 1H) , 7.28-7.26 (m, 1H) , 7.19-7.17 (m, 1H) , 7.01-6.99 (m, 1H) , 5.89 (d, J = 17.2 Hz, 1H) , 5.38 –5.34 (m, 2H) , 3.75-3.72 (m, 1H) , 3.29-3.27 (m, 1H) . LCMS calc. for C14H13N2O4S2 [M+H] +: m/z = 337.0; Found: 337.0.
Example 13: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -2-ethyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
Step 1: 2-ethyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
This compound was prepared by procedures analogous to those described for Example 9 Step 1 using 5-oxo-2-vinyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid (Example 12 Step 1) to afford the title product as a yellow solid. LCMS calc. for C10H9NO3S [M+H] +: m/z = 224.0; Found: 224.2.
Step 2: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-ethyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 2-ethyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H) , 10.33 (d, J = 7.8 Hz, 1H) , 8.91 (s, 1H) , 7.88 (s, 1H) , 7.27 (dd, J = 6.6, 2.0 Hz, 1H) , 7.00 (dd, J = 6.6, 3.0 Hz, 1H) , 5.38 (dd, J = 5.8, 3.6 Hz, 1H) , 3.75 (dd, J = 13.8, 7.8 Hz, 1H) , 3.28 (dd, J = 13.8, 4.2 Hz, 1H) , 2.75 (q, J = 7.4 Hz, 2H) , 1.20 (t, J = 7.4 Hz, 3H) . LCMS calc. for C14H15N2O4S2 [M+H] +: m/z = 339.0; Found: 339.0.
Example 14: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -3-methyl-5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
Step 1: methyl 3- ( (tert-butoxycarbonyl) amino) -4-methylthiophene-2-carboxylate
A mixture of methyl 3-amino-4-methylthiophene-2-carboxylate (6 g, 35.1 mmol) , TEA (10.6 g, 105.3 mmol) , di-tert-butyl dicarbonate (8.4 g, 38.6 mmol) and 4-dimethylaminopyridine (4.28 mg, 35.1 mmol) in DCM (60 mL) was stirred at 0 ℃ for 1 h.. Then the reaction mixture was stirred at r.t. overnight. The mixture was concentrated under reduced pressure. The reside was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -10%) to afford the title product (4.25 g, 45%) as an oil. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H) , 7.48 (d, J = 1.0 Hz, 1H) , 3.75  (s, 3H) , 2.06 (d, J = 0.8 Hz, 3H) , 1.43 (s, 9H) . LCMS calc. for C12H18NO4S [M+H] +: m/z = 272.1; Found: 216.2 [M+H-56] +.
Step 2: tert-butyl (2- (hydroxymethyl) -4-methylthiophen-3-yl) carbamate
To a solution of methyl 3- ( (tert-butoxycarbonyl) amino) -4-methylthiophene-2-carboxylate (4.4 g, 16.3 mmol) in THF (60 mL) was added LAH (17.9 mL, 17.9 mmol) at 0 ℃. After the mixture was stirred at 0 ℃ for 1 h., Na2SO4 .10H2O was added partwise and then Na2SO4 was added. The mixture was stirred for 30 min. and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford crude product (3.44 g, 87%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H) , 6.96 (d, J = 1.0 Hz, 1H) , 5.26 (t, J = 5.6 Hz, 1H) , 4.44 (d, J = 5.7 Hz, 2H) , 1.99 (s, 3H) , 1.45 (s, 9H) . LCMS calc. for C11H17NO3SNa [M+Na] +: m/z = 266.1; Found: 266.3 [M+Na] +.
Step 3: tert-butyl (2-formyl-4-methylthiophen-3-yl) carbamate
To a solution of tert-butyl (2- (hydroxymethyl) -4-methylthiophen-3-yl) carbamate (3.45 g, 14.2 mmol) in DCM (40 mL) was added Dess-martin (6.0 g, 14.2 mmol) at 0 ℃. The mixture was stirred at r.t. overnight, and filtered. The filtrate was concentrated under reduced pressure to afford the crude title product (3.2 g, 94%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 9.79 (d, J = 1.2 Hz, 1H) , 9.43 (s, 1H) , 7.73 –7.68 (m, 1H) , 2.09 (d, J = 1.2 Hz, 3H) , 1.46 (s, 9H) . LCMS calc. for C11H16NO3S [M+H] +: m/z = 242.1; Found: 186.1 [M+H-56] +.
Step 4: ethyl 3-methyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate
A solution of tert-butyl (2-formyl-4-methylthiophen-3-yl) carbamate (3.2 g, 13.3 mmol) , diethyl malonate (4.3 g, 26.6 mmol) , MeONa (2.2 g, 39.8 mmol) , piperidine (1.13 g, 13.3 mmol) in EtOH (40 mL) was stirred at 85 ℃ overnight. The mixture was filtered. The filter cake was stirred in MeOH (5 mL) for 10 min., filtered and concentrated under reduced pressure to afford the crude title product (1.2 g, 38%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H) , 8.63 (s, 1H) , 7.80 (s, 1H) , 4.24 (d, J = 6.8 Hz, 2H) , 2.28 (s, 3H) , 1.29 (t, J = 7.0 Hz, 3H) . LCMS calc. for C11H12NO3S [M+H] +: m/z = 238.1; Found: 238.1.
Step 5: ethyl 2-bromo-3-methyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate
To a solution of ethyl 3-methyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate (260 mg, 1.1 mmol) in DMF (3 mL) was added NBS (235 mg, 1.3 mmol) . The mixture was stirred at 85 ℃overnight. The mixture was filtered. The filter cake was washed by water, dried in vacuo to afford the crude product (110 mg, 32%yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H) , 8.65 (s, 1H) , 4.25 (s, 2H) , 2.26 (s, 3H) , 1.29 (t, J = 7.0 Hz, 3H) . LCMS calc. for C11H11NO3S [M+H] +: m/z = 315.9; Found: 316.1.
Step 6: ethyl 3-methyl-5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate
A solution of ethyl 2-bromo-3-methyl-5-oxo-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate (110 mg, 0.35 mmol) , phenylboronic acid (85 mg, 0.70 mmol) , Pd (dppf) Cl2 (57 mg, 0.07 mmol) and K2CO3 (145 mg, 1.05 mmol) in 1, 4-dioxane (5 mL) and H2O (0.5 mL) was stirred at 90 ℃ for 4 h. under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with EtOAc/PE (0 -70%) to afford the title product (80 mg, 73%yield) as a yellow solid. LCMS calc. for C17H16NO3S [M+H] +: m/z = 314.1; Found: 314.3.
Step 7: 3-methyl-5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid
A mixture of ethyl 3-methyl-5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylate (80 mg, 0.26 mmol) and LiOH (31 mg, 1.30 mmol) in THF (2 mL) , MeOH (2 mL) and H2O (0.5 mL) was stirred at r.t. overnight. The reaction mixture was adjusted pH to 5-6 with aq. HCl (1 N) . The precipitate was collected by filtration, washed with H2O and dried in vacuo to afford the title product (40 mg, 55%yield) as a white solid. LCMS calc. for C15H12NO3S [M+H] +: m/z = 286.0; Found: 286.2.
Step 8: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -3-methyl-5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxamide
This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 3-methyl-5-oxo-2-phenyl-4, 5-dihydrothieno [3, 2-b] pyridine-6-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title product as a yellow solid. 1H NMR  (400 MHz, DMSO-d6) δ 12.81 (s, 1H) , 10.33 (d, J = 7.8 Hz, 1H) , 8.94 (s, 1H) , 7.60 –7.51 (m, 5H) , 7.28 (dd, J = 6.6, 1.9 Hz, 1H) , 7.02 (dd, J = 6.6, 3.0 Hz, 1H) , 5.40 (s, 1H) , 3.76 (dd, J = 13.8, 7.8 Hz, 1H) , 3.28 (d, J = 4.2 Hz, 1H) , 2.37 (s, 3H) . LCMS calc. for C19H17N2O4S2 [M+H] +: m/z = 401.1; Found: 401.1.
Example 15: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -4-hydroxyquinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride and 4-hydroxyquinoline-3-carboxylic acid to afford the title compound (8.5 mg, 27.93%yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 12.53 (s, 1H) , 10.55 (d, J = 7.9 Hz, 1H) , 8.76 (s, 1H) , 8.25 (dd, J = 8.1, 1.0 Hz, 1H) , 7.80 –7.75 (m, 1H) , 7.71 (d, J = 7.9 Hz, 1H) , 7.52 –7.47 (m, 1H) , 7.27 (dd, J = 6.6, 1.9 Hz, 1H) , 7.00 (dd, J = 6.6, 3.1 Hz, 1H) , 5.44 –5.37 (m, 1H) , 3.75 (dd, J = 13.8, 7.9 Hz, 1H) , 3.26 (dd, J = 13.8, 3.9 Hz, 1H) . LCMS calc. for C14H13N2O4S [M+H] +: m/z =305.1; Found: 305.1.
Example 16: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-7- (prop-1-en-2-yl) -1, 2-dihydro quinoline-3-carboxamide
Step 1: diethyl 2- (4-bromo-2-nitrobenzylidene) malonate
A mixture of 4-bromo-2-nitrobenzaldehyde (1 g, 4.35 mmol) , diethyl malonate (696 mg, 4.35 mmol) , potassium carbonate (908 mg, 6.52 mmol) in acetic anhydride (10 mL) was stirred at 80 ℃for 4 h.. The reaction mixture was diluted with ice water, and extracted with DCM (50 mL x 3) . 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%) to afford the title compound (1.1 g, 68 %yield) as a yellow oil. LCMS calc. for C14H15BrNO6 [M+H] +: m/z = 372.0; Found: 372.1.
Step 2: ethyl 7-bromo-2-hydroxyquinoline-3-carboxylate
A solution of diethyl 2- (4-bromo-2-nitrobenzylidene) malonate (1 g, 2.68 mmol) in AcOH (13 mL) was added Fe powder (1.2 g, 21.4 mmol) . The mixture was stirred at 80 ℃ for 2 h., and filtered through a pad of celite. The filtrate was concentrated to obtain the title compound (530 mg, 67 %yield) as a white solid which was used in the next step without further purification. LCMS calc. for C12H11BrNO3 [M+H] +: m/z = 295.9; Found: 296.2.
Step 3: ethyl 2-hydroxy-7- (prop-1-en-2-yl) quinoline-3-carboxylate
A mixture of ethyl 7-bromo-2-hydroxyquinoline-3-carboxylate (530 mg, 1.8 mmol) , 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane (393 mg, 2.3 mmol) , K2CO3 (497 mg, 3.6 mmol) and [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (132 mg, 0.18 mmol) in dioxane (6 ml) and H2O (2 mL) was stirred at 100 ℃ overnight under N2. The reaction mixture was diluted with water and extracted with EtOAc (30 mL x 3) . 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 (5%) to afford the title compound (355 mg, 77 %yield) as a light yellow solid. LCMS calc. for C15H16NO3 [M+H] +: m/z = 258.1; Found: 257.8.
Step 4: 2-hydroxy-7- (prop-1-en-2-yl) quinoline-3-carboxylic acid
A mixture of ethyl 2-hydroxy-7- (prop-1-en-2-yl) quinoline-3-carboxylate (75 mg, 0.30 mmol) and aq. NaOH (0.75 mL, 6 M) in EtOH (2 mL) was stirred at 90 ℃ for 3 h.. The reaction mixture was concentrated under reduced pressure. The residue was cooled to 0 ℃, and adjusted to pH ～2 with aq. HCl (2 M) . The precipitate was collected and dried in vacuo to afford the title compound (60 mg, 87%yield) as an off-grey solid. LCMS calc. for C13H12NO3 [M+H] +: m/z = 230.1; Found: 229.6.
Step 5: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-7- (prop-1-en-2-yl) -1, 2-dihydroquinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 2-hydroxy-7- (prop-1-en-2-yl) quinoline-3-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to obtain the title product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H) , 10.19 (d, J = 8.0 Hz, 1H) , 8.85 (s, 1H) , 7.94 (d, J = 8.4 Hz, 1H) , 7.54 –7.48 (m, 2H) , 7.29 (dd, J = 6.4, 2.0 Hz, 1H) , 7.01 (dd, J = 6.4, 3.2 Hz, 1H) , 5.62 (s, 1H) , 5.41-5.39 (m, 1H) , 5.32 (s,  1H) , 3.76-3.74 (m, 1H) , 3.32-3.30 (m, 1H) , 2.15 (s, 3H) . LCMS calc. for C17H17N2O4S [M+H] +: m/z = 345.1; Found: 345.2.
Example 17: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -7-isopropyl-2-oxo-1, 2-dihydroquinoline-3-carboxamide
Step 1: ethyl 2-hydroxy-7-isopropylquinoline-3-carboxylate
This compound was prepared by procedures analogous to those described for Example 9 Step 1 using ethyl 2-hydroxy-7- (prop-1-en-2-yl) quinoline-3-carboxylate to afford the title product as a white solid. LCMS calc. for C15H18NO3 [M+H] +: m/z = 260.1; Found: 259.5.
Step 2: 2-hydroxy-7-isopropylquinoline-3-carboxylic acid
This compound was prepared by procedures analogous to those described for Example 16 Step 4 using ethyl 2-hydroxy-7-isopropylquinoline-3-carboxylate to get the title product as a white solid. LCMS calc. for C13H14NO3 [M+H] +: m/z = 232.1; Found: 231.6.
Step 3: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -7-isopropyl-2-oxo-1, 2-dihydroquinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 2-hydroxy-7-isopropylquinoline-3-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H) , 10.21 (d, J = 7.8 Hz, 1H) , 8.82 (s, 1H) , 7.89 (d, J = 8.2 Hz, 1H) , 7.29-7.23 (m, 3H) , 7.00 (dd, J = 6.6, 3.0 Hz, 1H) , 5.43-5.37 (m, 1H) , 3.75 (dd, J = 13.8, 7.8 Hz, 1H) , 3.28 (d, J = 4.0 Hz, 1H) , 3.00 (dt, J = 13.8, 6.8 Hz, 1H) , 1.24 (d, J = 6.8 Hz, 6H) . LCMS calc. for C17H19N2O4S [M+H] +: m/z = 347.1; Found: 347.2.
Example 18: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -4-oxo-1, 4-dihydropyrrolo [1, 2-b] pyridazine-3-carboxamide
Step 1: 4-oxo-1, 4-dihydropyrrolo [1, 2-b] pyridazine-3-carboxylic acid
A mixture of ethyl 4-oxo-1, 4-dihydropyrrolo [1, 2-b] pyridazine-3-carboxylate (824 mg, 4.0 mmol) in aq. NaOH (8 N, 3 mL) and EtOH (10 mL) was stirred at 80 ℃ for 6 h.. The resulting mixture was concentrated and diluted with water (10 mL) . The mixture was adjusted pH to 6 with aq. HCl (1N) , the precipitate was collected by filtration to afford the title compound (700 mg, 92%yield) as a gray solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H) , 7.91 (dd, J = 2.6, 1.5 Hz, 1H) , 6.91 (dd, J = 4.4, 1.6 Hz, 1H) , 6.81 (dd, J = 4.4, 2.6 Hz, 1H) . LCMS calc. for C8H7N2O3 [M+H] +: m/z = 179.0; Found: 179.0.
Step 2: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -4-oxo-1, 4-dihydropyrrolo [1, 2-b] pyridazine-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 5 Step 6 using 4-oxo-1, 4-dihydropyrrolo [1, 2-b] pyridazine-3-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to afford the title product as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H) , 8.50 (s, 1H) , 7.87 (s, 1H) , 7.31 (dd, J = 6.8, 2.2 Hz, 1H) , 6.96 (dd, J = 6.8, 2.8 Hz, 1H) , 6.88 (dd, J = 4.2, 1.4 Hz, 1H) , 6.80-6.79 (dd, J = 4.2, 2.6 Hz, 1H) , 5.45-5.42 (m, 1H) , 3.84-3.80 (m, 1H) , 3.30-3.26 (m, 1H) . LCMS calc. for C12H12N3O4S [M+H] +: m/z = 294.0; Found: 294.3.
Example 20: 2- (3, 4-Dimethylphenyl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -7-hydroxythiazolo [4, 5-c] pyridine-6-carboxamide
Step 1: ethyl (2, 4-dimethoxybenzyl) glycinate
A mixture of (2, 4-dimethoxyphenyl) methanamine (20 g, 119.6 mmol) , ethyl 2-bromoacetate (20 g, 119.61 mmol) and TEA (12.1 g, 119.6 mmol) in DCM (200 mL) was stirred at r.t. overnight. Then the reaction mixture was quenched with water, and extracted with DCM (200 mL x 3) . 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 (3 %) to afford  the title compound (19 g, 63 %yield) as a yellow oil. LCMS calc. for C13H20NO4 [M+H] +: m/z = 254.1, Found: 254.2.
Step 2: ethyl 2-bromo-4- (bromomethyl) thiazole-5-carboxylate
To a solution of ethyl 2-bromo-4-methylthiazole-5-carboxylate (6.0 g, 24.00 mmol) in CCl4 (80 mL) was added NBS (4.6 g, 26.4 mmol) and BPO (1.2 mg, 4.8 mmol) . The reaction mixture was stirred at 80 ℃ for 5 h., quenched with water and extracted with DCM (200 mL x 3) . The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude title compound (6.2 g) as a yellow oil which was used directly in the next step. LCMS calc. for C7H8Br2NO2S [M+H] +: m/z = 327.8, Found: 327.6
Step 3: ethyl 2-bromo-4- ( ( (2, 4-dimethoxybenzyl) (2-ethoxy-2-oxoethyl) amino) methyl) thiazole-5-carboxylate
A mixture of ethyl 2-bromo-4- (bromomethyl) thiazole-5-carboxylate (6.5 g, 19.7 mmol) , ethyl (2, 4-dimethoxybenzyl) glycinate (5.0 g, 19.7 mmol) and K2CO3 (5.5 g, 39.5 mmol) in DMF (80 mL) was stirred at r.t overnight. Then the reaction mixture was quenched with water and extracted with DCM (200 mL x 3) . 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 (3 %) to afford the title compound (4.1 g, 41%yield) as a yellow oil. LCMS calc. for C20H26BrN2O6S [M+H] +: m/z = 501.1, Found: 500.6.
Step 4: ethyl 4- ( ( (2, 4-dimethoxybenzyl) (2-ethoxy-2-oxoethyl) amino) methyl) -2- (3, 4-dimethylphenyl) thiazole-5-carboxylate
A mixture of ethyl 2-bromo-4- ( ( (2, 4-dimethoxybenzyl) (2-ethoxy-2-oxoethyl) amino) methyl) thiazole-5-carboxylate (3.0 g, 6 mmol) , (3, 4-dimethylphenyl) boronic acid (1.8 g, 12 mmol) , Cs2CO3 (4.3 g, 13.2 mmol) and Pd (PPh3) 4 (1.04 g, 0.90 mmol) in dioxane (40 ml) was stirred at 100 ℃ overnight under N2. The reaction mixture was cooled and extracted with EtOAc (100 mL x 3) . 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 (5%) to afford the title compound (2.1 g, 67 %yield) as a yellow solid. LCMS calc. for C28H35N2O6S [M+H] +: m/z = 527.2, Found: 527.0.
Step 5: ethyl 5- (2, 4-dimethoxybenzyl) -2- (3, 4-dimethylphenyl) -7-oxo-4, 5, 6, 7-tetrahydrothiazolo [4, 5-c] pyridine-6-carboxylate
To a mixture of ethyl 4- ( ( (2, 4-dimethoxybenzyl) (2-ethoxy-2-oxoethyl) amino) methyl) -2- (3, 4-dimethylphenyl) thiazole-5-carboxylate (1 g, 1.9 mmol) in THF was added dropwise LiHMDS (3.8 mL, 3.8 mmol) at -78 ℃ and stirred for 1 h.. Then the reaction solution was quenched with water, extracted with EtOAc (50 mL x 3) . The combined organic layers were concentrated under reduced pressure. The residue was purified by Pre-HPLC on a C18 column eluting with MeCN/H2O (45 -70%, with 0.05%FA) to afford title product (700 mg, 77 %yield) as a white solid. LCMS calc. for C26H29N2O5S [M+H] +: m/z = 481.2; Found: 481.2.
Step 6: ethyl 2- (3, 4-dimethylphenyl) -7-oxo-6, 7-dihydrothiazolo [4, 5-c] pyridine-6-carboxylate
A mixture of ethyl 5- (2, 4-dimethoxybenzyl) -2- (3, 4-dimethylphenyl) -7-oxo-4, 5, 6, 7-tetrahydrothiazolo [4, 5-c] pyridine-6-carboxylate (700 mg, 1.45 mmol) in DCM (10 mL) was added SOCl2 (1.05 mL, 1.73g, 14.5 mmol) and stirred at r.t. for 1 h.. After completion, the reaction solution was concentrated under reduced pressure. The residue was purified by Pre-HPLC on a C18 column eluting with MeCN/H2O (45 -70%, with 0.05%FA) to afford the title product (420 mg, 78 %yield) as white solid. LCMS calc. for C17H17N2O3S [M+H] +: m/z = 329.1; Found: 329.2.
Step 7: 2- (3, 4-dimethylphenyl) -7-oxo-6, 7-dihydrothiazolo [4, 5-c] pyridine-6-carboxylic acid
A solution of ethyl 2- (3, 4-dimethylphenyl) -7-oxo-6, 7-dihydrothiazolo [4, 5-c] pyridine-6-carboxylate (100 mg, 0.3 mmol) in DCM (5 mL) was added BBr3 (1M in DCM, 1.2 mL) . The mixture was stirred at r.t overnight, quenched with MeOH, concentrated under reduced pressure. The residue was purified by Pre-HPLC on a C18 column eluting with MeCN/H2O (45 -70%, with 0.05%FA) to afford the title product (25 mg, 27 %yield) as white solid. LCMS calc. for C15H13N2O3S [M+H] +: m/z = 301.1; Found: 301.2.
Step 8: 2- (3, 4-dimethylphenyl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -7-hydroxythiazolo [4, 5-c] pyridine-6-carboxamide
A mixture of 2- (3, 4-dimethylphenyl) -7-oxo-6, 7-dihydrothiazolo [4, 5-c] pyridine-6-carboxylic acid (25 mg, 0.08 mmol) , 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride (11 mg, 0.10 mmol) , HATU (25 mg, 0.08 mmol) and K2CO3 (25 mg, 0.08 mmol) in DMF (2 mL) was stirred at r.t. for 1 h.. Then the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by Pre-HPLC on a C18 column eluting with MeCN/H2O (45 -70%, with 0.1%FA) to afford the title product (5 mg, 15 %yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H) , 9.87 (d, J = 8.0 Hz, 1H) , 8.89 (s, 1H) , 7.97 –7.92 (m, 1H) , 7.88 (dd, J = 7.8, 2.0 Hz, 1H) , 7.37 (d, J = 7.8 Hz, 1H) , 7.26 (dd, J = 6.7, 2.3 Hz, 1H) , 6.98 (dd, J = 6.7, 2.4 Hz, 1H) , 5.43 (ddp, J = 8.3, 6.0, 2.5 Hz, 1H) , 3.80 (dd, J = 13.4, 7.9 Hz, 1H) , 3.51 (dd, J = 13.6, 5.9 Hz, 1H) , 2.35 (s, 3H) , 2.32 (s, 3H) . LCMS calc. for C19H18N3O4S2 [M+H] +: m/z = 416.1; Found: 416.2.
Example 21: 7- (Cyclopent-1-en-1-yl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-hydroxyquinoline-3-carboxamide
Step 1: ethyl 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylate
A mixture of ethyl 7-bromo-2-hydroxyquinoline-3-carboxylate (400.0 mg, 1.35 mmol, Example 16 Step 2) , 2- (cyclopent-1-en-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (392.0 mg, 2.02 mmol) , Pd (dtbpf) Cl2 (130.0 mg, 0.2 mmol) and Cs2CO3 (1.3g, 4.0 mmol) in dixoane (7 mL) and H2O (1.4 mL) was stirred at 100℃ in MW tube for 2 h. under N2. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with DCM/MeOH (0-5%) to afford the title compound (200 mg, 52.2 %yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H) , 8.45 (s, 1H) , 7.75 (d, J = 8.3 Hz, 1H) , 7.44 (d, J = 8.3 Hz, 1H) ,  7.27 (s, 1H) , 6.50 (s, 1H) , 4.26 (q, J = 7.1 Hz, 2H) , 2.72 –2.64 (m, 2H) , 2.58 –2.53 (m, 2H) , 2.05 –1.94 (m, 2H) , 1.30 (t, J = 7.1 Hz, 3H) . LCMS calc. for C17H18NO3 [M+H] +: m/z =284.1; Found: 284.4. Step 2: 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylic acid
A mixture of ethyl 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylate (30.0 mg, 0.11 mmol) , LiOH. H2O (5.1 mg, 0.22 mmol) in THF (2 mL) and H2O (0.2 mL) was stirred at r.t. overnight. The reaction mixture diluted with DCM (20 mL) and adjusted pH to 2-3 with aq. HCl (2 N) . The mixture was extracted with DCM (20 mL x 3) , dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (18.0 mg, 64.1%yield) as a white solid. LCMS calc. for C15H14NO3 [M+H] +: m/z =256.1; Found: 256.0.
Step 3: 7- (cyclopent-1-en-1-yl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-hydroxyquinoline-3-carboxamide
A mixture of 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylic acid (9.0 mg, 0.035 mmol) , 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride (7.1 mg, 0.042 mmol) , HATU (19.9 mg, 0.053mmol) and DIPEA (15.8 mg, 0.12mmol) in DMF (1.5 mL) was stirred at r.t. overnight. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2) . The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC on a C18 column eluting with MeCN/H2O (30 -60%, with 10 mM NH4HCO3) to afford the title compound (3.2 mg, 24.6%yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H) , 10.19 (d, J = 7.9 Hz, 1H) , 8.82 (s, 1H) , 7.90 (d, J = 8.4 Hz, 1H) , 7.54 (d, J = 8.4 Hz, 1H) , 7.37 (s, 1H) , 7.28 (dd, J = 6.6, 1.9 Hz, 1H) , 7.00 (dd, J = 6.6, 3.0 Hz, 1H) , 6.55 (s, 1H) , 5.40 (s, 1H) , 3.75 (dd, J = 13.8, 7.9 Hz, 1H) , 3.31 –3.26 (m, 1H) , 2.78 –2.61 (m, 2H) , 2.59 –2.52 (m, 2H) , 2.06 –1.94 (m, 2H) . LCMS calc. for C19H19N2O4S [M+H] +: m/z =371.1; Found: 371.3.
Example 22: 7-Cyclopentyl-N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-hydroxyquinoline-3-carboxamide
Step 1: ethyl 7-cyclopentyl-2-hydroxyquinoline-3-carboxylate
To a solution of ethyl 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylate (100.0 mg, 0.35 mmol, Example 21 Step 1) in MeOH (7 mL) was added Pd/C (100.0 mg, 10%wet) . The resulting mixture was charged with H2 and stirred at r.t. for 2 h.. The reaction mixture was diluted with MeOH (20 mL) and stirred for 10 min.. The mixture was filtered by a pad of celite. The filtrate was concentrated under reduced pressure to give the title compound (70 mg, 70.2 %yield) as a yellow solid. LCMS calc. for C17H20NO3 [M+H] +: m/z =286.1; Found: 286.1.
Step 2: 7-cyclopentyl-N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-hydroxyquinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 21 Step 2-3 using ethyl 7-cyclopentyl-2-hydroxyquinoline-3-carboxylate to replace ethyl 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylate in Step 2 to afford the title product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H) , 10.20 (d, J = 7.9 Hz, 1H) , 8.82 (s, 1H) , 7.87 (d, J = 8.3 Hz, 1H) , 7.30 (s, 1H) , 7.28 (dd, J = 6.7, 1.9 Hz, 1H) , 7.23 (dd, J = 8.3, 1.2 Hz, 1H) , 7.00 (dd, J = 6.6, 3.0 Hz, 1H) , 5.39 (d, J = 4.2 Hz, 1H) , 3.75 (dd, J = 13.8, 7.9 Hz, 1H) , 3.31 –3.26 (m, 1H) , 3.15 –3.02 (m, 1H) , 2.11 –2.00 (m, 2H) , 1.85 –1.73 (m, 2H) , 1.73 –1.63 (m, 2H) , 1.63 –1.46 (m, 2H) . LCMS calc. for C19H21N2O4S [M+H] +: m/z =373.1; Found: 373.4.
Example 23: 7- (Dimethylamino) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-methoxyquinoline-3-carboxamide
Step 1: ethyl 7-bromo-2-chloroquinoline-3-carboxylate
A mixture of ethyl 7-bromo-2-hydroxyquinoline-3-carboxylate (5.0g, 16.8 mmol, Example 16 Step 2) and POCl3 (40 mL) was stirred at 80℃ for 2 h. under N2. The mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and adjusted pH to 7-8 with aq. NaHCO3. The mixture was extracted with EtOAc (50 mL x 2) . The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (5.1 g, 96.4%yield) as a yellow solid. LCMS calc. for C12H10BrClNO2 [M+H] +: m/z =314.0; Found: 314.0.
Step 2: methyl 7-bromo-2-methoxyquinoline-3-carboxylate
To a solution of ethyl 7-bromo-2-chloroquinoline-3-carboxylate (5.1 g, 16.20 mmol) in MeOH (70 mL) was added NaOMe (30 wt. %in MeOH, 8.5 mL) dropwise at r.t.. The reaction mixture was stirred at 70 ℃ for 2 h. under N2. After cooling to temperature. t., the reaction mixture was quenched with water (100 mL) , and extracted with DCM (100 mL x 3) The 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 PE/EA (5%) to afford the title compound (2.5 g, 52.4 %yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H) , 8.09 –7.92 (m, 2H) , 7.67 (dd, J = 8.6, 1.9 Hz, 1H) , 4.04 (s, 3H) , 3.87 (s, 3H) . LCMS calc. for C12H11BrNO3 [M+H] +: m/z =296.1; Found: 296.1.
Step 3: methyl 7- (dimethylamino) -2-methoxyquinoline-3-carboxylate
A mixture of methyl 7-bromo-2-methoxyquinoline-3-carboxylate (250 mg, 0.85 mmol) , dimethylamine hydrochloride (145.2 mg, 1.27 mmol) , Pd2 (dba) 3 (77.8 mg, 0.085 mmol) , X-phos (80.9 mg, 0.17 mmol) and Cs2CO3 (830.8 mg, 2.55 mmol) in dioxane (6 mL) was stirred at 100℃ for 18 h. under N2. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with PE/EA (10%) to afford the title compound (200 mg, 52.2 %yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H) , 7.79 (d, J = 9.1 Hz, 1H) , 7.10 (dd, J = 9.1, 2.5 Hz, 1H) , 6.76 (d, J = 2.3 Hz, 1H) , 3.97 (s, 3H) , 3.81 (s, 3H) , 3.09 (s, 6H) . LCMS calc. for C14H17N2O3 [M+H] +: m/z =261.1; Found: 261.0.
Step 4: 7- (dimethylamino) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-methoxyquinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 21 Step 2-3 using methyl 7- (dimethylamino) -2-methoxyquinoline-3-carboxylate to replace ethyl 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylate in step 2 to afford the title product as a white solid. LCMS calc. for C17H20N3O4S [M+H] +: m/z =362.1; Found: 362.4.
Example 24: 7- (Dimethylamino) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-hydroxyquinoline-3-carboxamide
A mixture of 7- (dimethylamino) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-methoxyquinoline-3-carboxamide (60.0 mg, 0.17 mmol, Example 23) in aq. HCl (6 N, 3.0 mL) was  stirred at 90 ℃ for 3 h.. The solid formed was collected by filtration and the filter cake was washed with water (5 mL x 2) and sat. aq. NaHCO3 (5 mL) . The solid was re-stirred in MeOH (5 mL) for 15 min. and filtered. The filter cake was dried in vacuo to afford the title compound (28.4 mg, 48.0%yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H) , 10.24 (d, J = 6.5 Hz, 1H) , 8.60 (s, 1H) , 7.68 (d, J = 9.0 Hz, 1H) , 7.25 (dd, J = 6.6, 1.9 Hz, 1H) , 6.98 (dd, J = 6.6, 3.0 Hz, 1H) , 6.80 (dd, J = 9.0, 2.3 Hz, 1H) , 6.49 (d, J = 2.1 Hz, 1H) , 5.37 (s, 1H) , 3.73 (dd, J = 13.8, 7.9 Hz, 1H) , 3.24 (dd, J = 13.8, 4.0 Hz, 1H) , 3.04 (s, 6H) . LCMS calc. for C16H18N3O4S [M+H] +: m/z =348.1; Found: 348.3.
Example 25: 7-Bromo-N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-methoxyquinoline-3-carboxamide
Step 1: 7-bromo-2-methoxyquinoline-3-carboxylic acid
To a solution of ethyl 7-bromo-2-chloroquinoline-3-carboxylate (610.0 mg, 1.94 mmol, Example 23 Step 1) in MeOH (12 mL) was added CH3ONa (30 wt. %in MeOH, 1.4 mL) dropwise. The reaction mixture was stirred at 70℃ for 2 h. under N2. After cooling to temperature. t., and quenched with water (40 mL) . The mixture was washed with DCM (50 mL) . The aqueous layer was adjusted to pH 2-3 with aq. HCl (2 N) , Tand extracted with DCM (50 mL x 3) . The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (100.1 mg, 18.6 %yield) as a white solid. LCMS calc. for C11H9BrNO3 [M+H] +: m/z =282.0; Found: 282.1.
Step 2: 7-bromo-N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-methoxyquinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 21 Step 3 using 7-bromo-2-methoxyquinoline-3-carboxylic acid to replace 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylic acid to afford the title product as a white solid. LCMS calc. for C15H14BrN2O4S [M+H] +: m/z =397.0; Found: 397.2.
Example 26: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -6-isopropyl-2-methoxyquinoline-3-carboxamide
Step 1: methyl 6-bromo-2-hydroxyquinoline-3-carboxylate
To a solution of 2-amino-5-bromobenzaldehyde (5 g, 25 mmol) in EtOH (80 mL) were added piperidine (8.5 g, 100 mmol) , AcOH (1 mL) and dimethyl malonate (13.2 g, 100 mmol) at r.t.. The mixture was stirred at 80 ℃ for 4 h.. The reaction mixture was filtered. The filter cake was washed with EtOH and dried in vacuo to give the title compound (6.6 g, 93%yield) as a yellow solid. LCMS calc. for C11H9BrNO3 [M+H] +: m/z = 281.9; Found: 281.9.
Step 2: methyl 6-bromo-2-chloroquinoline-3-carboxylate
This compound was prepared by procedures analogous to those described for Example 23 Step 1 using methyl 6-bromo-2-hydroxyquinoline-3-carboxylate to replace ethyl 7-bromo-2-hydroxyquinoline-3-carboxylate to afford the title product as a light yellow solid. LCMS calc. for C11H8BrClNO2 [M+H] +: m/z = 299.9; Found: 299.9.
Step 3: 6-bromo-2-methoxyquinoline-3-carboxylic acid
This compound was prepared by procedures analogous to those described for Example 25 Step 1 using methyl 6-bromo-2-chloroquinoline-3-carboxylate to replace ethyl 7-bromo-2-chloroquinoline-3-carboxylate to afford the title product as a white solid. LCMS calc. for C11H9BrNO3 [M+H] +: m/z = 281.9; Found: 281.9.
Step 4: 2-methoxy-6- (prop-1-en-2-yl) quinoline-3-carboxylic acid
A mixture of 6-bromo-2-methoxyquinoline-3-carboxylic acid (110 mg, 0.39 mmol) , 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane (328 mg, 1.95 mmol) , Pd (dppf) Cl2 (29 mg, 0.039 mmol) and K2CO3 (161 mg, 1.17 mmol) in 1, 4-dioxane (2.5 mL) and water (0.5 mL) was stirred in MW tube at 100 ℃ for 2 h. under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EA (20 mL) and washed with water (15 mL x 3) . The aqueous phase was adjusted to pH 2 –3 with aq. HCl (1 M) and extracted with EA (20 mL x 3) . The  combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (94 mg, 99%yield) as a yellow solid. LCMS calc. for C14H14NO3 [M+H] +: m/z = 244.1; Found: 244.0.
Step 5: 6-isopropyl-2-methoxyquinoline-3-carboxylic acid
To a solution of 2-methoxy-6- (prop-1-en-2-yl) quinoline-3-carboxylic acid (73 mg, 0.3 mmol) in EA (3 mL) was added Pd/C (20 mg, 10%wet) . The resulting mixture was charged with H2 and stirred at r.t. for 16 h. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford the title compound (66 g, 85%yield) as a yellow solid. LCMS calc. for C14H16NO3 [M+H] +: m/z = 246.1; Found: 246.0.
Step 6: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -6-isopropyl-2-methoxyquinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 21 Step 3 using 6-isopropyl-2-methoxyquinoline-3-carboxylic acid to replace 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylic acid to afford the title product as a white solid. LCMS calc. for C18H21N2O4S [M+H] +: m/z = 361.1; Found: 361.1.
Example 27: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -2-hydroxy-6-isopropylquinoline-3-carboxamide
A suspension of N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -6-isopropyl-2-methoxyquinoline-3-carboxamide (60 mg, 0.167 mmol, Example 26 Step 6) in aq. HCl (6 M, 4 mL) was stirred at 90 ℃ for 3 h.. The precipitation was filtered and the filter cake was washed with water. The crude product was purified by Prep-HPLC on a C18 column eluting with MeCN/H2O (0%-100%, with 0.1%FA) to afford the title compound (15.7 mg, 27%yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 12.45 (s, 1H) , 10.25 (d, J = 7.9 Hz, 1H) , 8.83 (s, 1H) , 7.82 (d, J = 1.8 Hz, 1H) , 7.61 (dd, J = 8.6, 1.9 Hz, 1H) , 7.38 (d, J = 8.6 Hz, 1H) , 7.28 (dd, J = 6.6, 1.9 Hz, 1H) , 7.01 (dd, J = 6.6, 3.0 Hz, 1H) , 5.45 –5.36 (m, 1H) , 3.75 (dd, J = 13.8, 7.9 Hz, 1H) , 3.29 (t, J = 3.7 Hz, 1H) , 2.97 (dt, J = 13.7, 6.9 Hz, 1H) , 1.24 (d, J = 6.9 Hz, 6H) . LCMS calc. for C17H19N2O4S [M+H] +: m/z = 347.1; Found: 347.0.
Example 28: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -2, 6-dimethoxyquinoline-3-carboxamide
Step 1: 2-amino-5-methoxybenzaldehyde
To a solution of 5-methoxy-2-nitrobenzaldehyde (2 g, 11.05 mmol) in MeOH (40 mL) was added Pd/C (500 mg, 10%wet) . The mixture was charged with H2 and stirred at 35 ℃ for 2 h. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford the title compound (1.7 g crude) as a brown oil. LCMS calc. for C8H10NO2 [M+H] +: m/z = 152.1; Found: 152.1.
Step 2: methyl 2-hydroxy-6-methoxyquinoline-3-carboxylate
To a solution of 2-amino-5-methoxybenzaldehyde (1.7 g crude, 11.05 mmol) in EtOH (40 mL) were added piperidine (3.76 g, 44.2 mmol) , AcOH (0.5 mL) and dimethyl malonate (5.83 g, 44.2 mmol) at r.t.. The mixture was stirred at 80 ℃ for 4 h.. The precipitation was filtered. The filter cake was washed with EtOH and dried in vacuo to give the title compound (820 mg, 32%yield) as a yellow solid. LCMS calc. for C12H12NO4 [M+H] +: m/z = 234.1; Found: 234.0.
Step 3: methyl 2-chloro-6-methoxyquinoline-3-carboxylate
This compound was prepared by procedures analogous to those described for Example 23 Step 1 using methyl 2-hydroxy-6-methoxyquinoline-3-carboxylate to replace ethyl 7-bromo-2-hydroxyquinoline-3-carboxylate to afford the title product as a light yellow solid. LCMS calc. for C12H11ClNO3 [M+H] +: m/z = 252.0; Found: 252.0.
Step 4: 2, 6-dimethoxyquinoline-3-carboxylic acid
This compound was prepared by procedures analogous to those described for Example 25 Step 1 using methyl 2-chloro-6-methoxyquinoline-3-carboxylate to replace ethyl 7-bromo-2-chloroquinoline-3-carboxylate to afford the title product as a white solid. LCMS calc. for C12H12NO4 [M+H] +: m/z = 234.1; Found: 234.0.
Step 5: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2, 6-dimethoxyquinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 21 Step 3 using 2, 6-dimethoxyquinoline-3-carboxylic acid to replace 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylic acid to afford the title product as a white solid. LCMS calc. for C16H17N2O5S [M+H] +: m/z = 349.1; Found: 349.0.
Example 29: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-hydroxy-6-methoxyquinoline-3-carboxamide
A suspension of N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2, 6-dimethoxyquinoline-3-carboxamide (78 mg, 0.224 mmol) in aq. HCl (6 M, 4 mL) was stirred at 90 ℃ for 3 h. The precipitation was filtered and the filter cake was washed with water. The crude product was washed with MeOH to afford the title compound (27.1 mg, 36%yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 12.47 (s, 1H) , 10.32 (d, J = 7.9 Hz, 1H) , 8.83 (s, 1H) , 7.53 (d, J = 2.6 Hz, 1H) , 7.39 (d, J = 9.0 Hz, 1H) , 7.34 (dd, J = 9.0, 2.7 Hz, 1H) , 7.29 (dd, J = 6.6, 1.9 Hz, 1H) , 7.01 (dd, J = 6.6, 3.0 Hz, 1H) , 5.45 –5.36 (m, 1H) , 3.81 (s, 3H) , 3.76 (dd, J = 13.8, 7.9 Hz, 1H) , 3.32 –3.27 (m, 1H) . LCMS calc. for C15H15N2O5S [M+H] +: m/z = 335.1; Found: 335.0.
Example 30: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -2-hydroxy-6- (prop-1-en-2-yl) quinoline-3-carboxamide
Step 1: methyl 2-hydroxy-6- (prop-1-en-2-yl) quinoline-3-carboxylate
A mixture of methyl 6-bromo-2-hydroxyquinoline-3-carboxylate (120 mg, 0.43 mmol, Example 26 Step 1) , 4, 4, 5, 5-tetramethyl-2- (prop-1-en-2-yl) -1, 3, 2-dioxaborolane (361.2 mg, 2.15 mmol) , Pd (dppf) Cl2 (31.4 mg, 0.043 mmol) and K2CO3 (178 mg, 1.29 mmol) in 1, 4-dioxane (3 mL) and water (0.6 mL) was stirred at 100 ℃ for 16 h. under N2 atmosphere. The reaction mixture was filtered and  the filtrate was concentrated under reduced pressure. The residue was diluted with EA (20 mL) and washed with water (15 mL x 3) . The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound (60 mg, 57.1 %yield) as a yellow oil. LCMS calc. for C14H14NO3 [M+H] +: m/z = 244.1; Found: 244.0.
Step 2: 2-hydroxy-6- (prop-1-en-2-yl) quinoline-3-carboxylic acid
To a solution of methyl 2-hydroxy-6- (prop-1-en-2-yl) quinoline-3-carboxylate (60.0 mg, 0.26 mmol) in THF (5 mL) and H2O (0.5 mL) was added LiOH. H2O (20.8 mg, 0.52 mmol) . The mixture was stirred at r.t. for 1h. The reaction mixture was diluted with DCM (5 mL) and adjusted pH to 2-3 with aq. HCl (2 N) . The mixture was extracted with DCM (5 mL x 3) and dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (25.0 mg, 42.0 %yield) as a yellow solid. LCMS calc. for C13H12NO3 [M+H] +: m/z =230.0; Found: 230.0. Step 3: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-methoxy-6- (prop-1-en-2-yl) quinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 21 Step 3 using 2-hydroxy-6- (prop-1-en-2-yl) quinoline-3-carboxylic acid to replace 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylic acid to afford the title product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H) , 10.19 (d, J = 7.8 Hz, 1H) , 8.90 (s, 1H) , 8.10 (d, J = 1.8 Hz, 1H) , 7.90 (dd, J = 8.8, 2.0 Hz, 1H) , 7.41 (d, J = 8.8 Hz, 1H) , 7.29 (dd, J = 6.6, 1.8 Hz, 1H) , 7.01 (dd, J = 6.6, 3.0 Hz , 1H) , 5.52 (s, 1H) , 5.41 (s, 1H) , 5.16 (s, 1H) , 3.76 (dd, J = 13.8, 7.8 Hz, 1H) , 3.29 (d, J = 3.8 Hz, 1H) 2.12 (s, 3H) . LCMS calc. for C17H17N2O4S [M+H] +: m/z =345.1; Found: 345.0.
Example 31: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -2-methoxy-6- (prop-1-en-2-yl) quinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 21 Step 3 using 2-methoxy-6- (prop-1-en-2-yl) quinoline-3-carboxylic acid (Example 26 Step 4) to replace 7- (cyclopent-1-en-1-yl) -2-hydroxyquinoline-3-carboxylic acid to afford the title product as a white solid. 1H NMR (400 MHz, DMSO-d6 ) δ 8.98 (d, J = 7.8 Hz, 1H) , 8.63 (d, J = 6.6 Hz, 1H) , 8.09 (d, J = 2.0 Hz, 1H) , 7.99 (dd, J = 8.8, 2.0 Hz, 1H) , 7.78 (d, J = 8.8 Hz, 1H) , 7.26 (dd, J = 6.8, 2.2 Hz, 1H) , 6.95 (dd, J = 6.8, 2.6 Hz, 1H) , 5.61 (s, 1H) , 5.44-5.38 (m, 1H) , 5.23 (s, 1H) , 4.06 (s, 3H) , 3.82 (dd, J = 13.6, 8.0 Hz, 1H) , 3.31 –3.26 (m, 1H) , 2.21 (s, 3H) . LCMS calc. for C18H19N2O4S [M+H] +: m/z =359.0; Found: 359.0.
Example 32: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -7- (2-fluorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxamide
Step 1: ethyl 7- (2-fluorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylate
To a mixture of ethyl 7-bromo-2-hydroxyquinoline-3-carboxylate (300 mg, 1.013 mmol, Example 16 Step 2) in dioxane (3 mL) was added (2-fluorophenyl) boronic acid (142 mg, 1.013 mmol) , Pd (dppf) Cl2 (74 mg, 0.101 mmol) , K2CO3 (280 mg, 2.026 mmol) and water (1 mL) . The reaction mixture was stirred at 80℃ overnight under N2 atmosphere. The reaction mixture was quenched by H2O (10 mL) , and then extracted with EA (3 x 10 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 (200 mg) as a brown solid. LCMS calc. for C18H15FNO3 [M+H] +: m/z = 312.1; Found: 312.1.
Step 2: 7- (2-fluorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid
To a mixture of ethyl 7- (2-fluorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylate (200 mg, 0.64 mmol) in THF (2 mL) was added NaOH (51 mg, 1.28 mmol) , H2O (1 mL) . The reaction mixture was stirred at r.t. for 12 h.. The mixture was adjusted to pH～2-3 with aq. HCl (2 M) and then concentrated under reduced pressure to remove THF. The precipitate was collected and washed with water. The solid was dried in vacuo to afford the title compound (100 mg) as a brown solid. LCMS calc. for C16H9FNO3 [M-H] -: m/z = 282.1; Found: 282.1.
Step 3: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -7- (2-fluorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxamide
To a mixture of 7- (2-fluorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid (20 mg, 0.07 mmol) in DMF (0.5 mL) was added 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride (14 mg,  0.08 mmol) , HATU (32 mg, 0.08 mmol) and DIEA (27 mg, 0.21 mmol) . The reaction mixture was stirred at r.t. for 2 h., and then concentrated under reduced pressure. The residue was purified by prep-HPLC on a C18 column eluting with CH3CN/H2O (30%) to afford the title compound (11.3 mg) as a white solid. LCMS calc. for C20H14FN2O4S [M-H] -: m/z = 397.1; Found: 397.1.
Example 33: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-7-phenyl-1, 2-dihydroquinoline-3-carboxamide
Step 1: 2-oxo-7-phenyl-1, 2-dihydroquinoline-3-carboxylic acid
This compound was prepared by procedures analogous to those described for Example 32 Step 1-2 using phenylboronic acid to replace (2-fluorophenyl) boronic acid in Step 1 to obtain the title product. LCMS calc. for C16H10NO3 [M-H] -: m/z = 264.1; Found: 264.1.
Step 2: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-7-phenyl-1, 2-dihydroquinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 32 Step 3 using 2-oxo-7-phenyl-1, 2-dihydroquinoline-3-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to obtain the title product as a white solid. LCMS calc. for C20H15N2O4S [M-H] -: m/z = 379.1; Found: 379.1.
Example 34: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxamide
Step 1: 7- (1-methyl-1H-pyrazol-4-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid
This compound was prepared by procedures analogous to those described for Example 32 Step 1-2 using (1-methyl-1H-pyrazol-4-yl) boronic acid to replace (2-fluorophenyl) boronic acid in Step 1 to obtain the title product as a brown solid. LCMS calc. for C14H10N3O3 [M-H] -: m/z = 268.1; Found: 268.1.
Step 2: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -7- (1-methyl-1H-pyrazol-4-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 32 Step 3 using 7- (1-methyl-1H-pyrazol-4-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to obtain the title product as a white solid. LCMS calc. for C18H15N4O4S [M-H] -: m/z = 383.1; Found: 383.1.
Example 35: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-7- (thiophen-2-yl) -1, 2-dihydroquinoline-3-carboxamide
Step 1: 2-oxo-7- (thiophen-2-yl) -1, 2-dihydroquinoline-3-carboxylic acid
This compound was prepared by procedures analogous to those described for Example 32 Step 1-2 using 4, 4, 5, 5-tetramethyl-2- (thiophen-2-yl) -1, 3, 2-dioxaborolane to replace (2-fluorophenyl) boronic acid in Step 1 to obtain the title product as a brown solid. LCMS calc. for C14H8NO3S [M-H] -: m/z = 270.0; Found: 270.1.
Step 2: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-7- (thiophen-2-yl) -1, 2-dihydroquinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 32 Step 3 using 2-oxo-7- (thiophen-2-yl) -1, 2-dihydroquinoline-3-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to obtain the title product as a white solid. LCMS calc. for C18H13N2O4S2 [M-H] -: m/z = 385.0; Found: 385.0.
Example 36: 7- (3, 6-Dihydro-2H-pyran-4-yl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxamide
Step 1: ethyl 7- (3, 6-dihydro-2H-pyran-4-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxylate
This compound was prepared by procedures analogous to those described for Example 32 Step 1 using 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane to replace (2-fluorophenyl) boronic acid to obtain the title product as a brown solid. LCMS calc. for C17H16NO4 [M+H] +: m/z = 300.1; Found: 300.1.
Step 2: 7- (3, 6-dihydro-2H-pyran-4-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid
This compound was prepared by procedures analogous to those described for Example 32 Step 2 using ethyl 7- (3, 6-dihydro-2H-pyran-4-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxylate to replace ethyl 7- (2-fluorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylate to obtain the title product as a brown solid. LCMS calc. for C15H12NO4 [M-H] -: m/z = 270.1; Found: 270.1.
Step 3: 7- (3, 6-dihydro-2H-pyran-4-yl) -N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 32 Step 3 using 7- (3, 6-dihydro-2H-pyran-4-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid and 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride to obtain the title product as a white solid. LCMS calc. for C19H17N2O5S [M-H] -: m/z = 385.1; Found: 385.1.
Example 37: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-7- (tetrahydro-2H-pyran-4-yl) -1, 2-dihydroquinoline-3-carboxamide
Step 1: ethyl 2-oxo-7- (tetrahydro-2H-pyran-4-yl) -1, 2-dihydroquinoline-3-carboxylate
To a mixture of ethyl 7- (3, 6-dihydro-2H-pyran-4-yl) -2-oxo-1, 2-dihydroquinoline-3-carboxylate (200 mg, 0.668 mmol, Example 36 Step 1) in MeOH (10 mL) was Pd/C (200 mg, 10 %wet) . The reaction mixture was stirred at r.t. overnight under H2 atomosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (100 mg) as a brown oil. LCMS calc. for C17H20NO4 [M+H] +: m/z = 302.1; Found: 302.1.
Step 2: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -2-oxo-7- (tetrahydro-2H-pyran-4-yl) -1, 2-dihydroquinoline-3-carboxamide
This compound was prepared by procedures analogous to those described for Example 32 Step 2-3 using ethyl 2-oxo-7- (tetrahydro-2H-pyran-4-yl) -1, 2-dihydroquinoline-3-carboxylate to replace ethyl 7- (2-fluorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylate in Step 2 to obtain the title product as a white solid. LCMS calc. for C19H19N2O5S [M-H] -: m/z = 387.1; Found: 387.1.
Example 38: N- (1, 1-Dioxido-2, 3-dihydrothiophen-3-yl) -6- (ethylamino) -2-hydroxyquinoline-3-carboxamide
Step 1: methyl 6-bromo-2-methoxyquinoline-3-carboxylate
To a suspension of 6-bromo-2-methoxyquinoline-3-carboxylic acid (300 mg, 1.064 mmol, Example 26 Step 3) in MeOH (8 mL) was added SOCl2 (380 mg, 3.191 mmol) at 0 ℃. The mixture was stirred at 50 ℃ for 3 h.. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted pH to 7 –8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with EA (20 mL x 3) . The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was  purified by flash chromatography on a silica gel column eluting with EA/PE (10%～ 20%) to afford the title compound (77 mg, 25 %yield) as a white solid. LCMS calc. for C12H11BrNO3 [M+H] +: m/z = 296.0; Found: 296.0.
Step 2: methyl 6- ( (tert-butoxycarbonyl) (ethyl) amino) -2-methoxyquinoline-3-carboxylate
A mixture of methyl 6-bromo-2-methoxyquinoline-3-carboxylate (77.0 mg, 0.26 mmol) , tert-butyl ethylcarbamate (56.5 mg, 0.39 mmol) , Pd2 (dba) 3 (23.8 mg, 0.026 mmol) , X-phos (24.7 mg, 0.052 mmol) and Cs2CO3 (253.5 mg, 0.78 mmol) in dixoane (3 mL) was stirred at 100 ℃ for 18 h. under N2. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with PE/EA (10 %) to afford the title compound (35 mg, 47.1 %yield) as a yellow solid. LCMS calc. for C19H25N2O5 [M+H] +: m/z =361.1; Found: 361.3.
Step 3: 6- ( (tert-butoxycarbonyl) (ethyl) amino) -2-methoxyquinoline-3-carboxylic acid
A mixture of methyl 6- ( (tert-butoxycarbonyl) (ethyl) amino) -2-methoxyquinoline-3-carboxylate (30.0 mg, 0.083 mmol) and LiOH. H2O (3.8 mg, 0.17 mmol) in THF (2 mL) and H2O (0.5mL) was stirred at r.t. overnight. The reaction mixture was diluted with water (8 mL) and adjusted pH to 2-3 with aq. HCl (2 N) . The mixture was extracted with DCM (30 mL x 3) and dried over Na2SO4. The organic layers were filtered and concentrated to give the title compound (20.0 mg, 69.6 yield) as a white solid. LCMS calc. for C18H23N2O5 [M+H] +: m/z =347.1; Found: 347.1.
Step 4: tert-butyl (3- ( (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) carbamoyl) -2-methoxyquinolin-6-yl) (ethyl) carbamate
To a solution of 6- ( (tert-butoxycarbonyl) (ethyl) amino) -2-methoxyquinoline-3-carboxylic acid (20.0mg, 0.058 mmol) in DMF (2.5 mL) was added 3-amino-2, 3-dihydrothiophene 1, 1-dioxide hydrochloride (11.7 mg, 0.069 mmol) , HATU (33.0 mg, 0.087mmol, 1.5 eq) and DIPEA (26.2 mg, 0.203mmol) . The mixture was stirred at r.t. overnight. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL x 2) . 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 (30 -45%) to afford the title  compound (22.0 mg, 82.4%yield) as a white solid. LCMS calc. for C22H28N3O6S [M+H] +: m/z =462.1; Found: 462.1.
Step 5: N- (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) -6- (ethylamino) -2-hydroxyquinoline-3-carboxamide
A mixture of tert-butyl (3- ( (1, 1-dioxido-2, 3-dihydrothiophen-3-yl) carbamoyl) -2-methoxyquinolin-6-yl) (ethyl) carbamate (20.0mg, 0.043 mmol, 1.0 eq) in aq. HCl (6 N, 1.0 mL) was stirred at 90℃ for 3h.. The mixture was concentrated under reduced pressure. The residue was basified to pH～8 with con. NH3. H2O and then purified by prep-HPLC on C18 column eluting with MeCN/H2O (0%-100%, with 10mM NH4HCO3) to afford the title compound (4.7 mg, 31.5 %yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (d, J = 7.9 Hz, 1H) , 8.68 (s, 1H) , 7.27 (dd, J = 6.6, 1.9 Hz, 1H) , 7.23 (d, J = 8.9 Hz, 1H) , 7.08 (dd, J = 8.9, 2.5 Hz, 1H) , 7.00 (dd, J = 6.6, 3.0 Hz, 1H) , 6.88 (d, J = 2.4 Hz, 1H) , 5.72 (s, 1H) , 5.39 (s, 1H) , 3.75 (dd, J = 13.8, 7.9 Hz, 1H) , 3.27 (dd, J = 13.8, 4.0 Hz, 1H) , 3.10 –2.98 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) . LCMS calc. for C16H18N3O4S [M+H] +: m/z =348.1; Found: 348.3.
Example A: WRN ATPase assay
WRN ATPase assay was initiated to evaluate potential inhibitory effect of compounds for ATP hydrolysis activity of WRN protein. WRN [UniPro: Q14191 (WRN_HUMAN) , N500-C946] was expressed and purified in insect system and stored at -80℃ in aliquots. FORKF DNA was annealed with equal amounts of OLIGOA-BHQ2 (TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCGTACCC-GATGTGTTCGTTC-BHQ2) and OLIGOB-TAMRA (TAMRAGAACGAACACATCGGGTACG-TTTTTTTTTTTTTTTTTTTTTTTTTTTTTT) in equal amounts, boiling for 5 min and allowing the oligos to slowly cool to room temperature in the presence of 50 mM NaCl. ADP quantity produced from ATP hydrolysis by WRN catalytic reaction was measured using a commercially available ADP-Glo Assay (ADP-GloTM Kinase Assay from Promega, 10000 assays, #V9102) . The assay buffer was comprised of 30 mM HEPES pH7.4 (Gibco, 15630-080) , 40 mM KCl (Sigma, P9541-500G) , 5%Glycerol (sigma, G7757-1L) , 8 mM MgCl2 (Invitrogen, AM9530G) , 0.1 mg/ml BSA (PerkinElmer, CR84-100) . Compounds dissolved in DMSO (Sigma, D8418) were plated into a 96-well intermediate plate (BioFil, VWP-032-096) for 3-fold serial titration for 10 points using DMSO, and well-to-well transfer the titrated compounds into another 96-well intermediate plate including assay buffer in advance. Shake the 96-well intermediate plate at 600 rpm for 10 min to fully mix. Specifically, a 4× working mixture of WRN was diluted to a concentration of 8 nM in assay buffer. A 2× working mixture of FORKF DNA and ATP was diluted to a concentration of 30 nM and 120 uM, respectively. 2.5 μL titrated compounds from 96-well intermediate plate and 2.5 μL 4× WRN working mixture were delivered into 384-well assay plate (PerkinElmer, 6007290) using electronic pipettor. After Centrifuging at 1000 rpm and shaking at 500 rpm, the assay plate was pre-incubated for 30 min. Then,  5 μL 2× FORKF DNA and ATP working mixture was dispensed into assay plate. Plate was sealed, centrifuged and incubated for an additional 40 min at 37 ℃. The reaction was stopped with the addition of 10 μL of the first ADP-Glo reagent and incubated for 40 min to remove the excess amount of ATP. Afterwards, 20 μL of ATP detection reagent was added and incubated for 30 min before reading. Luminescence output was recorded using BMG CLARIO star plus reader. Each concentration of compound was tested in duplicates in the assay plate. Average luminescence signal of high control (Wells with 1 %DMSO) was calculated as High Control (HC) . Average luminescence signal of low control (Wells with no WRN protein) 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: a “+” denotes an IC50 value of >10 μM, a “++” denotes an IC50 value of 1 μM< IC50<=10 μM, and a “+++” denotes an IC50 value of <=1 μM.
Table 1. WRN enzymatic activity assay
Example B: WRN unwinding assay
WRN unwinding assay was initiated to evaluate potential inhibitory effect of compounds for WEN helicase activity. WRN [UniPro: Q14191 (WRN_HUMAN) , N500-C946] was expressed and purified in insect system and stored at -80℃ in aliquots. FORKF DNA was annealed with equal amounts of OLIGOA-BHQ2 (TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCGTACCCGATGTGTTCGTTC-BHQ2) and OLIGOB-TAMRA (TAMRA-GAACGAACACATCGGGTACGTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT) in equal amounts, boiling for 5 min and allowing the oligos to slowly cool to room temperature in the presence of 50 mM NaCl. The assay buffer was comprised of 30 mM HEPES pH7.4 (Gibco, 15630-080) , 40 mM KCl (Sigma, P9541-500G) , 5%Glycerol (sigma, G7757-1L) , 8 mM MgCl2 (Invitrogen, AM9530G) , 0.1 mg/ml BSA (PerkinElmer, CR84-100) . Compounds dissolved in DMSO (Sigma, D8418) were plated into a 96-well intermediate plate (BioFil, VWP-032-096) for 3-fold serial titration for 10 points using DMSO, and well-to-well transfer the titrated compounds into another 96-well intermediate plate including assay buffer in advance. Shake the 96-well intermediate plate at 600 rpm for 10 min to fully  mix. Specifically, a 4× working mixture of WRN was diluted to a concentration of 80 nM in assay buffer. A 2× working mixture of FORKF DNA and ATP was diluted to a concentration of 25 nM and 400 uM, respectively. 2.5 μL titrated compounds from 96-well intermediate plate and 2.5 μL 4× WRN working mixture were delivered into 384-well assay plate (PerkinElmer, 6008260) using electronic pipettor. After Centrifuging at 1000 rpm and shaking at 500 rpm, the assay plate was pre-incubated for 4 h. Then, 5 μL 2× FORKF DNA and ATP working mixture was dispensed into assay plate. Plate was sealed, centrifuged and incubated for an additional 60 min at 25 ℃. Fluorescence (Ex558 nm/Em586 nm) output was recorded using BMG CLARIO star plus reader. Each concentration of compound was tested in duplicates in the assay plate. Average fluorescence signal of high control (Wells with 1 %DMSO) was calculated as High Control (HC) . Average fluorescence signal of low control (Wells with no WRN protein) 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: a “+” denotes an IC50 value of >10 μM, a “++” denotes an IC50 value of 1 μM< IC50<=10 μM, and a “+++” denotes an IC50 value of <=1 μM.
Table 2. WRN unwinding assay
Example C: Cell viability assay
Cell viability studies were conducted in colon carcinoma cell lines SW48 which is MSI-H cell lines. As a control, MSS cell line SW620 was included for viability assay. 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 1000 cells/well for SW48 cell and 500 cells/well for SW620 cell. 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 6 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 (BMG CLARIO star 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: a IC50 value of >10 μM, a “++” denotes an IC50 value of 1 μM< IC50<=10 μM, and a “+++” denotes an IC50 value of <=1 μM.
Although the present invention 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 invention.

Claims (51)

  1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof, wherein:
    L is -S (O) 2-, -S (O) (=NR2) -, -C (O) -, -S (O) 2NHC (O) -, -C (O) NHS (O) 2-, or -C (O) NHS (O) (=NR2) -;
    Cy is selected from 5-10 membered partially unsaturated heterocycloalkyl or 5-10 membered heteroaryl; wherein, the Cy is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R3;
    when n is 1 and L is -C (O) -, then Cy is notwherein, the position *is attached to L, the position **is attached to R1;
    m is 1, 2 or 3;
    n is 1 or 2;
    each R is independently selected from H, D, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, OC1-C6 alkyl, OC1-C6 haloalkyl, -NH (C1-C6 alkyl) , or -N (C1-C6 alkyl) 2; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N3, NO2, SF5, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl;
    or two R groups together with the same ring carbon atom to which they are attached form C3-C5 cycloalkyl or 4-5 membered heterocycloalkyl; wherein, the C3-C5 cycloalkyl or 4-5 membered heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from D, halo, OH, oxo, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl;
    R1 is selected from H, D, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, ORA, SRA, or NRCRD; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4;
    each R2 is independently selected from H, D, CN, OH, C1-C4 alkyl or OC1-C4 alkyl; wherein, the C1-C4 alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from D, halo, CN, OH, -O-C1-C4 alkyl, -OC1-C4 haloalkyl, NH2, -NH (C1-C4 alkyl) , or -N (C1-C4 alkyl) 2;
    each R3 is independently selected from H, D, halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl, ORA, SRA, or NRCRD; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb;
    wherein, two R3 together with the same ring carbon atom to which they are attached form oxo, C3-C4 cycloalkyl, 4 membered heterocycloalkyl; wherein, the C3-C4 cycloalkyl, 4 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, or -OC1-C6 haloalkyl;
    wherein, two R3 together with the atoms to which they are attached form C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; wherein, the C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, or -OC1-C6 haloalkyl;
    each R4 is independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NRCRD, ORA, SRA, C (O) RB, C (O) ORA, OC (O) RB, C (O) NRCRD, NRCC (O) RB, OC (O) NRCRD, OC (O) ORA, NRCC (O) NRCRD, NRCC (O) ORA, C (=NRC) NRCRD, NRDC (=NRC) NRCRD, NRDC (=NRC) RB, S (O) RB, S (O) NRCRD, S (O) 2RB, S (O) 2NRCRD, NRCS (O) 2RB, S (O) (=NRB) RB, NRCS (O) 2NRCRD, NRCS (O) (=NRB) RB, B (ORC) (ORD) , P (O) RERF, P (O) OREORF, OP (O) OREORF, Cy1, OCy1, C1-C6 alkyl-Cy1, or OC1-C6 alkyl-Cy1; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R5A;
    Cy1 is C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl; wherein, the C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl is optionally substituted 1, 2, 3, 4, 5 or 6 substituents independently selected from R5B;
    each R5A is independently selected from D, halo, CN, N3, oxo, ORa, Si (C1-C4 alkyl) 3 or OC1-C6 alkyl-OH;
    each R5B is independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, ORa, SRa, 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; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from H, D, halo, CN, NO2, N3, SF5, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, ORa1, C (O) ORa1, C (O) Rb1, NRc1Rd1, C (O) NRc1Rd1, S (O) 2Rb1, or S (O) 2NRc1Rd1;
    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, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, NO2, oxo, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, ORa, SRa, 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, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, OC2-C4 alkylOH, OC2-C4 alkyl-O-C1-C4 alkyl, OC2-C4 alkyl-O-C1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, ORa, SRa, 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-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, 3, 4 or 5 substituents independently selected from D, OH, CN, halo, oxo, SF5, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl, OC2-C4 alkylOH, OC2-C4 alkyl-O-C1-C4 alkyl, OC2-C4 alkyl-O-C1-C4 haloalkyl, C1-C4 alkyl-O-C1-C4 alkyl, C1-C4 alkyl-O-C1-C4 haloalkyl, ORa, SRa, C (O) Rb, 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, 3, 4 or 5 substituents independently selected from D, halo, oxo, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-CN, ORa, SRa, C (O) Rb, NRcRd;
    Ra and Ra1 are each 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, 3, 4 or 5 substituents independently selected from D, OH, halo, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, C1-C4 haloalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl;
    Rb and Rb1 are each 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, C6-C10 aryl-C1-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl; 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-C4 alkyl, 5-10 membered heteroaryl-C1-C4 alkyl, C3-C10 cycloalkyl-C1-C4 alkyl, or 4-10 membered heterocycloalkyl-C1-C4 alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, halo, C1-C4 alkyl, , C1-C4 haloalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl, C6-C10 aryl, C3-C10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl;
    Rc, Rc1, Rd and Rd1 are each 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, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (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-C4 alkyl, 5-10 membered heteroaryl-C3-C10 alkyl, C3-C10 cycloalkyl-C6-C10 alkyl, 4-10 membered heterocycloalkyl-C1-C4 alkyl, C6-C10 aryl-C3-C10 cycloalkyl, C6-C10 aryl-4-10 membered heterocycloalkyl, C6-C10 aryl-5-10 membered heteroaryl, bi (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 bi (5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, O-C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, 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-;
    Rc and Rd or Rc1 and Rd1 together with the N atom to which they are attached form 4-7 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, halo, OH, CN, -NH2, -NH (C1-C4 alkyl) , -N (C1-C4 alkyl) 2, C1-C4 alkyl, O-C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 haloalkyl, C1-C4 alkyl-OH, C1-C4 alkyl-CN, 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;
    RE and Re are 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, 4-10 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;
    RF and Rf are each 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.
  2. The compound of claim 1, wherein, the compounds of Formula (I) are represented by compounds of Formula (Ia) or (Ib) :
    or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
    wherein, Cy, L, R, R1, m and n are defined with respect to Formula (I) .
  3. The compound of claim 1 or 2, wherein, the compounds of Formula (I) are represented by compounds of Formula (II) or (III) :
    or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
    wherein, Cy, L, R, R1 and m are defined with respect to Formula (I) .
  4. The compound of anyone of claim 1-3, wherein, Cy is 5-10 membered partially unsaturated heterocycloalkyl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R3; and when n is 1 and L is -C (O) -, then Cy is notwherein, the position *is attached to L, the position **is attached to R1.
  5. The compound of anyone of claim 1-3, wherein, Cy is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R3.
  6. The compound of anyone of claim 1-5, wherein, the compounds of Formula (I) are represented by compounds of Formula (IVa) , (IVb) , (IVc) , (IVd) , (IVe) or (IVf) :
    or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
    wherein, is a single bond or double bond;
    X1 is N or CR3A;
    X1 is N or CR3B;
    X2 is N or CR3C;
    X3, X4 and X5 are each independently selected from N or CR3;
    Y1 and Y2 are each independently selected from N, NR3, O, S or CR3;
    Y3 is N or C;
    A1 and A2 are each independently selected from NR3, O, S or C (R3) 2;
    p is 1 or 2;
    R3A is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl;
    R3B is H, D, halo, OH;
    R3C is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, OC1-C3 haloalkyl;
    wherein, L, R, R1, R3 and m are defined with respect to Formula (I) ; in the formula (IVe) , one of R3 at any position is replaced by R1.
  7. The compound of anyone of claim 1-5, wherein, the compounds of Formula (I) are represented by compounds of Formula (Va) , (Vb) , (Vc) , (Vd) , (Ve) or (Vf) :
    or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
    wherein, is a single bond or double bond;
    X1 is N or CR3A;
    X1 is N or CR3B;
    X2 is N or CR3C;
    X3, X4 and X5 are each independently selected from N or CR3;
    Y1 and Y2 are each independently selected from N, NR3, O, S or CR3;
    Y3 is N or C;
    A1 and A2 are each independently selected from NR3, O, S or C (R3) 2;
    p is 1 or 2;
    R3A is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl;
    R3B is H, D, halo, OH;
    R3C is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, OC1-C3 haloalkyl;
    wherein, L, R, R1, R3 and m are defined with respect to Formula (I) ; in the formula (Ve) , one of R3 at any position is replaced by R1.
  8. The compound of anyone of claim 1-5 or 6, wherein, the compounds of Formula (I) are represented by compounds of Formula (VIa) , (VIb) , (VIc) , (VId) , (VIe) or (VIf) :
    or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
    wherein, X, X1, X2, X3, X4, X5, Y1, Y2, Y3, A1, A2, L, R, R1, R3, m and p are defined with respect to Formula (I) ; in the formula (VIe) , one of R3 at any position is replaced by R1.
  9. The compound of anyone of claim 1-5 or 7, wherein, the compounds of Formula (I) are represented by compounds of Formula (VIIa) , (VIIb) , (VIIc) , (VIId) , (VIIe) or (VIIf) :
    or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
    wherein, X, X1, X2, X3, X4, X5, Y1, Y2, Y3, A1, A2, L, R, R1, R3, m and p are defined with respect to Formula (I) ; in the formula (VIIe) , one of R3 at any position is replaced by R1.
  10. The compound of claim 9, wherein, the compounds of Formula (I) are represented by compounds of Formula (VIIIa) , (VIIIb) , (VIIIc) , (VIIId) , (VIIIe) or (VIIIf) :
    or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
    wherein, X, X1, X2, X3, X4, X5, Y1, Y2, Y3, A1, A2, L, R, R1, R3, m and p are defined with respect to Formula (I) ; in the formula (VIIIe) , one of R3 at any position is replaced by R1.
  11. The compound of claim 9, wherein, the compounds of Formula (I) are represented by compounds of Formula (IXa) , (IXb) , (IXc) , (IXd) , (IXe) or (IXf) :
    or a pharmaceutically acceptable salt, stereoisomer, solvate, N-oxide, tautomer, isotopic variant, prodrug or deuterated compound thereof;
    wherein, X, X1, X2, X3, X4, X5, Y1, Y2, Y3, A1, A2, L, R, R1, R3, m and p are defined with respect to Formula (I) ; in the formula (IXe) , one of R3 at any position is replaced by R1.
  12. The compound of anyone of claim 6-11, wherein, X is CR3A, X1 is CR3B, X2 is CR3C; X is CR3A, X1 is N, X2 is CR3C; X is CR3A, X1 is CR3B, X2 is N; X is N, X1 is CR3B, X2 is CR3C; or X is N, X1 is CR3B, X2 is N.
  13. The compound of anyone of claim 6-12, wherein, all of X3, X4 and X5 are CR3; X3 is CR3, X4 is N, and X5 is CR3; X3 is CR3, X4 is CR3, and X5 is N; X3 is CR3, X4 is N, and X5 is N; X3 is N, X4 is CR3, and X5 is CR3; or X3 is N, X4 is CR3, and X5 is N.
  14. The compound of anyone of claim 6-12, wherein, X3 is CR3, X4 is CR3; X3 is N, X4 is CR3; or X3 is CR3, X4 is N.
  15. The compound of anyone of claim 6-12, wherein, isand Y1 is N or CR3; Y2 is NR3, O or S; isand Y1 is NR3, O or S; Y2 is N or CR3; orisand Y1 is N or CR3; Y2 is N or CR3.
  16. The compound of anyone of claim 1-15, wherein, Cy is selected from:

    wherein, the position *is attached to L, the position **is attached to R1.
  17. The compound of anyone of claim 6-16, wherein, R3A is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl.
  18. The compound of anyone of claim 6-17, wherein, R3B is H, D, halo, OH.
  19. The compound of anyone of claim 6-18, wherein, R3C is H, D, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, OC1-C3 haloalkyl.
  20. The compound of anyone of claim 1-19, wherein, each R3 is independently selected from H, D, halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl, ORA, SRA, or NRCRD; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb; preferably, each R3 is independently selected from H, D, halo, CN, OH, OCH3, OCH2CH3, OCH2CH2CH3, OCH (CH3) 2, OCH2F, OCHF2, OCF3, SCH3, SCH2CH3, NH2, NHCH3, N (CH3) 2, NHCH2CH3, N (CH2CH3) 2, NHCH2CH2OH, N (CH3) CH2CH2OH, CH3, CH2CH3, CH2CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CF2CH3, CF2CF3, CH2OH, CH2CH2OH, CH (OH) CH3, CH2CN, CH2CH2CN.
  21. The compound of anyone of claim 1-20 wherein, each R3 is independently selected from H, D, halo, CN, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl, ORA, SRA, or NRCRD; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, 4-7 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from D, halo, CN, NO2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-OH, C1-C6 alkyl-CN, NRcRd, ORa, SRa, NHORa, C (O) Rb, C (O) ORa, OC (O) Rb, C (O) NRcRd, NRcC (O) Rb.
  22. The compound of anyone of claim 1-21, wherein, each R3 is independently selected from H, D, halo, CN, CH3, CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CF2CH3, -CH=CH2, -C (CH3) =CH2, OH, OCH3, OCH2CH3, NH2, NHCH3, N (CH3) 2.
  23. The compound of anyone of claim 1-27, wherein, each R is independently selected from H, D, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, OC1-C6 alkyl, OC1-C6 haloalkyl, -NH (C1-C6 alkyl) , or -N (C1-C6 alkyl) 2; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl is optionally substituted by 1, 2 or 3 substituents independently selected from D, halo, OH, CN, N3, NO2, SF5, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, OC1-C4 haloalkyl; preferably, each R is independently selected from H, D, halo, CH3, CH2CH3, CH2CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3.
  24. The compound of anyone of claim 1-30, wherein, R1 is selected from H, D, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents R4; preferably, R1 is H, D, halo, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, ethenyl, prop-1-en-1-yl, prop-1-en-2-yl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
  25. The compound of claim 31, wherein, R1 is C3-C10 saturated mono-cycloalkyl, C6-C10 saturated bicycloalkyl, C5-C10 saturated spiro-cycloalkyl, C5-C10 saturated bridged cycloalkyl, C8-C10 saturated fused cycloalkyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
  26. The compound of claim 32, wherein, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro [3.3] heptanyl, spiro [3.4] octanyl, spiro [3.5] nonanyl, spiro [3.6] decanyl, spiro [4.4] nonanyl, spiro [4.5] decanyl, spiro [4.6] undecanyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, bicyclo [5.2.0] nonanyl, octahydropentalenyl, octahydro-1H-indenyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
  27. The compound of claim 31, wherein, R1 is C5-C10 partially unsaturated mono-cycloalkyl, C6-C10 partially unsaturated bicycloalkyl, C7-C10 partially unsaturated spiro-cycloalkyl, C7-C10 partially unsaturated bridged cycloalkyl, C8-C10 partially unsaturated fused cycloalkyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
  28. The compound of claim 34, wherein, R1 is cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, or cyclohexenyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
  29. The compound of claim 31, wherein, R1 is 4-10 membered saturated mono-heterocycloalkyl, 6-10 membered saturated bicyclo heterocycloalkyl, 7-10 membered saturated spiro heterocycloalkyl, 6-10 membered saturated bridged heterocycloalkyl, or 8-10 membered saturated fused heterocycloalkyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
  30. The compound of claim 36, wherein, R1 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, dioxanyl tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, azepanyl, diazocanyl, diazepanyl, azepanyl, 2, 6-diazaspiro [3.3] heptanyl, 2-oxa-6-azaspiro [3.3] heptanyl, 2, 6-diazaspiro [3.4] octanyl, 2, 7-diazaspiro [3.5] nonanyl, 2, 7-diazaspiro [4.4] nonanyl, 3, 9-diazaspiro [5.5] undecanyl, 2-oxa-7-azaspiro [3.5] nonanyl, 2-oxa-6-azaspiro [3.4] octanyl, 7-oxa-2-azaspiro [3.5] nonanyl, 6-oxa-2-azaspiro [3.4] octanyl, octahydropyrrolo [3, 4-c] pyrrolyl, hexahydrofuro [3, 4-c] pyrrolyl, hexahydrothieno [3, 4-c] pyrrolyl, octahydrocyclopenta [b] pyrrolyl, octahydropyrrolo [3, 2-b] pyrrolyl, hexahydrofuro [3, 2-b] pyrrolyl, octahydropyrano [3, 2-b] pyrrolyl, octahydropyrrolo [3, 2-b] pyridinyl, hexahydropyrrolo [1, 2-a] imidazolyl, octahydropyrrolo [2, 3-c] pyridinyl, octahydropyrrolo [3, 2-c] pyridinyl, octahydroimidazo [1, 2-a] pyridinyl, octahydropyrrolo [3, 4-c] pyridinyl, decahydroquinolinyl, octahydrochromenyl, decahydroquinoxalinyl, octahydropyrido [1, 2-a] pyrazinyl, octahydropyrazino [2, 1-c] [1, 4] oxazinyl, octahydropyrido [2, 1-c] [1, 4] oxazineyl, octahydropyrano [3, 2-c] pyridinyl, decahydro-2, 6-naphthyridinyl, hexahydro-1H-furo [3, 4-c] pyrrolyl, octahydro-1H-pyrano [3, 4-c] pyridinyl, octahydro-2H-pyrido [1, 2-a] pyrazinyl, octahydropyrrolo [1, 2-a] pyrazinyl, hexahydro-3H-oxazolo [3, 4-a] pyrazinyl, hexahydro-5H-cyclopenta [b] [1, 4] dioxinyl, benzo [d] [1, 3] dioxolyl, 2-azabicyclo [1.1.1] pentanyl, 5-azabicyclo [2.1.1] hexanyl, 2-azabicyclo [2.2.1] heptanyl, 2-azabicyclo [2.2.2] octanyl, 6-azabicyclo [3.1.1] heptanyl, 3-azabicyclo [3.2.1] octanyl, 3-azabicyclo [3.3.1] nonanyl, 3-azabicyclo [3.3.2] decanyl, 1, 2, 3, 6-tetrahydropyrrolo [2, 3-b] pyrrolyl, 1, 2, 3, 5-tetrahydropyrrolo [3, 4-b] pyrrolyl, 4, 5, 6, 7-tetrahydropyrrolo [2, 3-b] pyridinyl, 2, 3, 4, 5-tetrahydropyrrolo [2, 3-b] pyrazinyl, 2, 3, 4, 5-tetrahydropyrrolo [3, 2-b] [1, 4] oxazinyl, 2, 3-dihydropyrrolo [1, 2-a] imidazolyl, 1, 2, 3, 4-tetrahydropyrrolo [1, 2-a] pyrimidinyl, 2, 3, 4, 6-tetrahydropyrrolo [3, 4-b] pyrazinyl, 2, 3, 4, 6-tetrahydropyrrolo [3, 4-b] [1, 4] oxazinyl, 5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazinyl, 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a] pyrazinyl, 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyrazinyl, indolinyl, 1, 2, 3, 4-tetrahydroquinolinyl, 1, 2, 3, 4-tetrahydroquinoxalinyl, 3, 4-dihydrobenzo [b] [1, 4] oxazinyl, 2, 3-dihydropyrrolo [2, 3-b] pyridinyl, 1, 2, 3, 4-tetrahydro-1, 7- naphthyridinyl, 1, 2, 3, 4-tetrahydropyrido [3, 4-b] pyrazinyl, 3, 4-dihydropyrido [4, 3-b] [1, 4] oxazinyl, 5, 6, 7, 8-tetrahydro-1, 7-naphthyridinyl, 5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidinyl, 5, 6, 7, 8-tetrahydro-1, 6-naphthyridinyl, 5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidinyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
  31. The compound of claim 31, wherein, R1 is 5-10 membered partially unsaturated mono-heterocycloalkyl, 6-10 membered partially unsaturated bicyclo heterocycloalkyl, 7-10 membered partially unsaturated spiro heterocycloalkyl, 7-10 membered partially unsaturated bridged heterocycloalkyl, or 8-10 membered partially unsaturated fused heterocycloalkyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
  32. The compound of claim 31, wherein, R1 is C6-C10 aryl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
  33. The compound of claim 39, wherein, R1 is phenyl, naphthalenyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
  34. The compound of claim 31, wherein, R1 is 5-10 membered heteroaryl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
  35. The compound of claim 41, wherein, R1 is pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzo [b] thiophenyl, benzo [c] thiophenyl, indazolyl, benzo [d] imidazolyl, pyrrolo [3, 2-b] pyridinyl, pyrrolo [3, 2-c] pyridinyl, pyrrolo [2, 3-c] pyridinyl, pyrrolo [2, 3-b] pyridinyl, pyrrolo [3, 4-b] pyridinyl, pyrrolo [3, 4-c] pyridinyl, benzo [d] isoxazolyl, benzo [d] oxazolyl, furo [3, 2-b] pyridinyl, furo [3, 2-c] pyridinyl, furo [2, 3-c] pyridinyl, furo [2, 3-b] pyridinyl, benzo [c] isoxazolyl, furo [3, 4-b] pyridinyl, furo [3, 4-c] pyridinyl, benzo [d] isothiazolyl, benzo [d] thiazolyl, thieno [3, 2-b] pyridinyl, thieno [3, 4-c] pyridinyl, benzo [d] [1, 2, 3] triazolyl, pyrazolo [4, 3-b] pyridinyl, pyrazolo [4, 3-c] pyridinyl, pyrazolo [3, 4-c] pyridinyl, pyrazolo [3, 4-b] pyridinyl, imidazo [4, 5-b] pyridinyl, imidazo [4, 5-c] pyridinyl, imidazo [4, 5-c] pyridinyl, imidazo [4, 5-b] pyridinyl, pyrrolo [3, 2-c] pyridazinyl, pyrrolo [3, 2-d] pyrimidinyl, pyrrolo [2, 3-b] pyrazinyl, pyrrolo [2, 3-d] pyridazinyl, pyrrolo [2, 3-d] pyrimidinyl, pyrrolo [2, 3-c] pyridazinyl, pyrrolo [3, 4-c] pyridazinyl, pyrrolo [3, 4-d] pyrimidinyl, pyrrolo [3, 4-b] pyrazinyl, pyrrolo [3, 4-d] pyridazinyl, pyrrolo [3, 4-d] pyrimidinyl, 6H-pyrrolo [3, 4-c] pyridazinyl; each is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from R4.
  36. The compound of anyone of claim 1-42, wherein, R1 is selected from H, D, halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, ORA, SRA, or NRCRD; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C3-C10 cycloalkyl, 4- 10 membered heterocycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents R4.
  37. The compound of anyone of claim 1-38, wherein, R1 is selected from H, D, halo, CN, CH3, CH2CH3, CH (CH3) 2, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CF2CH3, -CH=CH2, -C (CH3) =CH2, OH, OCH3, OCH2CH3, NH2, NHCH3, N (CH3) 2, phenyl, 
  38. The compound of anyone of claim 1-37, wherein, the compound of Formula (I) is:

    or a pharmaceutically acceptable salt thereof.
  39. A pharmaceutical composition comprising a compound of anyone of claim 1-38 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  40. A method of inhibiting WRN in a cell expressing WRN, wherein, the method comprising contacting the cell with the compound of anyone of claim 1-38 or a pharmaceutically acceptable salt thereof.
  41. The method of claim 40, wherein, the cell is associated with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) .
  42. The method of claim 40 or 41, wherein, the cell is in a subject.
  43. A method of inhibiting WRN in a subject, wherein, the method comprises administering to the subject a therapeutically effective amount of the compound of anyone of claim 1-38, or a pharmaceutically acceptable salt thereof.
  44. A method of treating a disease which can be treated by WRN inhibition in a subject, comprising administering to the subject a therapeutically effective amount of the compound of anyone of claim 1-38, or a pharmaceutically acceptable salt thereof.
  45. The method of claim 44, wherein, the disease is cancer.
  46. The method of claim 45, wherein, the cancer is characterized as MSI-H or dMMR.
  47. The method of claim 46, wherein, the cancer characterized as MSI-H or dMMR is selected from colorectal, gastric, prostate, endometrial, adrenocortical, uterine, cervical, esophageal, breast, kidney and ovarian cancer.
  48. The method of claim 47, wherein, the cancer characterized as MSI-H or dMMR is selected from colorectal, gastric and endometrial cancer.
  49. The method of claim 48, wherein, the cancer characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) is selected from prostate cancer, uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal carcinoma, breast carcinoma, kidney renal clear cell carcinoma and ovarian serous cystadenocarcinoma.
  50. Use of the compound of anyone of claim 1-38 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.
  51. The use of claim 50, wherein, the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) .
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