WO2022012456A1 - Novel heterocyclic compounds as bet inhibitors - Google Patents

Novel heterocyclic compounds as bet inhibitors Download PDF

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Publication number
WO2022012456A1
WO2022012456A1 PCT/CN2021/105686 CN2021105686W WO2022012456A1 WO 2022012456 A1 WO2022012456 A1 WO 2022012456A1 CN 2021105686 W CN2021105686 W CN 2021105686W WO 2022012456 A1 WO2022012456 A1 WO 2022012456A1
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WIPO (PCT)
Prior art keywords
methyl
pyrrolo
dihydro
oxo
pyridine
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PCT/CN2021/105686
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French (fr)
Inventor
Haiquan Fang
Xinfeng LUO
Tianbo SHU
Jibing ZHANG
Xianqiang WU
Hui Zhu
Ying Wang
Original Assignee
Chengdu Easton Biopharmaceuticals Co., Ltd.
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Application filed by Chengdu Easton Biopharmaceuticals Co., Ltd. filed Critical Chengdu Easton Biopharmaceuticals Co., Ltd.
Priority to CN202180034999.XA priority Critical patent/CN115667237A/en
Publication of WO2022012456A1 publication Critical patent/WO2022012456A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel heterocyclic compounds of formula (I) , wherein X 0 to X 3 , L, R 0 to R 4 are described herein, as bromodomain and extraterminal (BET) inhibitors, pharmaceutical compositions comprising the compounds, their synthesis and their use for treating diseases and conditions wherein inhibition of one or more BET bromodomains provides a benefit.
  • BET bromodomain and extraterminal
  • BET domains Proteins containing bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription.
  • BET family has BRD2, BRD3, BRD4 and BRDT four members and each of them has two N-terminal bromodomains and extra C-terminal domain (ET) exhibiting high levels of sequence conservation.
  • BRD2 and BRD3 associate with histones along actively transcribed genes and maybe involved in facilitating transcriptional elongation (Leroy et al., Mol. Cell 2008 30 (1) : 51-60) .
  • BRD4 appears to be involved in the recruitment of the positive transcriptional elongation factor complex (pTEF-I3) , which plays an essential role in the regulation of transcription by RNA polymerase and increased transcriptional output (Hargreaves et al., Cell, 2009 138 (1) : 129-145) .
  • pTEF-I3 positive transcriptional elongation factor complex
  • BRDT expression is normally testis-specific (M.H. Jones et al, Genomics, 1997 (45) , 529-534) and BRDT is essential for spermatogenesis (E. Shang et al, Development, 2007 (134) , 3507-3515) . All BET family members have some function in controlling or executing aspects of the cell cycle, and remain in complex with chromosomes during cell division-implying a role in the maintenance of epigenetic memory. Dysfunction of them have critical roles in a variety of human disease.
  • BET inhibitors that are reported in development include GSK-525762A, GSK282015 1, OTX-015, CPI-0610, TEN-010, ABBV-075, ABBV-744, BI 894999, BMS-986158, INCB054329, ZEN-3694 GS-5829 as well as an inhibitor, CC-90010.
  • BET inhibitors that have improved properties over existing BET inhibitors (Emily J. Faivre et al, Nature 2020 (578) , 306-310) , for example, improved potency, selectivity, safety, tolerability, pharmacokinetics and/or pharmacodynamics.
  • the present invention comprises a compound useful as BET inhibitor having a structure of Formula (I) , or a pharmaceutically acceptable salt thereof, or stereoisomer thereof:
  • L is hydrogen, O, S, CR 5 R 6 , -C (CH 3 ) 2 OH or NR 7 ;
  • R 0 is hydrogen, halogen or C 1 -C 3 alkyl
  • R 1 is C 1 -C 3 alkyl
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen, -C (O) NHR 3a ;
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • X 0 is C or N
  • X 1 is O, S, S (O) , S (O) 2 , CR 8 or NR 8 ;
  • X 2 is CR 9 or NR 9 ;
  • X 3 is CR 10 , N or NR 10 ;
  • R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy;
  • R 7 is hydrogen, C 1 -C 6 alkyl
  • R 8 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 8a R 8b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , or -CH 2 R 8c ;
  • R 9 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 9a R 9b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CONH 2 , -CO (C 1 -C 6 alkyl) or -CH 2 R 9c ;
  • R 10 is absent, hydrogen, halogen, C 1 -C 6 alkyl, -C (CH 3 ) 2 OH, -CR 10a R 10b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CH 2 R 10c or -OR10 d ;
  • R 3a is hydrogen, CD 2 CD 3 , C 1 -C 3 alkyl, C 1 -C 6 haloalkyl, a C 3 -C 6 cycloalkyl, a phenyl, or a 5-6 membered monocyclic heteroaryl; wherein the C 3 -C 6 cycloalkyl, the phenyl, or the 5-6 membered monocyclic heteroaryl are each optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
  • R 3b is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy;
  • R 4a , R 4b , R 8c , R 9c , R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered
  • R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl
  • R 8a and R 8b are hydrogen, halogen, C 1 -C 2 alkyl, or R 8a , R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
  • R 9a and R 9b are hydrogen, halogen, C 1 -C 2 alkyl, or R 9a , R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
  • R 10a and R 10b are hydrogen, halogen, C 1 -C 2 alkyl, or R 10a , R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
  • the present invention comprises a compound having a structure of formula (II) :
  • L is hydrogen, O, S, CR 5 R 6 , -C (CH 3 ) 2 OH or NR 7 ;
  • R 0 is hydrogen, halogen or C 1 -C 3 alkyl
  • R 1 is C 1 -C 3 alkyl
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen, -C (O) NHR 3a ;
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • X 0 is C or N
  • X 1 is O, S, S (O) , S (O) 2 , CR 8 or NR 8 ;
  • X 2 is CR 9 or NR 9 ;
  • X 3 is CR 10 , N or NR 10 ;
  • R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy;
  • R 7 is hydrogen, C 1 -C 6 alkyl
  • R 8 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 8a R 8b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , or -CH 2 R 8c ;
  • R 9 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 9a R 9b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CONH 2 , -CO (C 1 -C 6 alkyl) or -CH 2 R 9c ;
  • R 10 is absent, hydrogen, halogen, C 1 -C 6 alkyl, -C (CH 3 ) 2 OH, -CR 10a R 10b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CH 2 R 10c or -OR10 d ;
  • R 3a is hydrogen, CD 2 CD 3 , C 1 -C 3 alkyl, C 1 -C 6 haloalkyl, a C 3 -C 6 cycloalkyl, a phenyl, or a 5-6 membered monocyclic heteroaryl; wherein the C 3 -C 6 cycloalkyl, the phenyl, or the 5-6 membered monocyclic heteroaryl are each optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
  • R 3b is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
  • R 4a , R 4b , R 8c , R 9c , R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered
  • R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl
  • R 8a and R 8b are hydrogen, halogen, C 1 -C 2 alkyl, or R 8a , R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
  • R 9a and R 9b are hydrogen, halogen, C 1 -C 2 alkyl, or R 9a , R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
  • R 10a and R 10b are hydrogen, halogen, C 1 -C 2 alkyl, or R 10a , R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • R 0 is hydrogen
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • R 1 is methyl
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • R 2 is hydrogen
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • R 3 is hydrogen, -C (O) NHR 3a ;
  • R 3a is hydrogen, CD 2 CD 3 , C 1 -C 3 alkyl, C 1 -C 6 haloalkyl, a C 3 -C 6 cycloalkyl; wherein the C 3 -C 6 cycloalkyl is optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
  • R 3b is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy.
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • R 3 is hydrogen, -C (O) NHR 3a ;
  • R 3a is methyl, ethyl, isopropyl, cyclcopropyl.
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • R 4a , R 4b are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4b is wherein are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium.
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • L is hydrogen, O, S, CR 5 R 6 , -C (CH 3 ) 2 OH or NR 7 ;
  • R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy;
  • R 7 is hydrogen, C 1 -C 3 alkyl.
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • L is hydrogen, O, S, CR 5 R 6 , -C (CH 3 ) 2 OH or NR 7 ;
  • R 5 and R 6 are each independently hydrogen, halogen, or methyl
  • R 7 is hydrogen, or methyl.
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • L is hydrogen, O, S, CR 5 R 6 , -C (CH 3 ) 2 OH or NR 7 ;
  • R 5 , R 6 and R 7 are hydrogen.
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • R 8 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 8a R 8b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , or -CH 2 R 8c ;
  • R 8c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 8a and R 8b are hydrogen, halogen, C 1 -C 2 alkyl, or R 8a , R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl.
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • R 9 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 9a R 9b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CONH 2 , -CO (C 1 -C 6 alkyl) or -CH 2 R 9c ;
  • R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 9a and R 9b are hydrogen, halogen, C 1 -C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl.
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • R 10 is absent, hydrogen, halogen, C 1 -C 6 alkyl, -C (CH 3 ) 2 OH, -CR 10a R 10b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CH 2 R 10c or -OR10 d ;
  • R 10c and R 10d are each independently phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 10a and R 10b are hydrogen, halogen, C 1 -C 2 alkyl, or R 10a , R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • R 0 is hydrogen
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is hydrogen, -C (O) NHR 3a ;
  • R 3a is hydrogen, CD 2 CD 3 , C 1 -C 3 alkyl, C 1 -C 6 haloalkyl, a C 3 -C 6 cycloalkyl; wherein the C 3 -C 6 cycloalkyl is optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
  • R 3b is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy;
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • R 4a , R 4b are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4b is wherein are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium
  • L is hydrogen, O, S, CR 5 R 6 , -C (CH 3 ) 2 OH or NR 7 ;
  • R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy;
  • R 7 is hydrogen, C 1 -C 3 alkyl
  • R 8 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 8a R 8b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , or -CH 2 R 8c ;
  • R 8c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 8a and R 8b are hydrogen, halogen, C 1 -C 2 alkyl, or R 8a , R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
  • R 9 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 9a R 9b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CONH 2 , -CO (C 1 -C 6 alkyl) or -CH 2 R 9c ;
  • R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 9a and R 9b are hydrogen, halogen, C 1 -C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
  • R 10 is absent, hydrogen, halogen, C 1 -C 6 alkyl, -C (CH 3 ) 2 OH, -CR 10a R 10b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CH 2 R 10c or -OR10 d ;
  • R 10c and R 10d are each independently phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 10a and R 10b are hydrogen, halogen, C 1 -C 2 alkyl, or R 10a , R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • R 3 is hydrogen, -C (O) NHR 3a ;
  • R 3a is methyl, ethyl, isopropyl, cyclcopropyl
  • L is hydrogen, O, S, CR 5 R 6 , -C (CH 3 ) 2 OH or NR 7 ;
  • R 5 and R 6 are each independently hydrogen, halogen, or methyl
  • R 7 is hydrogen, or methyl.
  • the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
  • L is hydrogen, O, S, CR 5 R 6 , -C (CH 3 ) 2 OH or NR 7 ;
  • R 5 , R 6 and R 7 are hydrogen.
  • the present invention comprises a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof:
  • L is hydrogen, O, S, CR 5 R 6 , -C (CH 3 ) 2 OH or NR 7 ;
  • R 0 is hydrogen, halogen or C 1 -C 3 alkyl
  • R 1 is C 1 -C 3 alkyl
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen, -C (O) NHR 3a ;
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • X 1 is O, S, S (O) , S (O) 2 , CR 8 or NR 8 ;
  • X 3 is CR 10 , N or NR 10 ;
  • R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy;
  • R 7 is hydrogen, C 1 -C 6 alkyl
  • R 8 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 8a R 8b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , or -CH 2 R 8c ;
  • R 9 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 9a R 9b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CONH 2 , -CO (C 1 -C 6 alkyl) or -CH 2 R 9c ;
  • R 10 is absent, hydrogen, halogen, C 1 -C 6 alkyl, -C (CH 3 ) 2 OH, -CR 10a R 10b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CH 2 R 10c or -OR10 d ;
  • R 3a is hydrogen, CD 2 CD 3 , C 1 -C 3 alkyl, C 1 -C 6 haloalkyl, a C 3 -C 6 cycloalkyl, a phenyl, or a 5-6 membered monocyclic heteroaryl; wherein the C 3 -C 6 cycloalkyl, the phenyl, or the 5-6 membered monocyclic heteroaryl are each optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
  • R 3b is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy;
  • R 4a , R 4b , R 8c , R 9c , R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered
  • R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl
  • R 8a and R 8b are hydrogen, halogen, C 1 -C 2 alkyl, or R 8a , R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
  • R 9a and R 9b are hydrogen, halogen, C 1 -C 2 alkyl, or R 9a , R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
  • R 10a and R 10b are hydrogen, halogen, C 1 -C 2 alkyl, or R 10a , R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
  • the present invention comprises a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof:
  • X 1 is S or O
  • X 3 is CR 10 or N
  • L is hydrogen, O or NR 7 ;
  • R 7 is hydrogen
  • R 0 is hydrogen
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is hydrogen, -C (O) NHR 3a ;
  • R 3a is methyl, ethyl, isopropyl, cyclcopropyl
  • R 9 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 9a R 9b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CONH 2 , or -CO (C 1 -C 6 alkyl) ;
  • R 10 is absent, hydrogen, methyl, halogen, OR 10d ;
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • R 4a and R 10d are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4b is wherein are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium
  • R 9a and R 9b are hydrogen, halogen, C 1 -C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
  • R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
  • the present invention comprises a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof:
  • X 1 is S, X 3 is N, R 10 is absent.
  • the present invention comprises a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof:
  • X 1 is S, X 3 is CH.
  • the present invention comprises a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof:
  • X 1 is S, X 3 is CH;
  • L is hydrogen, O or NR 7 ;
  • R 7 is hydrogen
  • R 0 is hydrogen
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is hydrogen, -C (O) NHR 3a ;
  • R 3a is methyl, ethyl, isopropyl, cyclcopropyl
  • R 9 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 9a R 9b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CONH 2 , or -CO (C 1 -C 6 alkyl) ;
  • R 10 is absent, hydrogen, methyl, halogen, OR 10d ;
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • R 4a and R 10d are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4b is wherein are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium
  • R 9a and R 9b are each independently hydrogen, halogen, C 1 -C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
  • R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
  • the present invention comprises a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof:
  • X 1 is O, X 3 is N, R 10 is absent.
  • the present invention comprises a compound having a structure of formula (IV) or a pharmaceutically acceptable salt thereof:
  • L is hydrogen, O or NH
  • R 0 is hydrogen
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is hydrogen, -C (O) NHR 3a ;
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • R 8 is hydrogen, -C (CH 3 ) 2 OH
  • R 10 is hydrogen
  • R 3a is methyl, ethyl, isopropyl, cyclcopropyl
  • R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4b is wherein are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium.
  • the present invention comprises a compound having a structure of formula (V) or a pharmaceutically acceptable salt thereof:
  • L is hydrogen, O or NH
  • R 0 is hydrogen
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is hydrogen, -C (O) NHR 3a ;
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • R 8 is absent, hydrogen, -CH 2 C (CH 3 ) 2 OH, or -CH 2 R 8c ;
  • R 9 is absent, or -CH 2 R 9c ;
  • R 10 is hydrogen, -C (CH 3 ) 2 OH
  • R 3a is methyl, ethyl, isopropyl, cyclcopropyl
  • R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4b is wherein are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium
  • R 8c and R 9c are each independently phenyl, tetrahydropyranyl, wherein phenyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
  • the present invention comprises a compound having a structure of formula (VI) or a pharmaceutically acceptable salt thereof:
  • L is O or NH
  • R 0 is hydrogen
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is hydrogen, -C (O) NHR 3a ;
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • R 8 is absent, hydrogen, -CH 2 C (CH 3 ) 2 OH, or -CH 2 R 8c ;
  • R 9 is absent, -C (CH 3 ) 2 OH or -CH 2 R 9c ;
  • R 10 is hydrogen
  • R 3a is methyl, ethyl, isopropyl, cyclcopropyl
  • R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4b is wherein are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium
  • R 8c and R 9c are each independently phenyl, tetrahydropyranyl, wherein phenyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
  • the present invention provides an intermediate compound of the formula (VII) ,
  • L is hydrogen, O, S, CR 5 R 6 , -C (CH 3 ) 2 OH or NR 7 ;
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • X 1 is O, S, S (O) , S (O) 2 , CR 8 or NR 8 ;
  • X 3 is CR 10 , N or NR 10 ;
  • R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy;
  • R 7 is hydrogen, C 1 -C 6 alkyl
  • R 8 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 8a R 8b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , or -CH 2 R 8c ;
  • R 9 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 9a R 9b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CONH 2 , -CO (C 1 -C 6 alkyl) or -CH 2 R 9c ;
  • R 10 is absent, hydrogen, halogen, C 1 -C 6 alkyl, -C (CH 3 ) 2 OH, -CR 10a R 10b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CH 2 R 10c or -OR10 d ;
  • R 4a , R 4b , R 8c , R 9c , R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered
  • R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl
  • R 8a and R 8b are hydrogen, halogen, C 1 -C 2 alkyl, or R 8a , R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
  • R 9a and R 9b are hydrogen, halogen, C 1 -C 2 alkyl, or R 9a , R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
  • R 10a and R 10b are hydrogen, halogen, C 1 -C 2 alkyl, or R 10a , R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl;
  • X is halide
  • the present invention provides an intermediate compound of the formula (VII) ,
  • X 1 is S or O
  • X 3 is CR 10 or N
  • L is hydrogen, O or NR 7 ;
  • R 7 is hydrogen
  • R 9 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 9a R 9b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CONH 2 , or -CO (C 1 -C 6 alkyl) ;
  • R 10 is absent, hydrogen, methyl, halogen, OR 10d ;
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • R 4a and R 10d are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4b is wherein are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium
  • R 9a and R 9b are hydrogen, halogen, C 1 -C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
  • R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • X is CI, Br , I or triflate.
  • the present invention provides an intermediate compound of the formula (VIII) ,
  • L is hydrogen, O, S, CR 5 R 6 , -C (CH 3 ) 2 OH or NR 7 ;
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • X 1 is O, S, S (O) , S (O) 2 , CR 8 or NR 8 ;
  • X 3 is CR 10 , N or NR 10 ;
  • R 5 and R 6 are each independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy;
  • R 7 is hydrogen, C 1 -C 6 alkyl
  • R 8 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 8a R 8b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , or -CH 2 R 8c ;
  • R 9 is absent, hydrogen, -C (CH 3 ) 2 OH, -CR 9a R 9b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CONH 2 , -CO (C 1 -C 6 alkyl) or -CH 2 R 9c ;
  • R 10 is absent, hydrogen, halogen, C 1 -C 6 alkyl, -C (CH 3 ) 2 OH, -CR 10a R 10b C (CH 3 ) 2 OH, -S (O) 2 (C 1 -C 6 alkyl) , -P (O) (C 1 -C 2 alkyl) 2 , -S (O) 2 NH 2 , -CH 2 R 10c or -OR10 d ;
  • R 4a , R 4b , R 8c , R 9c , R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered
  • R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl
  • R 8a and R 8b are hydrogen, halogen, C 1 -C 2 alkyl, or R 8a , R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
  • R 9a and R 9b are hydrogen, halogen, C 1 -C 2 alkyl, or R 9a , R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
  • R 10a and R 10b are hydrogen, halogen, C 1 -C 2 alkyl, or R 10a , R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl;
  • R is C 1 -C 6 alkyl.
  • the present invention provides an intermediate compound of the formula (IX) ,
  • L is hydrogen, O or NH
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • R 8 is hydrogen, -C (CH 3 ) 2 OH
  • R 10 is hydrogen
  • R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4b is wherein are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium
  • X is CI, Br , I or triflate.
  • the present invention provides an intermediate compound of the formula (X) ,
  • L is hydrogen, O or NH
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • R 8 is absent, hydrogen, -CH 2 C (CH 3 ) 2 OH, or -CH 2 R 8c ;
  • R 9 is absent, or -CH 2 R 9c ;
  • R 10 is hydrogen, -C (CH 3 ) 2 OH
  • R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4b is wherein are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium
  • R 8c and R 9c are each independently phenyl, tetrahydropyranyl, wherein phenyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • X is CI, Br , I or triflate.
  • the present invention provides an intermediate compound of the formula (XI) ,
  • L is O or NH
  • R 4 is absent, R 4a or –CR 4b R 4c R 4d ;
  • R 9 is absent, -C (CH 3 ) 2 OH or -CH 2 R 9c ;
  • R 10 is hydrogen
  • R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4b is wherein are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
  • R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium
  • R 9c is phenyl, tetrahydropyranyl, wherein phenyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
  • the present invention provides compounds of formula (II) and pharmaceutically acceptable salts, solvates (e.g., hydrates) , diastereoisomers, and isotopically labeled derivatives thereof, wherein R 0 -R 4 , L, X 0 -X 3 and subvariables thereof are as defined herein.
  • solvates e.g., hydrates
  • X 0 -X 3 e.g., hydrates
  • compositions within the scope of the invention can contain a compound of Formula (II) (or a pharmaceutically acceptable salt, solvate (e.g., hydrate) , diastereoisomers, or isotopic form thereof) and a pharmaceutically acceptable excipient.
  • the active ingredient e.g., a compound of Formula (II)
  • a pharmaceutically acceptable salt, solvate e.g., hydrate
  • diastereoisomers e.g., hydrate
  • isotopic form thereof e.g., hydrate
  • pharmaceutically acceptable excipient e.g., a pharmaceutically acceptable excipient.
  • the active ingredient e.g., a compound of Formula (II)
  • the pharmaceutical compositions described herein can be packaged in unit dosages, fractions thereof or multiples thereof.
  • the present invention provides for methods for treating or preventing disorders that are ameliorated by inhibition of BET.
  • Such methods comprise of administering to the subject a therapeutically effective amount of a compound of formula (II) , alone, or in combination with a pharmaceutically acceptable carrier.
  • the present invention also provides a combination pharmaceutical product comprising the compound described herein, together with one or more other therapeutically active agents.
  • Some of the methods are directed to treating or preventing an inflammatory disease or cancer or AIDS.
  • the present invention relates to methods of treating cancer in a subject comprising administering a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the cancer is selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic) , acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasi), acute a
  • the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
  • the additional therapeutic agent is selected from the group consisting of cytarabine, bortezomib, and 5-azacitidine.
  • the present invention relates to methods of treating a disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (II) , or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease (COPD) , Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel.
  • a disease or condition is selected from the group consisting of: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease (COPD) , Crohn'
  • the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
  • the present invention relates to methods of treating a chronic kidney disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (II) , or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease, and tubular interstitial nephritis.
  • the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
  • the present invention relates to methods of treating an acute kidney injury or disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (II) , or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said acute kidney injury or disease or condition is selected from the group consisting of: ischemia-reperfusion induced kidney disease, cardiac and major surgery induced kidney disease, percutaneous coronary intervention induced kidney disease, radio-contrast agent induced kidney disease, sepsis induced kidney disease, pneumonia induced kidney disease, and drug toxicity induced kidney disease.
  • the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
  • the present invention relates to methods of treating AIDS in a subject comprising administering a therapeutically effective amount of a compound of formula (II) , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
  • the present invention relates to methods of treating obesity, dyslipidemia, hypercholesterolemia, Alzheimer’s disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy, or diabetic neuropathy in a subject comprising administering a therapeutically effective amount of a compound of formula (II) , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
  • the present invention relates to methods of preventing conception by inhibiting spermatogenesis in a subject comprising administering a therapeutically effective amount of a compound of formula (II) , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
  • a further aspect of the invention provides the use of a compound of formula (II) , alone or in combination with at least one additional therapeutic agent, in the manufacture of a medicament for treating or preventing conditions and disorders disclosed herein, with or without a pharmaceutically acceptable carrier.
  • compositions comprising a compound of formula (II) , or a pharmaceutically acceptable salt, alone or in combination with at least one additional therapeutic agent, are also provided.
  • a compound includes a single compound as well as one or more of the same or different compounds
  • a pharmaceutically acceptable carrier means a single pharmaceutically acceptable carrier as well as one or more pharmaceutically acceptable carriers, and the like.
  • halogen as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
  • halogen groups include F, CI and Br.
  • alkyl includes saturated monovalent hydrocarbon radicals having straight or branched.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclcobutyl, n-pentyl, 3- (-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclcopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
  • C _ as in Ci_6 alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
  • alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • methylene i.e., -CH 2 -
  • ethylene i.e., -CH 2 -CH 2 -or -CH (CH 3 ) -
  • propylene i.e., -CH 2 -CH 2 -CH 2 -, -CH (-CH 2 -CH 3 ) -or -CH 2 -CH (CH 3 ) -
  • alkenyl means a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length.
  • C2-C6 alkenyl contains from 2 to 6 carbon atoms.
  • Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-l-yl, hepetenyl, octenyl and the like.
  • alkynyl contains a straight-or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length.
  • C2-C6 alkynyl contains from 2 to 6 carbon atoms.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • alkoxy radicals are oxygen ethers formed from the previously described alkyl groups.
  • aryl refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.
  • heterocyclic refers to unsubstituted and substituted mono-or polycyclic non-aromatic ring system containing one or more heteroatoms.
  • Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to eight membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition.
  • heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
  • heteroaryl represents an aromatic ring system containing carbon (s) and at least one heteroatom.
  • Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
  • a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclic heteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) .
  • heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.
  • Carbocyclic refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated ring, which optionally includes an alkylene linker through which the cycloalkyl may be attached.
  • Examplary "cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
  • carboxyl refers to the group C (O) OH.
  • treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • “treat, ” “treating, ” and “treatment” refer to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • “treat” , “treating” , and “treatment” refer to modulating the disease or disorder, either physically (for example, stabilization of a discernible symptom) , physiologically (for example, , stabilization of a physical parameter) , or both.
  • “treat” , “treating” , and “treatment” refer to slowing the progression of the disease or disorder.
  • prevent refers to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
  • prevent also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount means an amount of a compound, or a pharmaceutically acceptable salt thereof, sufficient to prevent the development of or to alleviate to some extent one or more of the symptoms of the condition or disorder being treated when administered alone or in conjunction with another therapeutic agent for treatment in a particular subject or subject population.
  • the “therapeutically effective amount” may vary depending on the compound, the disease and its severity, and the age, weight, health, etc., of the subject to be treated. For example in a human or other mammal, a therapeutically effective amount may be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and subject being treated.
  • subject is defined herein to refer to animals such as mammals, including, but not limited to, primates (e.g., humans) , cows, sheep, goats, pigs, horses, dogs, cats, rabbits, rats, mice and the like. In one embodiment, the subject is a human.
  • primates e.g., humans
  • the subject is a human.
  • patient, and subject are used interchangeably herein.
  • the term ‘at least one additional therapeutic agent’ means one to four therapeutic agents other than the compounds of the invention. In one embodiment it means one to three additional therapeutic agents. In further embodiments it means one or two additional therapeutic agents. In a yet further embodiment it means one additional therapeutic agent. In a yet further embodiment it means two additional therapeutic agents. In a yet further embodiment it means three additional therapeutic agents.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
  • the compounds of the present invention may also be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts" .
  • the present invention includes within its scope the prodrugs of the compounds of this invention.
  • such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs” , ed. H. Bundgaard, Elsevier, 1985.
  • the present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the above Formula is shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of Formula and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the isotopes of hydrogen can be denoted as 1H (hydrogen) , 2H (deuterium) and 3H (tritium) . They are also commonly denoted as D for deuterium and T for tritium.
  • CD3 denoted a methyl group wherein all of the hydrogen atoms are deuterium.
  • the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
  • the present invention includes any possible solvates and polymorphic forms.
  • a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone or the like can be used.
  • a further aspect of the invention provides the use of a compound of formula (II) , alone or in combination with at least one additional therapeutic agent, in the manufacture of a medicament for treating or preventing conditions and disorders disclosed herein, with or without a pharmaceutically acceptable carrier.
  • compositions comprising a compound of formula (II) , or a pharmaceutically acceptable salt, alone or in combination with at least one additional therapeutic agent, are also provided.
  • the compound of Formula (II) is a compound selected, but not limited, from the group consisting of:
  • N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2 -yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
  • N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thi ophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
  • N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) metho xy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
  • N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
  • N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
  • N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thi ophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
  • N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiop hen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
  • N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (1-methylpyrrolidin-2-yl) me thoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbo xamide;
  • N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2 -yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2 -carboxamide;
  • N-cyclopropyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) -4 -methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
  • N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxam ide;
  • N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxam ide;
  • N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-methyl-3- ( (1-methylpyrrolidin-2-yl) meth oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
  • N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbo xamide;
  • N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (1-methylpyrrolidin-2-yl) meth oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
  • N-cyclopropyl-4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (3-methylpyridin-2-yl) ox y) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
  • N-cyclopropyl-4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-car boxamide;
  • N-cyclopropyl-4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methyl-5-oxopyrrolidi n-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridin e-2-carboxamide;
  • N-cyclopropyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethyl butan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-c arboxamide;
  • N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (3-methylpyridin-2-yl) oxy) thio phen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
  • N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methylpyrrolidin-2-yl) metho xy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
  • N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-ca rboxamide;
  • N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
  • N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
  • N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (1-methylpyrrolidin-2 -yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2 -carboxamide;
  • N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (1-methyl-5-oxopyrro lidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyri dine-2-carboxamide;
  • N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
  • N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
  • N-ethyl-4- (5- (2-hydroxypropan-2-yl) -1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyraz ol-3-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
  • the compounds of the present innovation can be prepared in a number ways well known to one skilled in the art of organic synthesis using the methods described bellow or variations thereon as appreciated by those skilled in the art. Those described bellow are preferred, but a not limited to.
  • the references cited herein are hereby incorporated by reference in their entirety.
  • compounds of formula (III) may be synthesized as shown in Scheme 2 by Suzuki coupling reaction (N. Miyama and A. Suzuki, Chem. Rev. 1995, 95: 2457-2483, J. Organomet. Chem. 1999, 576: 147-148) between intermediate 3, wherein X is halide, e.g., Cl, Br, I, or triflate and boronic acids or a derivative thereof (e.g., a pinacol ester) of 4.
  • Suzuki coupling reaction N. Miyama and A. Suzuki, Chem. Rev. 1995, 95: 2457-2483, J. Organomet. Chem. 1999, 576: 147-1478
  • X is halide, e.g., Cl, Br, I, or triflate and boronic acids or a derivative thereof (e.g., a pinacol ester) of 4.
  • Displacement ( ⁇ ) of the nuclear magnetic resonance (1H NMR) is given in a unit of parts per million (ppm) ; measurement by nuclear magnetic resonance (1H NMR) is carried out on Bruker AVANCE-400 NMR instrument, wherein the measuring solvent is deuterated chloroform (CDCl3) , the internal standard is tetramethyl silane (TMS) , and the chemical displacement is given in a unit of parts per million (ppm) .
  • HPLC Agilent 1260 instrument
  • MS Agilent G6120B instrument; Waters XBridge reverse-phase column (C18, 3.5 microns silica, 4.6 mm diameter, 50 mm length, flow rate of 1.0 mL/min) .
  • Eluent A 0.05%TFA in water
  • Eluent B pure CH3CN
  • Gradient B 5%2min, 100%2min, 5%2 min.
  • Column temperature 35 °C.
  • Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate is used in the thin layer silica gel assay.
  • Yantai Huanghai 200-300 mesh silica gel is generally used as a carrier in column chromatography.
  • nitrogen atmosphere refers, for example, to connecting the reaction flask to a nitrogen balloon with 1L volume.
  • the solutions mentioned in the reaction of the present invention refer to the aqueous solutions.
  • room temperature refers to the temperature between 10°C and 25°C.
  • reaction mixture was vacuumed, backfilled with N 2 , and this procedure was repeated three times, followed by addition of Pd 2 (dba) 3 (80.0 mg, 0.0840 mmol) . After the mixture was vacuumed, backfilled with N 2 , and this procedure was repeated three times.
  • the reaction mixture was then warmed to 75 °C and stirred O/N.
  • the reaction mixture was cooled to rt, followed by addition of ammonium pyrrolidine dithiocarbamate (69.0 mg, 0.420 mmol) , EtOAc (20 mL) and water (20 mL) .
  • the mixture was continued stirring for 30 min. The two layers were separated, the aqueous layer was extracted with EtOAc (2 x 20 mL) .
  • reaction mixture was flushed with N 2 gas, sealed, and stirred at rt for 3 days.
  • the reaction mixture was concentrated to ⁇ 0.5 mL and the residue was purified on a thin layer silica gel plate developing with PE/EtOAc (2: 1 volume ratio) to afford the title intermediate (5 mg, 9%yield) as a brown oil.
  • ESI-MS: m/z 523 (M+H) + .

Abstract

Provided are heterocyclic compounds of formula (I) as bromodomain and extraterminal (BET) inhibitors, pharmaceutical compositions comprising the compounds, their synthesis and their use for treating diseases and conditions wherein inhibition of one or more BET bromodomains provides a benefit.

Description

Novel Heterocyclic Compounds as BET Inhibitors FIELD OF THE INVENTION
The present invention relates to novel heterocyclic compounds of formula (I) , wherein X 0 to X 3, L, R 0 to R 4 are described herein, as bromodomain and extraterminal (BET) inhibitors, pharmaceutical compositions comprising the compounds, their synthesis and their use for treating diseases and conditions wherein inhibition of one or more BET bromodomains provides a benefit.
BACKGROUND OF THE INVENTION
Proteins containing bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. BET family has BRD2, BRD3, BRD4 and BRDT four members and each of them has two N-terminal bromodomains and extra C-terminal domain (ET) exhibiting high levels of sequence conservation. As reported, BRD2 and BRD3 associate with histones along actively transcribed genes and maybe involved in facilitating transcriptional elongation (Leroy et al., Mol. Cell 2008 30 (1) : 51-60) . BRD4 appears to be involved in the recruitment of the positive transcriptional elongation factor complex (pTEF-I3) , which plays an essential role in the regulation of transcription by RNA polymerase and increased transcriptional output (Hargreaves et al., Cell, 2009 138 (1) : 129-145) . Unlike the other three BET proteins expressed ubiquitiously, BRDT expression is normally testis-specific (M.H. Jones et al, Genomics, 1997 (45) , 529-534) and BRDT is essential for spermatogenesis (E. Shang et al, Development, 2007 (134) , 3507-3515) . All BET family members have some function in controlling or executing aspects of the cell cycle, and remain in complex with chromosomes during cell division-implying a role in the maintenance of epigenetic memory. Dysfunction of them have critical roles in a variety of human disease.
Disrupting the protein-protein interactions between BET protein and acetylated histones becomes a promising target for human diseases including virology, hart failure, inflammation, central nervous system (CNS) disorders and variety cancers. Small molecule BET inhibitors that are reported in development include GSK-525762A, GSK282015 1, OTX-015, CPI-0610, TEN-010, ABBV-075, ABBV-744, BI 894999, BMS-986158, INCB054329, ZEN-3694 GS-5829 as well as an inhibitor, CC-90010. There exists a need for generating further BET inhibitors that have improved properties over existing BET inhibitors (Emily J. Faivre et al, Nature 2020 (578) , 306-310) , for example, improved potency, selectivity, safety, tolerability, pharmacokinetics and/or pharmacodynamics.
SUMMARY OF THE INVENTION
In one aspect, the present invention comprises a compound useful as BET inhibitor having a structure of Formula (I) , or a pharmaceutically acceptable salt thereof, or stereoisomer thereof:
Figure PCTCN2021105686-appb-000001
Wherein:
for
Figure PCTCN2021105686-appb-000002
two of
Figure PCTCN2021105686-appb-000003
are double bond and the other three
Figure PCTCN2021105686-appb-000004
are single bond to form a 5-membered heteroaromatic ring system;
L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
R 0 is hydrogen, halogen or C 1-C 3 alkyl;
R 1 is C 1-C 3 alkyl;
R 2 is hydrogen or methyl;
R 3 is hydrogen, -C (O) NHR 3a;
R 4 is absent, R 4a or –CR 4bR 4cR 4d ;
X 0 is C or N;
X 1 is O, S, S (O) , S (O)  2 , CR 8or NR 8;
X 2 is CR 9or NR 9;
X 3 is CR 10, N or NR 10;
R 5and R 6 are each independently hydrogen, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
R 7 is hydrogen, C 1-C 6 alkyl;
R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2 , -CO (C 1-C 6 alkyl) or -CH 2R 9c;
R 10 is absent, hydrogen, halogen, C 1-C 6 alkyl, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
R 3a is hydrogen, CD 2CD 3, C 1-C 3 alkyl, C 1-C 6 haloalkyl, a C 3-C 6 cycloalkyl, a phenyl, or a 5-6 membered monocyclic heteroaryl; wherein the C 3-C 6 cycloalkyl, the phenyl, or the 5-6 membered monocyclic heteroaryl are each optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
R 3b is halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
R 4a , R 4b , R 8c, R 9c , R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6  membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1-C 3 alkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkyl, C 1-C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered cyclyl alkoxy, 3-6 membered heterocyclyl alkoxy, -S (C 1-C 6 alkyl) , -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2 or – (C 1-C 6 alkylenyl) -OH;
R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl;
R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a, R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
In another aspect, the present invention comprises a compound having a structure of formula (II) :
Figure PCTCN2021105686-appb-000005
for
Figure PCTCN2021105686-appb-000006
two of
Figure PCTCN2021105686-appb-000007
are double bond and the other three
Figure PCTCN2021105686-appb-000008
are single bond to form a 5-membered heteroaromatic ring system;
L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
R 0 is hydrogen, halogen or C 1-C 3 alkyl;
R 1 is C 1-C 3 alkyl;
R 2 is hydrogen or methyl;
R 3 is hydrogen, -C (O) NHR 3a;
R 4 is absent, R 4a or –CR 4bR 4cR 4d ;
X 0 is C or N;
X 1 is O, S, S (O) , S (O)  2 , CR 8or NR 8;
X 2 is CR 9or NR 9;
X 3 is CR 10, N or NR 10;
R 5and R 6 are each independently hydrogen, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
R 7 is hydrogen, C 1-C 6 alkyl;
R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2 , -CO (C 1-C 6 alkyl) or -CH 2R 9c;
R 10 is absent, hydrogen, halogen, C 1-C 6 alkyl, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
R 3a is hydrogen, CD 2CD 3, C 1-C 3 alkyl, C 1-C 6 haloalkyl, a C 3-C 6 cycloalkyl, a phenyl, or a 5-6 membered monocyclic heteroaryl; wherein the C 3-C 6 cycloalkyl, the phenyl, or the 5-6 membered monocyclic heteroaryl are each optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
R 3b is halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, or C 1-C 6 haloalkoxy;
R 4a , R 4b , R 8c, R 9c , R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1-C 3 alkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkyl, C 1-C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered cyclyl alkoxy, 3-6 membered heterocyclyl alkoxy, -S (C 1-C 6 alkyl) , -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2 or – (C 1-C 6 alkylenyl) -OH;
R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl;
R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a, R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
R 0 is hydrogen.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is methyl.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
R 2 is hydrogen.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
R 3 is hydrogen, -C (O) NHR 3a;
R 3a is hydrogen, CD 2CD 3, C 1-C 3 alkyl, C 1-C 6 haloalkyl, a C 3-C 6 cycloalkyl; wherein the C 3-C 6 cycloalkyl is optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
R 3b is halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
R 3 is hydrogen, -C (O) NHR 3a;
R 3a is methyl, ethyl, isopropyl, cyclcopropyl.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
R 4 is absent, R 4a or –CR 4bR 4cR 4d ;
R 4a , R 4b are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4b is
Figure PCTCN2021105686-appb-000009
wherein
Figure PCTCN2021105686-appb-000010
are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
R 5and R 6 are each independently hydrogen, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkoxy;
R 7 is hydrogen, C 1-C 3 alkyl.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
R 5and R 6 are each independently hydrogen, halogen, or methyl;
R 7 is hydrogen, or methyl.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
R 5, R 6 and R 7 are hydrogen.
In another aspect, the present invention comprises a compound having a structure  of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
R 8c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2 , -CO (C 1-C 6 alkyl) or -CH 2R 9c;
R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
R 10 is absent, hydrogen, halogen, C 1-C 6 alkyl, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
R 10c and R 10d are each independently phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
R 0 is hydrogen;
R 1 is methyl;
R 2 is hydrogen;
R 3 is hydrogen, -C (O) NHR 3a;
R 3a is hydrogen, CD 2CD 3, C 1-C 3 alkyl, C 1-C 6 haloalkyl, a C 3-C 6 cycloalkyl; wherein the C 3-C 6 cycloalkyl is optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
R 3b is halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
R 4 is absent, R 4a or –CR 4bR 4cR 4d;
R 4a, R 4b are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4b is
Figure PCTCN2021105686-appb-000011
wherein
Figure PCTCN2021105686-appb-000012
are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
R 5and R 6 are each independently hydrogen, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkoxy;
R 7 is hydrogen, C 1-C 3 alkyl;
R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
R 8c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2 , -CO (C 1-C 6 alkyl) or -CH 2R 9c;
R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
R 10 is absent, hydrogen, halogen, C 1-C 6 alkyl, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
R 10c and R 10d are each independently phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
R 3 is hydrogen, -C (O) NHR 3a;
R 3a is methyl, ethyl, isopropyl, cyclcopropyl;
L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
R 5and R 6 are each independently hydrogen, halogen, or methyl;
R 7 is hydrogen, or methyl.
In another aspect, the present invention comprises a compound having a structure of formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
R 5, R 6 and R 7 are hydrogen.
In another aspect, the present invention comprises a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021105686-appb-000013
wherein:
L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
R 0 is hydrogen, halogen or C 1-C 3 alkyl;
R 1 is C 1-C 3 alkyl;
R 2 is hydrogen or methyl;
R 3 is hydrogen, -C (O) NHR 3a;
R 4 is absent, R 4a or –CR 4bR 4cR 4d ;
X 1 is O, S, S (O) , S (O)  2 , CR 8or NR 8;
X 3 is CR 10, N or NR 10;
R 5and R 6 are each independently hydrogen, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
R 7 is hydrogen, C 1-C 6 alkyl;
R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2 , -CO (C 1-C 6 alkyl) or -CH 2R 9c;
R 10 is absent, hydrogen, halogen, C 1-C 6 alkyl, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
R 3a is hydrogen, CD 2CD 3, C 1-C 3 alkyl, C 1-C 6 haloalkyl, a C 3-C 6 cycloalkyl, a phenyl, or a 5-6 membered monocyclic heteroaryl; wherein the C 3-C 6 cycloalkyl, the phenyl, or the 5-6 membered monocyclic heteroaryl are each optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
R 3b is halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
R 4a , R 4b , R 8c, R 9c , R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1-C 3 alkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkyl, C 1-C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered cyclyl alkoxy, 3-6 membered heterocyclyl alkoxy, -S (C 1-C 6 alkyl) , -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2 or – (C 1-C 6 alkylenyl) -OH;
R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl;
R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a, R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
In another aspect, the present invention comprises a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof:
wherein:
X 1 is S or O;
X 3 is CR 10 or N;
L is hydrogen, O or NR 7;
R 7 is hydrogen;
R 0 is hydrogen;
R 1 is methyl;
R 2 is hydrogen;
R 3 is hydrogen, -C (O) NHR 3a;
R 3a is methyl, ethyl, isopropyl, cyclcopropyl;
R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2 , or -CO (C 1-C 6 alkyl) ;
R 10 is absent, hydrogen, methyl, halogen, OR 10d;
R 4 is absent, R 4a or –CR 4bR 4cR 4d;
R 4a and R 10d are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4b is
Figure PCTCN2021105686-appb-000014
wherein
Figure PCTCN2021105686-appb-000015
are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
In another aspect, the present invention comprises a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof:
wherein:
X 1 is S, X 3 is N, R 10 is absent.
In another aspect, the present invention comprises a compound having a structure  of formula (III) or a pharmaceutically acceptable salt thereof:
wherein:
X 1 is S, X 3 is CH.
In another aspect, the present invention comprises a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof:
wherein:
X 1 is S, X 3 is CH;
L is hydrogen, O or NR 7;
R 7 is hydrogen;
R 0 is hydrogen;
R 1 is methyl;
R 2 is hydrogen;
R 3 is hydrogen, -C (O) NHR 3a;
R 3a is methyl, ethyl, isopropyl, cyclcopropyl;
R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2 , or -CO (C 1-C 6 alkyl) ;
R 10 is absent, hydrogen, methyl, halogen, OR 10d;
R 4 is absent, R 4a or –CR 4bR 4cR 4d;
R 4a and R 10d are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4b is
Figure PCTCN2021105686-appb-000016
wherein
Figure PCTCN2021105686-appb-000017
are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
R 9a and R 9b are each independently hydrogen, halogen, C 1-C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
In another aspect, the present invention comprises a compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof:
wherein:
X 1 is O, X 3 is N, R 10 is absent.
In another aspect, the present invention comprises a compound having a structure of formula (IV) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021105686-appb-000018
wherein:
L is hydrogen, O or NH;
R 0 is hydrogen;
R 1 is methyl;
R 2 is hydrogen;
R 3 is hydrogen, -C (O) NHR 3a;
R 4 is absent, R 4a or –CR 4bR 4cR 4d;
R 8 is hydrogen, -C (CH 3)  2OH;
R 10 is hydrogen;
R 3a is methyl, ethyl, isopropyl, cyclcopropyl;
R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4b is
Figure PCTCN2021105686-appb-000019
wherein
Figure PCTCN2021105686-appb-000020
are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium.
In another aspect, the present invention comprises a compound having a structure of formula (V) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021105686-appb-000021
wherein:
for
Figure PCTCN2021105686-appb-000022
two of
Figure PCTCN2021105686-appb-000023
are double bond and the other two
Figure PCTCN2021105686-appb-000024
are single bond to form a 5-membered heteroaromatic ring system;
L is hydrogen, O or NH;
R 0 is hydrogen;
R 1 is methyl;
R 2 is hydrogen;
R 3 is hydrogen, -C (O) NHR 3a;
R 4 is absent, R 4a or –CR 4bR 4cR 4d ;
R 8 is absent, hydrogen, -CH 2C (CH 3)  2OH, or -CH 2R 8c;
R 9 is absent, or -CH 2R 9c;
R 10 is hydrogen, -C (CH 3)  2OH;
R 3a is methyl, ethyl, isopropyl, cyclcopropyl;
R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4b is
Figure PCTCN2021105686-appb-000025
wherein
Figure PCTCN2021105686-appb-000026
are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
R 8c and R 9c are each independently phenyl, tetrahydropyranyl, wherein phenyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
In another aspect, the present invention comprises a compound having a structure of formula (VI) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021105686-appb-000027
Wherein:
L is O or NH;
R 0 is hydrogen;
R 1 is methyl;
R 2 is hydrogen;
R 3 is hydrogen, -C (O) NHR 3a;
R 4 is absent, R 4a or –CR 4bR 4cR 4d ;
R 8 is absent, hydrogen, -CH 2C (CH 3)  2OH, or -CH 2R 8c;
R 9 is absent, -C (CH 3)  2OH or -CH 2R 9c;
R 10 is hydrogen;
R 3a is methyl, ethyl, isopropyl, cyclcopropyl;
R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4b is
Figure PCTCN2021105686-appb-000028
wherein
Figure PCTCN2021105686-appb-000029
are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
R 8c and R 9c are each independently phenyl, tetrahydropyranyl, wherein phenyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
In another aspect, the present invention provides an intermediate compound of the formula (VII) ,
Figure PCTCN2021105686-appb-000030
wherein:
L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
R 4 is absent, R 4a or –CR 4bR 4cR 4d ;
X 1 is O, S, S (O) , S (O)  2 , CR 8or NR 8;
X 3 is CR 10, N or NR 10;
R 5and R 6 are each independently hydrogen, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
R 7 is hydrogen, C 1-C 6 alkyl;
R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2 , -CO (C 1-C 6 alkyl) or -CH 2R 9c;
R 10 is absent, hydrogen, halogen, C 1-C 6 alkyl, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH,  -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
R 4a , R 4b , R 8c, R 9c , R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1-C 3 alkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkyl, C 1-C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered cyclyl alkoxy, 3-6 membered heterocyclyl alkoxy, -S (C 1-C 6 alkyl) , -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2 or – (C 1-C 6 alkylenyl) -OH;
R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl;
R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a, R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl;
X is halide.
In another aspect, the present invention provides an intermediate compound of the formula (VII) ,
wherein:
X 1 is S or O;
X 3 is CR 10 or N;
L is hydrogen, O or NR 7;
R 7 is hydrogen;
R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2 , or -CO (C 1-C 6 alkyl) ;
R 10 is absent, hydrogen, methyl, halogen, OR 10d;
R 4 is absent, R 4a or –CR 4bR 4cR 4d ;
R 4a and R 10d are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4b is
Figure PCTCN2021105686-appb-000031
wherein
Figure PCTCN2021105686-appb-000032
are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
X is CI, Br , I or triflate.
In another aspect, the present invention provides an intermediate compound of the formula (VIII) ,
Figure PCTCN2021105686-appb-000033
wherein:
L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
R 4 is absent, R 4a or –CR 4bR 4cR 4d ;
X 1 is O, S, S (O) , S (O)  2 , CR 8or NR 8;
X 3 is CR 10, N or NR 10;
R 5and R 6 are each independently hydrogen, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
R 7 is hydrogen, C 1-C 6 alkyl;
R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2 , -CO (C 1-C 6 alkyl) or -CH 2R 9c;
R 10 is absent, hydrogen, halogen, C 1-C 6 alkyl, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
R 4a , R 4b , R 8c, R 9c , R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1-C 3 alkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkyl, C 1-C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered cyclyl alkoxy, 3-6 membered heterocyclyl alkoxy, -S (C 1-C 6 alkyl) , -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2 or – (C 1-C 6 alkylenyl) -OH;
R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl;
R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a, R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl;
R is C 1-C 6 alkyl.
In another aspect, the present invention provides an intermediate compound of the formula (IX) ,
Figure PCTCN2021105686-appb-000034
wherein:
L is hydrogen, O or NH;
R 4 is absent, R 4a or –CR 4bR 4cR 4d ;
R 8 is hydrogen, -C (CH 3)  2OH;
R 10 is hydrogen;
R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4b is
Figure PCTCN2021105686-appb-000035
wherein
Figure PCTCN2021105686-appb-000036
are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
X is CI, Br , I or triflate.
In another aspect, the present invention provides an intermediate compound of the formula (X) ,
Figure PCTCN2021105686-appb-000037
wherein:
for
Figure PCTCN2021105686-appb-000038
two of
Figure PCTCN2021105686-appb-000039
are double bond and the other two
Figure PCTCN2021105686-appb-000040
are single bond to form a 5-membered heteroaromatic ring system;
L is hydrogen, O or NH;
R 4 is absent, R 4a or –CR 4bR 4cR 4d ;
R 8 is absent, hydrogen, -CH 2C (CH 3)  2OH, or -CH 2R 8c;
R 9 is absent, or -CH 2R 9c;
R 10 is hydrogen, -C (CH 3)  2OH;
R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4b is
Figure PCTCN2021105686-appb-000041
wherein
Figure PCTCN2021105686-appb-000042
are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
R 8c and R 9c are each independently phenyl, tetrahydropyranyl, wherein phenyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
X is CI, Br , I or triflate.
In another aspect, the present invention provides an intermediate compound of the formula (XI) ,
Figure PCTCN2021105686-appb-000043
wherein:
L is O or NH;
R 4 is absent, R 4a or –CR 4bR 4cR 4d ;
R 9 is absent, -C (CH 3)  2OH or -CH 2R 9c;
R 10 is hydrogen;
R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4b is
Figure PCTCN2021105686-appb-000044
wherein
Figure PCTCN2021105686-appb-000045
are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
R 9c is phenyl, tetrahydropyranyl, wherein phenyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
In another aspect, the present invention provides compounds of formula (II) 
Figure PCTCN2021105686-appb-000046
and pharmaceutically acceptable salts, solvates (e.g., hydrates) , diastereoisomers, and isotopically labeled derivatives thereof, wherein R 0-R 4, L, X 0-X 3 and subvariables thereof are as defined herein. For ease of reading, we may not refer to both a compound of the invention and a pharmaceutically acceptable salt thereof when describing each and every composition, method, and use within the  scope of the invention. It is to be understood that where a compound of the invention can be used, a pharmaceutically acceptable salt thereof may also be useful, and making that determination is well within the ability of one of ordinary skill in the art.
While pharmaceutical compositions within the scope of the invention are described further below, we note here that they can contain a compound of Formula (II) (or a pharmaceutically acceptable salt, solvate (e.g., hydrate) , diastereoisomers, or isotopic form thereof) and a pharmaceutically acceptable excipient. The active ingredient (e.g., a compound of Formula (II) ) , regardless of its precise chemical form (e.g., isomeric or isotopic forms) , can be present in a therapeutically or prophylactically effective amount, and the pharmaceutical compositions described herein can be packaged in unit dosages, fractions thereof or multiples thereof.
In another aspect, the present invention provides for methods for treating or preventing disorders that are ameliorated by inhibition of BET. Such methods comprise of administering to the subject a therapeutically effective amount of a compound of formula (II) , alone, or in combination with a pharmaceutically acceptable carrier.
The present invention also provides a combination pharmaceutical product comprising the compound described herein, together with one or more other therapeutically active agents.
Some of the methods are directed to treating or preventing an inflammatory disease or cancer or AIDS.
In another aspect, the present invention relates to methods of treating cancer in a subject comprising administering a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the use for the preparation of a medicament for the treatment or diseases or conditions for which a bromodomain inhibitor is indicated. In certain embodiments, the cancer is selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic) , acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias) , embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin’s and non-Hodgkin’s) , malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC) , non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer,  rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas) , small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom’s macroglobulinemia, testicular tumors, uterine cancer, and Wilms’ tumor. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the additional therapeutic agent is selected from the group consisting of cytarabine, bortezomib, and 5-azacitidine.
In another aspect, the present invention relates to methods of treating a disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (II) , or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease (COPD) , Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel. disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
In another aspect, the present invention relates to methods of treating a chronic kidney disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (II) , or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease, and tubular interstitial nephritis. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
In another aspect, the present invention relates to methods of treating an acute kidney injury or disease or condition in a subject comprising administering a therapeutically effective amount of a compound of formula (II) , or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said acute kidney injury or disease or condition is selected from the group consisting of: ischemia-reperfusion induced kidney disease, cardiac and major surgery induced kidney disease, percutaneous coronary intervention induced kidney disease, radio-contrast agent induced kidney disease, sepsis induced kidney disease, pneumonia induced kidney disease, and drug toxicity induced kidney disease. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
In another aspect, the present invention relates to methods of treating AIDS in a subject comprising administering a therapeutically effective amount of a compound of formula (II) , or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the methods further comprise administering a therapeutically  effective amount of at least one additional therapeutic agent.
In another aspect, the present invention relates to methods of treating obesity, dyslipidemia, hypercholesterolemia, Alzheimer’s disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy, or diabetic neuropathy in a subject comprising administering a therapeutically effective amount of a compound of formula (II) , or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
In another aspect, the present invention relates to methods of preventing conception by inhibiting spermatogenesis in a subject comprising administering a therapeutically effective amount of a compound of formula (II) , or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.
A further aspect of the invention provides the use of a compound of formula (II) , alone or in combination with at least one additional therapeutic agent, in the manufacture of a medicament for treating or preventing conditions and disorders disclosed herein, with or without a pharmaceutically acceptable carrier.
Pharmaceutical compositions comprising a compound of formula (II) , or a pharmaceutically acceptable salt, alone or in combination with at least one additional therapeutic agent, are also provided.
DETAILED DESCRIPTION OF THE INVENTION
a. Definitions
It is noted that, as used in this specification and the intended claims, the singular form “a, ” “an, ” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a single compound as well as one or more of the same or different compounds, reference to “a pharmaceutically acceptable carrier” means a single pharmaceutically acceptable carrier as well as one or more pharmaceutically acceptable carriers, and the like.
As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:
The term "halogen" , as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. The preferred halogen groups include F, CI and Br.
The term "alkyl" , as used herein, unless otherwise indicated, alkyl includes saturated monovalent hydrocarbon radicals having straight or branched. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclcobutyl, n-pentyl, 3- (-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclcopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similary, C _, as in Ci_6 alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
The term "alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. For example, methylene (i.e., -CH 2 -) , ethylene (i.e., -CH 2 -CH 2 -or -CH (CH 3 ) -) and propylene (i.e., -CH 2-CH 2 -CH 2-, -CH (-CH 2-CH 3 ) -or -CH 2 -CH (CH 3 ) -) .
The term "alkenyl" means a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length. For example, "C2-C6 alkenyl" contains from 2 to 6 carbon atoms. Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl,  2-methyl-2-buten-l-yl, hepetenyl, octenyl and the like.
The term "alkynyl" contains a straight-or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. For example, "C2-C6 alkynyl" contains from 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
The term "alkoxy" radicals are oxygen ethers formed from the previously described alkyl groups.
The term "aryl" , as used herein, unless otherwise indicated, refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.
The term "heterocyclic" , as used herein, unless otherwise indicated, refers to unsubstituted and substituted mono-or polycyclic non-aromatic ring system containing one or more heteroatoms. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to eight membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition. Examples of such heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
The term "heteroaryl" , as used herein, unless otherwise indicated, represents an aromatic ring system containing carbon (s) and at least one heteroatom. Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms. A polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) . Examples of heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.
The term "carbocyclic" refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated ring, which optionally includes an alkylene linker through which the cycloalkyl may be attached. Examplary "cycloalkyl" groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
The term "carbonyl, =O or oxo" refers to the group C (O) .
The term "carboxyl" refers to the group C (O) OH.
The terms “treat” , “treating” , and “treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms. In certain embodiments, “treat, ” “treating, ” and “treatment” refer to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treat” , “treating” , and “treatment” refer to modulating the disease or disorder, either  physically (for example, stabilization of a discernible symptom) , physiologically (for example, , stabilization of a physical parameter) , or both. In a further embodiment, “treat” , “treating” , and “treatment” refer to slowing the progression of the disease or disorder.
The terms “prevent” , “preventing” , and “prevention” refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, “prevent” , “preventing” and “prevention” also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring or developing a disease or disorder.
The phrase “therapeutically effective amount” means an amount of a compound, or a pharmaceutically acceptable salt thereof, sufficient to prevent the development of or to alleviate to some extent one or more of the symptoms of the condition or disorder being treated when administered alone or in conjunction with another therapeutic agent for treatment in a particular subject or subject population. The “therapeutically effective amount” may vary depending on the compound, the disease and its severity, and the age, weight, health, etc., of the subject to be treated. For example in a human or other mammal, a therapeutically effective amount may be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and subject being treated.
The term “subject” is defined herein to refer to animals such as mammals, including, but not limited to, primates (e.g., humans) , cows, sheep, goats, pigs, horses, dogs, cats, rabbits, rats, mice and the like. In one embodiment, the subject is a human. The terms “human, ” “patient, ” and “subject” are used interchangeably herein.
The term ‘at least one additional therapeutic agent’ means one to four therapeutic agents other than the compounds of the invention. In one embodiment it means one to three additional therapeutic agents. In further embodiments it means one or two additional therapeutic agents. In a yet further embodiment it means one additional therapeutic agent. In a yet further embodiment it means two additional therapeutic agents. In a yet further embodiment it means three additional therapeutic agents.
The term "composition" , as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
The compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts" .
The present invention includes within its scope the prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed,  but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs" , ed. H. Bundgaard, Elsevier, 1985. It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.
The present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
The above Formula is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. The isotopes of hydrogen can be denoted as 1H (hydrogen) , 2H (deuterium) and 3H (tritium) . They are also commonly denoted as D for deuterium and T for tritium. In the application, CD3 denoted a methyl group wherein all of the hydrogen atoms are deuterium.
When a tautomer of the compound of Formula exists, the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
When the compound of Formula and pharmaceutically acceptable salts thereof exists in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.
A further aspect of the invention provides the use of a compound of formula (II) , alone or in combination with at least one additional therapeutic agent, in the manufacture of a medicament for treating or preventing conditions and disorders disclosed herein, with or without a pharmaceutically acceptable carrier.
Pharmaceutical compositions comprising a compound of formula (II) , or a pharmaceutically acceptable salt, alone or in combination with at least one additional therapeutic agent, are also provided.
b. Compounds
In some embodiments, the compound of Formula (II) is a compound selected, but not limited, from the group consisting of:
4- (3- (2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-meth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- (2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-meth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5-carbamoyl-3- (2, 6-dimethylphenoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isoprop yl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isop ropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isop ropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-i sopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N -isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isop ropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isop ropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isop ropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-is opropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2 -yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thioph en-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (2-hydroxypropan-2-yl) thioph en-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thi ophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) metho xy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-cyclopropyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) th iophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thioph en-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (2-hydroxypropan-2-yl) thioph en-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thioph  en-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (2-hydroxypropan-2-yl) thio phen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethy l-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethy l-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thi ophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen -2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethy l-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (4-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-et hyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5-acetyl-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5-acetyl-3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5-acetyl-3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5-acetyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5-acetyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-ethyl-6-met hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5-acetyl-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7 -oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5-acetyl-3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5-acetyl-3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5-acetyl-3- ( (4-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5-acetyl-3- ( (2, 4-dimethylpyridin-3-yl) amino) thiophen-2-yl) -N-ethyl-6-methyl-7-o xo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-6-methyl-4- (3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-6-methyl-4- (3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-6-methyl-4- (3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylthiophe n-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-meth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N, 6-dimethyl-4- (3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N, 6-dimethyl-4- (3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N, 6-dimethyl-4- (3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7 -oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-ox o-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-isopropyl-6-methyl-4- (3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-methy  l-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-methy l-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-isopropyl-6-methyl-4- (3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-isopropyl-6-methyl-4- (3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylthi ophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-meth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-methy l-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-methy l-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-met hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-6-methyl-4- (3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-met hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-met hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-6-methyl-4- (3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthioph en-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-6-methyl-4- (3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylt hiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5-sulfamoylthiophen-2-yl) -6-me thyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-met hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-met hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-m ethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-et hyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-e thyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) thiophen-2-yl) -N-ethy l-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N, 6-dimethy l-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N, 6-dime thyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiophen-2-yl) -N, 6-dime thyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N, 6 -dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -N, 6-dim ethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiophen-2-yl) -N, 6-dime thyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N, 6-dime thyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) thiophen-2-yl) -N, 6-di methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopro pyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiophen-2-yl) -N-isopro pyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-iso propyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl ) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-is opropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -N-isopro pyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiophen-2-yl) -N-isopro pyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopro pyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) thiophen-2-yl) -N-isop ropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiophen -2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiophen -2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiop hen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thio phen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- (4-fluoro-2, 6-dimethylphenoxy) thiophen -2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiophen -2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) thiophen -2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) thioph en-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen -2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) th iophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-c arboxamide;
4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophe n-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (3-methylpyridin-2-yl) oxy) t hiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-met hylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-met hylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (1-methylpyrrolidin-2-yl) me thoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbo xamide;
N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2 -yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2 -carboxamide;
N-cyclopropyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) -4 -methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
N-cyclopropyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) -4-met hylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-met hylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-cyclopropyl-4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-met hylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (2-hydroxypropan-2-yl) -4- methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbo xamide;
4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N -isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thi ophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-ca rboxamide;
4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophe n-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2 -yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
N-cyclopropyl-4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) th iophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxam ide;
N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxam ide;
N-cyclopropyl-4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) met hoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
N-cyclopropyl-4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropa n-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbo xamide;
N-cyclopropyl-4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxam ide;
N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxam ide;
N-cyclopropyl-4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxam ide;
N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-ethyl-4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen -2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) t hiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) met hoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
N-ethyl-4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thio phen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2 -yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-6-methyl-4- (4-methyl-3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-6-methyl-4- (4-methyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthio phen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-6-methyl-4- (4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfam oylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -4-methyl-5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-methyl-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N, 6-dimethyl-4- (4-methyl-3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-dimeth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-dimeth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N, 6-dimethyl-4- (4-methyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophe n-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N, 6-dimethyl-4- (4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylt hiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-d imethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (4-fluoro-2, 6-dimethylphenoxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-dimet hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-dimeth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-dimeth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-dim ethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4-fluoro-3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-meth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4-fluoro-3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4-fluoro-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylthiophe n-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5-sulfamoylthiophen-2-yl) -6- methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5-sulfamoylthiophen-2-yl) -N-ethyl-6 -methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4-fluoro-3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7 -oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N, 6-dimeth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N, 6-dimeth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4-fluoro-3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -N, 6-di methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4-fluoro-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-di methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimeth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N, 6-dimeth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N, 6-dimeth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5-sulfamoylthiophen-2-yl) -N, 6-dime thyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -4-methyl-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-i sopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -4-methyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2 -yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
4- (5- (dimethylphosphoryl) -4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thio phen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-car boxamide;
4- (5- (dimethylphosphoryl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (5- (dimethylphosphoryl) -3- (4-fluoro-2, 6-dimethylphenoxy) -4-methylthiophen-2-yl)  -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-methyl-3- ( (3-methylpyridin-2-yl) oxy) thi ophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-methy lthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamid e;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-methy lthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamid e;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-methyl-3- ( (1-methylpyrrolidin-2-yl) meth oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-c arboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbo xamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- (4-fluoro-2, 6-dimethylphenoxy) -4-methy lthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamid e;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-methy lthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamid e;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-methy lthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamid e;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-met hylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-is opropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluorothiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluorothiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2- yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiop hen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (5- (dimethylphosphoryl) -4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluorothiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluorothiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluorothiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (3-methylpyridin-2-yl) oxy) thio phen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (1-methylpyrrolidin-2-yl) meth oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-ca rboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-flu orothiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa  mide;
4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thi ophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophe n-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2 -yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thioph en-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbo xamide;
4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2 -carboxamide;
4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiop hen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa  mide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophe n-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
N-cyclopropyl-4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (3-methylpyridin-2-yl) ox y) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan -2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan -2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
N-cyclopropyl-4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-car boxamide;
N-cyclopropyl-4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methyl-5-oxopyrrolidi n-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridin e-2-carboxamide;
N-cyclopropyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethyl butan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-c arboxamide;
N-cyclopropyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (3-hydroxy-2, 3-dimethylbutan -2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan -2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
N-cyclopropyl-4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan -2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (3-hydroxy-2, 3-dimethylbut an-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen -2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiop hen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiop hen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb  oxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) t hiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) met hoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyrid ine-2-carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- (4-fluoro-2, 6-dimethylphenoxy) thiop hen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiop hen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) thiop hen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) thi ophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-ca rboxamide;
4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen -2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen -2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiop hen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thio phen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-car boxamide;
4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen -2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen -2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa  mide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen -2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thioph en-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbo xamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen -2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiop hen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiop hen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) t hiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) met hoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- (4-fluoro-2, 6-dimethylphenoxy) thiop hen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiop hen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) thiop hen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) thi ophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (3-methylpyridin-2-yl) oxy) thio phen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen -2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen -2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methylpyrrolidin-2-yl) metho xy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-ca rboxamide;
N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen -2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen -2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thioph en-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-car boxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-m ethylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2 -carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-m ethylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2 -carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridi ne-2-carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (1-methyl-5-oxopyrrolidin -2-yl) methoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyrid ine-2-carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- (4-fluoro-2, 6-dimethylphenoxy) -4-m ethylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2 -carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-m ethylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2 -carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-m ethylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2 -carboxamide;
4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) -4 -methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridin e-2-carboxamide;
N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-meth ylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-ca rboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-meth ylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-ca rboxamide;
N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (1-methylpyrrolidin-2 -yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2 -carboxamide;
N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (1-methyl-5-oxopyrro lidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyri dine-2-carboxamide;
N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-car boxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-meth ylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-ca rboxamide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-meth ylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-ca rboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-me thylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (3-methylpyridin-2-yl) o xy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) t hiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) t hiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
N-ethyl-4- (4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-c arboxamide;
N-ethyl-4- (4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methyl-5-oxopyrroli din-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyrid ine-2-carboxamide;
N-ethyl-4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimeth ylbutan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2 -carboxamide;
N-ethyl-4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (3-hydroxy-2, 3-dimethylbut an-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) t hiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) t hiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-ca rboxamide;
N-ethyl-4- (4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) thiop hen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) thiop hen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-ethyl-4- (4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) m ethoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide;
N-ethyl-4- (4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (3-hydroxy-3-methylbu tan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-car boxamide;
N-ethyl-4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (3-hydroxy-3-methylbutan-2 -yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) thiop hen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) thiop hen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) thi ophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
4- (5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) methoxy) thiophen-2-yl) -N, 6-d imethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (5-fluoro-3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6 -dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (2-hydroxypropan-2-yl) -3- ( (5-methylpyridin-2-yl) methoxy) thiophen-2-yl) -N, 6-d imethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( ( (2, 4-dimethylpyridin-3-yl) methyl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2 -yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N -ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N -ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thio phen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N -ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (5-methylpyridin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( ( (2, 4-dimethylpyridin-3-yl) methyl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2 -yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (2-hydroxypropan-2-yl) -3- (1- (3-methylpyridin-2-yl) ethoxy) thiophen-2-yl) -N, 6-d imethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (1- (3, 5-dimethylpyridin-2-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (1- (3, 5-dimethylpyridin-4-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N , 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (difluoro (mesityl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimeth yl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (1- (5-fluoro-3-methylpyridin-2-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (1- (4-fluoro-2, 6-dimethylphenyl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (1- (2, 4-dimethylpyridin-3-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (2-hydroxypropan-2-yl) -3- (1- (5-methylpyridin-2-yl) ethoxy) thiophen-2-yl) -N, 6-d imethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (1- (2, 4-dimethylpyridin-3-yl) ethyl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2 -yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- (1- (3-methylpyridin-2-yl) ethoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (1- (3, 5-dimethylpyridin-2-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N -ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (1- (3, 5-dimethylpyridin-4-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N -ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (d2 (mesityl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (difluoro (mesityl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- (1- (5-fluoro-3-methylpyridin-2-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thio phen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- (1- (4-fluoro-2, 6-dimethylphenyl) ethoxy) -5- (2-hydroxypropan-2-yl) thiop hen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (1- (2, 4-dimethylpyridin-3-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N -ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- (1- (5-methylpyridin-2-yl) ethoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (1- (2, 4-dimethylpyridin-3-yl) ethyl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2 -yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (fluoro (3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) fluoromethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2 -yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) fluoromethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2 -yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4- (fluoro (4-fluoro-2, 6-dimethylphenyl) methoxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
4- (4- (d2 (4-fluoro-2, 6-dimethylphenyl) methoxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (fluoro (5-fluoro-3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thioph en-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (fluoro (4-fluoro-2, 6-dimethylphenyl) methoxy) -5- (2-hydroxypropan-2-yl) thiophe n-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (2, 4-dimethylpyridin-3-yl) fluoromethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2 -yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (fluoro (5-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( ( (2, 4-dimethylpyridin-3-yl) fluoromethyl) amino) -5- (2-hydroxypropan-2-yl) thiop hen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- (fluoro (3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thioph en-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-2-yl) fluoromethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2 -yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( (3, 5-dimethylpyridin-4-yl) fluoromethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2 -yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4- (1- (4-fluoro-2, 6-dimethylphenyl) ethoxy) -2- (2-hydroxypropan-2-yl) thiaz ol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- (fluoro (5-fluoro-3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxam ide;
N-ethyl-4- (3- (fluoro (4-fluoro-2, 6-dimethylphenyl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamid e;
4- (3- ( (2, 4-dimethylpyridin-3-yl) fluoromethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2 -yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- (fluoro (5-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thioph en-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- ( ( (2, 4-dimethylpyridin-3-yl) fluoromethyl) amino) -5- (2-hydroxypropan-2-yl) thiop hen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-ethyl-4- (2- (2-hydroxypropan-2-yl) -4- ( (3-methylpyridin-2-yl) oxy) thiazol-5-yl) -6-m ethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (3, 5-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (3, 5-dimethylpyridin-4-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methylpyrrolidin-2-yl) methoxy) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thi azol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5 -yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (2, 4-dimethylpyridin-3-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (4, 6-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (2, 4-dimethylpyridin-3-yl) amino) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N-eth yl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (2- (2-hydroxypropan-2-yl) -4- ( (3-methylpyridin-2-yl) oxy) thiazol-5-yl) -N, 6-dimethy l-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (3, 5-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6-dim ethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (3, 5-dimethylpyridin-4-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6-dim ethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methylpyrrolidin-2-yl) methoxy) thiazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6 -dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6-dim ethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (2, 4-dimethylpyridin-3-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6-dim ethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (4, 6-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6-dim ethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (2, 4-dimethylpyridin-3-yl) amino) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6-di methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (2- (2-hydroxypropan-2-yl) -4- ( (3-methylpyridin-2-yl) oxy) oxazol-5-yl) -6-m ethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (3, 5-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (3, 5-dimethylpyridin-4-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methylpyrrolidin-2-yl) methoxy) oxazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) oxa zol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5 -yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) - 6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (2, 4-dimethylpyridin-3-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (4, 6-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (2, 4-dimethylpyridin-3-yl) amino) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N-ethy l-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (2- (2-hydroxypropan-2-yl) -4- ( (3-methylpyridin-2-yl) oxy) oxazol-5-yl) -N, 6-dimethy l-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (3, 5-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6-dime thyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (3, 5-dimethylpyridin-4-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6-dime thyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methylpyrrolidin-2-yl) methoxy) oxazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) oxazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6 -dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6-dim ethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (2, 4-dimethylpyridin-3-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6-dime thyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (4, 6-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6-dime thyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- ( (2, 4-dimethylpyridin-3-yl) amino) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6-di methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (4- (2, 6-dimethylphenoxy) -1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-5-yl) -N-ethyl -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (1-benzyl-4- (2, 6-dimethylphenoxy) -1H-pyrazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (5- (2-hydroxypropan-2-yl) -1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyraz ol-3-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (1- (2, 6-dimethylbenzyl) -5- (2-hydroxypropan-2-yl) -1H-pyrazol-3-yl) -N-ethyl-6-met hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (1- (2, 6-dimethylbenzyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-4-yl) -N-ethyl-6-met hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (1- (2, 6-dimethylbenzyl) -5- (2-hydroxypropan-2-yl) -1H-pyrazol-4-yl) -N-ethyl-6-met hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- (2-hydroxypropan-2-yl) -1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyraz ol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (1- (2, 6-dimethylbenzyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -N-ethyl-6-met hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (5- (2, 6-dimethylphenoxy) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) -6-methyl-1 H-pyrrolo [2, 3-c] pyridin-7 (6H) -one;
4- (3- (4-chloro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethy l-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (4-chloro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
4- (3- (4-chloro-2, 6-dimethylphenoxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) -4-methylthio phen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4- ( (2- (4-fluoro-2, 6-dimethylphenyl) propan-2-yl) oxy) -2- (2-hydroxypropan -2-yl) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
4- (4- (difluoro (4-fluoro-2, 6-dimethylphenyl) methoxy) -2- (2-hydroxypropan-2-yl) thiaz ol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
N-ethyl-4- (4-fluoro-3- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) -5- (2-hydroxypropan-2-yl) t hiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4-fluoro-3- (1- (4-fluoro-2, 6-dimethylphenyl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide;
N-ethyl-4- (4-fluoro-3- (fluoro (4-fluoro-2, 6-dimethylphenyl) methoxy) -5- (2-hydroxypr opan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-ca rboxamide;
N-ethyl-4- (4-fluoro-3- ( (2- (4-fluoro-2, 6-dimethylphenyl) propan-2-yl) oxy) -5- (2-hydro xypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine -2-carboxamide;
4- (3- (difluoro (4-fluoro-2, 6-dimethylphenyl) methoxy) -4-fluoro-5- (2-hydroxypropan-2 -yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
N-ethyl-4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan -2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
N-ethyl-4- (4-fluoro-3- (1- (5-fluoro-3-methylpyridin-2-yl) ethoxy) -5- (2-hydroxypropan -2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbox amide;
N-ethyl-4- (4-fluoro-3- (fluoro (5-fluoro-3-methylpyridin-2-yl) methoxy) -5- (2-hydroxyp ropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-c arboxamide;
N-ethyl-4- (4-fluoro-3- ( (2- (5-fluoro-3-methylpyridin-2-yl) propan-2-yl) oxy) -5- (2-hydr oxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridin e-2-carboxamide;
4- (3- (difluoro (5-fluoro-3-methylpyridin-2-yl) methoxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2 -carboxamide.
c. Methods of Preparation
Abbreviations: The following abbreviations may be used herein
AcOH Glacial acetic acid
CH 3CN acetonitrile
NH 4OAc Ammonium Acetate
aq or aq. aqueous
PdCl 2 (dppf) 1, 1'-Bis (diphenylphosphino) ferrocene-palladium (II) dichloride
BOC or Boc Tert-butyloxy carbonyl
(Boc)  2O BOC anhydrate
CCl 4 Carbon tetrachloride
Cs 2CO 3 Cesium carbonate
CuO Cuprous oxide
CuCl Copper (I) chloride
CuCl 2. 2H 2O Copper (II) chloride dihydrate
DCE 1, 2-dichloroethane
DCM dichloromethane
DMAP 4-dimethylaminopyridine
DME 1, 2-dimethoxyethane
DMF N, N-dimethylformamide
DMSO Dimethyl sulfoxide
Dppf, DPPF or dppf 1, 1’-bis (diphenylphosphino) ferrocene
eq or eq. or equiv. equivalent
Et Ethyl
Et 2O Diethyl ether
Et 3N Triethyl amine
EtOH Ethanol
EtOAc Ethyl acetate
Fe Iron powder
g grams
h or hr hour
HPLC High pressure liquid chromatography
H 2 Hydrogen gas
H 2O Water
H 2O 2 Hydrogen peroxide
K 2CO 3 Potassium carbonate
MeOH Methanol
NaHCO 3 Sodium bicarbonate
NaIO 4 Sodium Metaperiodate
NaNO 2 Sodium nitrite
Na 2SO 4 Sodium sulphate
NBS N-bromosuccinimide
MeI Methyl iodide
Na 2S 2O 3 Sodium thiosulfate
N 2 Nitrogen gas
O/N Over night
Pd 2 (dba)  3 Tris (dibenzylideneacetone) dipalladium
PE Petroleum ether
KOAc Potassium acetate
K 3PO 4 Potassium phosphate tribasic
rt Room temperature
RT Retention time
Sec or sec. second
sat. aq. Saturated aqueous
SEM 2- (trimethylsilyl) ethoxymethyl
SEM-Cl 2- (trimethylsilyl) ethoxymethyl chloride
TBAF Tetrabutylammonium fluoride
TFA Trifluoroacetic Acid
THF Tetrahydrofuran
TLC Thin layer chromatography
X-Phos or X-phos 2-Dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl
Zn Zink powder
The compounds of the present innovation can be prepared in a number ways well known to one skilled in the art of organic synthesis using the methods described bellow or variations thereon as appreciated by those skilled in the art. Those described bellow are preferred, but a not limited to. The references cited herein are hereby incorporated by reference in their entirety.
The methods of synthesis described herein after are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis.
Compounds of formula (II) may be synthesized by reference to methods illustrated in the following examples. The common intermediate is generally useful for the preparation of more than one Example. As shown herein, the end compound is a product having the same structural formula (II) depicted as formula (II) . It will be understood that any compound of formula (II) may be prepared by the suitable selection of reagents with appropriate substitution. Solvents, temperature, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3 rd edition, John Wiley &Sons) . These groups are removed at certain stage of the compound synthesis using the methods that are apparent to those skilled in the art.
Scheme 1
Figure PCTCN2021105686-appb-000047
Compounds of formula (III) may be synthesized as shown in Scheme 1 by Suzuki coupling reaction (N. Miyama and A. Suzuki, Chem. Rev. 1995, 95: 2457-2483, J. Organomet. Chem. 1999, 576: 147-148) between boronic acids or a derivative thereof (e.g., a pinacol ester) of intermediate 1 and a suitable coupling partner 2, wherein X is halide, e.g., Cl, Br, I, or triflate, R 0-R 4, R 9, X 1, and X 2 are depicted previously in the text or a functional group that can be converted to the desired final substituent.
Scheme 2
Figure PCTCN2021105686-appb-000048
Alternatively, compounds of formula (III) may be synthesized as shown in Scheme 2 by Suzuki coupling reaction (N. Miyama and A. Suzuki, Chem. Rev. 1995, 95: 2457-2483, J. Organomet. Chem. 1999, 576: 147-148) between intermediate 3, wherein X is halide, e.g., Cl, Br, I, or triflate and boronic acids or a derivative thereof (e.g., a pinacol ester) of 4.
General rout to compounds (IV) illustrated in the invention are outlined in Scheme 3, where the R 0-R 4, R 8, R 10, and L are depicted previously in the text. Herein, X is halide, e.g., Cl, Br, and I.
Scheme 3
Figure PCTCN2021105686-appb-000049
General rout to compounds (V) illustrated in the invention are outlined in Scheme 4, where the R 0 -R 4, R 8 -R 10, and L are depicted previously in the text. Herein, X is  halide, e.g., Cl, Br, and I.
Scheme 4
Figure PCTCN2021105686-appb-000050
General rout to compounds (VI) illustrated in the invention are outlined in Scheme 5, where the R 0 -R 4, R 9 -R 10, and L are depicted previously in the text.
Scheme 5
Figure PCTCN2021105686-appb-000051
Structures of compounds are verified by mass spectrometry (MS) or nuclear magnetic resonance (1H NMR) .
Displacement (δ) of the nuclear magnetic resonance (1H NMR) is given in a unit of parts per million (ppm) ; measurement by nuclear magnetic resonance (1H NMR) is carried out on Bruker AVANCE-400 NMR instrument, wherein the measuring solvent is deuterated chloroform (CDCl3) , the internal standard is tetramethyl silane (TMS) , and the chemical displacement is given in a unit of parts per million (ppm) .
HPLC: Agilent 1260 instrument;
MS: Agilent G6120B instrument; Waters XBridge reverse-phase column (C18, 3.5 microns silica, 4.6 mm diameter, 50 mm length, flow rate of 1.0 mL/min) . Eluent A: 0.05%TFA in water; Eluent B: pure CH3CN; Gradient: B 5%2min, 100%2min, 5%2 min. Column temperature: 35 ℃.
Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate is used in the thin layer silica gel assay.
Yantai Huanghai 200-300 mesh silica gel is generally used as a carrier in column chromatography.
Unless otherwise specified, the reactions mentioned in the present invention are carried out under the nitrogen atmosphere.
In the present invention, the term "nitrogen atmosphere" refers, for example, to connecting the reaction flask to a nitrogen balloon with 1L volume.
Unless otherwise specified, the solutions mentioned in the reaction of the present invention refer to the aqueous solutions.
In the present invention, the term "room temperature" refers to the temperature  between 10℃ and 25℃.
Synthesis of Intermediate 1
N-ethyl-6-methyl-7-oxo-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
Figure PCTCN2021105686-appb-000052
Step 1:
(E) -2- (5-bromo-2-methoxy-3-nitropyridin-4-yl) -N, N-dimethylethen-1-amine
To a solution of 5-bromo-2-methoxy-4-methyl-3-nitropyridine (10.0 g, 40.5 mmol) in DMF (150 mL) was dropwisely added MeOLi (0.770 g, 20.3 mmol) at 0 ℃ under N 2. The resulting mixture was warmed to 100 ℃ and stirred for 30 min, followed by dropwise addition of 1, 1-dimethoxy-N, N-dimethylmethanamine (38.6 g, 324 mmol) at 95 ℃. After 60 min, the reaction mixture was slowly poured into an ice-water with stirring, solids came out from the solution, and continued stirring for 30 min. The solids were collected by filtration and washing with cold water (3x) , then dried under vacuum at 50 ℃ to afford the expected intermediate (8.40 g, 69%yield) as a red solids. ESI-MS: m/z = 302/304 (M+H)  +.
Step 2: 4-Bromo-7-methoxy-1H-pyrrolo [2, 3-c] pyridine
To a solution of
(E) -2- (5-bromo-2-methoxy-3-nitropyridin-4-yl) -N, N-dimethylethen-1-amin (8.10 g, 80.4 mmol) in AcOH (80 mL) was added Fe powder in small portions at 0 ℃ under N2. The mixture was stirred for 4h at 110 ℃ , then cooled to rt and diluted with EtOAc (200mL) . The mixture was collected by a filtration through a thin pad of celite with EtOAc (3 x 100 mL) . The obtained organic phase was washed with water (100 mL) , brine (100 mL) , dried under anhydrous Na 2SO 4, and filtered. The filtrate was concentrated on a rotary evaporator and the residue was purified with chromatography on a silica gel column eluting with Et 2O/EtOAc (15: 1 volume ratio) to afford the expected title compound (4.00 g, 66%yield) as a white solids. ESI-MS: m/z = 226/228 (M+H)  +.
Step 3: 4-Bromo-7-methoxy-1-tosyl-1H-pyrrolo [2, 3-c] pyridine
To a solution of 4-bromo-7-methoxy-1H-pyrrolo [2, 3-c] pyridine (5.0 g, 22.0 mmol) in DMF (60 mL) was added NaH (60%, 2.20 g, 55.0 mmol) at 0 ℃ under N 2. The resulting reaction mixture was stirred for 30 min, followed by addition of 4-methylbenzenesulfonyl chloride (7.55 g, 39.6 mmol) . The mixture was warmed to rt and continued stirring for 1 h. The mixture was cooled to 0 ℃ in an ice-water bath, quenched with ice-water (50 mL) and extracted with EtOAc (3 x 50 mL) . The combined organic layers were washed with water (50 mL0, brine (50 mL) , dried under Na2SO4, and filtered. The filtrate was concentrated on a rotary evaporator to afford the crude compound which was purified by chromatography on a silica gel  column eluting with PE/EtOAc (20/1 volume ratio) to afford the title compound (6.2 g, 74%yield) as a white solids. ESI-MS: m/z = 381/383 (M+H)  +.
Step 4: Propyl
4-bromo-7-methoxy-1-tosyl-1H-pyrrolo [2, 3-c] pyridine-2-carboxylate
To a solution of 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo [2, 3-c] pyridine (17.4 g, 45.6 mmol) in THF (170 mL) was dropwisely added (i-Pr)  2NLi (2 M, 34.0 mL, 168 mmol) at -78 ℃ under N 2. The reaction mixture was continued stirring at -65 ℃ for 1 h under N 2, then cooled to -78 ℃ and followed by dropwise addition of propyl carbonochloridate (8.39 g, 68.4 mmol) . After 2 h, the reaction was quenched with addition of sat. aq. NH 4Cl (200 mL) . The reaction mixture was extracted with EtOAc (3 x 200 mL) and the combined organic phases were washed with water (200 mL) and brine (200 mL) , dried under Na 2SO 4 and filtered. The filtrate was concentrated on a rotary evaporator to afford the expected crude title compound (21.3 g, 100 %yield) as an orange oil. ESI-MS: m/z = 467/469 (M+H)  +.
Step 5: Propyl
4-bromo-7-oxo-1-tosyl-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxylate
To a solution of propyl
4-bromo-7-methoxy-1-tosyl-1H-pyrrolo [2, 3-c] pyridine-2-carboxylate (24 g, 51.4 mmol) in CH 3CN (240 mL) was added NaI (11.6 g, 77.1 mmol) Me 3SiCl (8.33 g, 77.1 mmol) at 0 ℃ under N 2 atmosphere. The resulting mixture was warmed to rt, and stirred for 30 min. Water (463 mg, 25.7 mmol) was dropwise added. The mixture was warmed to 60 ℃ and stirred for additional 1 hr. The reaction was cooled to rt and solids came out from the solution. The solids were collected by filtration and re-dissolved in H 2O (250 mL) and EtOAc (200 ml) . After separation, the aqueous layer was extracted with EtOAc (3 x 150 mL) . The combined organic layers were washed with H 2O (200 mL) , brine (3 x 200 mL) , dried under Na 2SO 4, and filtered. The filtrate was concentrated on a rotary evaporator to afford the expected title crude compound (23.3 g, 100 %yield) as a dark brown oil. ESI-MS: m/z = 453/455 (M+H)  +.
Step 6:
4-Bromo-N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
To a solution of propyl 4-bromo-7-oxo-1-tosyl-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxylate (23.3 g, 51.4 mmol) in DMF (230 mL) was was added Cs 2CO 3 (25.1 g, 77.1 mmol) , stirred for 10 min, followed by addition of MeI (10.9 g, 77.1 mmol) at 0 ℃. The reaction was warmed to rt and stirred for 1h until completion of the reaction. The reaction mixture was cooled to 0 ℃, poured into H 2O (1000 mL) and extracted with EtOAc (3 x 300 mL) . The combined organic layers were washed with H 2O (200 mL) , brine (200 mL) , dried under Ns 2SO 4, and filtered. The filtrate was concentrated on a rotary evaporator. The residue was purified using a silica gel chromatography eluting with PE/EtOac (4/1 volume ratio) to afford the title compound (13.8 g, 57%yield) as a light yellow solids. ESI-MS: m/z = 467/469 (M+H)  +;  1H NMR (400 MHz, d 6-DMSO) δ 8.29 (d, J = 8.4 Hz, 2H) , 7.95 (s, 1H) , 7.52 (d, J = 8.0 Hz, 2H) , 7.04 (s, 1H) , 4.31 (t, J = 6.4 Hz, 2H) , 3.45 (s, 3H) , 2.43 (s, 3H) , 1.79 –1.70 (m, 2H) , 0.97 (t, J = 7.2 Hz, 3H) .
Step 7:
4-Bromo-N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbo  xamide
To a high pressure reaction container was charged with 4-bromo-N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (1.70 g, 3.64 mmol) , MgOMe (1.10 g, 12.7 mmol) , a solution of ethylamine (2M, 20.0 mL, 40.0 mmol) in THF , and MeOH (16 mL) . The resulting mixture was flushed with N 2 for 10 sec., sealed, warmed to 55 ℃, and stirred for 4 h. The reaction mixture was cooled to rt and the solvent was taken off. The residue was purified using liquid chromatography eluting with DCM/MeOH (10/1 volume ratio) to afford the title compound (756 mg, 70 %yield) as a white solids. ESI-MS: m/z = 298/300 (M+H)  +;  1H NMR (400 MHz, d 6-DMSO) δ 12.61 (s, 1H) , 8.46 (t, J = 4.2 Hz, 1H) , 7.61 (s, 1H) , 6.87 (d, J = 2.0 Hz, 1H) , 3.50 (s, 3H) , 3.31-3.26 (m, 2H) , 1.14 (t, J = 7.2 Hz, 3H) .
Step 8:
N-ethyl-6-methyl-7-oxo-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Intermediate 1)
To a solution of 4-bromo-N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (500 mg, 1.68 mmol) in a degassed 2-methyl -tetrahydrofurane (30 ml) was charged with 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (860 mg, 3.36 mmol) , X-Phos (80.0 mg, 0.168 mmol) and KOAc (500 mg, 5.04 mmol) respectively under a N 2 stream. The reaction mixture was vacuumed, backfilled with N 2, and this procedure was repeated three times, followed by addition of Pd 2 (dba)  3 (80.0 mg, 0.0840 mmol) . After the mixture was vacuumed, backfilled with N 2, and this procedure was repeated three times. The reaction mixture was then warmed to 75 ℃ and stirred O/N. The reaction mixture was cooled to rt, followed by addition of ammonium pyrrolidine dithiocarbamate (69.0 mg, 0.420 mmol) , EtOAc (20 mL) and water (20 mL) . The mixture was continued stirring for 30 min. The two layers were separated, the aqueous layer was extracted with EtOAc (2 x 20 mL) . The combined organic layers were washed with brine (10 mL) , dried under Na 2SO 4, and filtered. The solvent of the filtrate was taken off. The residue was purified using a high pressure liquid chromatography to afford the title compound (210 mg, 36%yield) . ESI-MS: m/z = 346.31 (M+H)  +;  1H NMR (400 MHz, DMSO-d 6) δ 12.12 (s, 1H) , 8.39 (t, J = 4.2 Hz, 1H) , 7.60 (s, 1H) , 7.05 (d, J = 2.4 Hz, 1H) , 3.51 (s, 3H) , 3.29-3.25 (m, 2H) , 1.31 (s, 12H) , 1.13 (t, J = 7.2 Hz, 3H) .
Example 1
4- (5- (2, 6-Dimethylphenoxy) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) -6-methy l-1, 6-dihydro-7H-pyrrolo [2, 3-c] pyridin-7-one
Figure PCTCN2021105686-appb-000053
Step1:
4-Bromo-7-methoxy-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-c] pyridine
Figure PCTCN2021105686-appb-000054
To a solution of 4-bromo-7-methoxy-1H-pyrrolo [2, 3-c] pyridine (obtained from Step 2 of the synthesis of intermediate, 1.01 g, 4.00 mmol) in anhydrous of THF (10 mL) was added NaH (60 %, 0.176 g, 4.40 mmol) in portions over 1 0 sec. at 0 ℃ under a nitrogen atmosphere. The resulting mixture was stirred for 1 hr, followed by dropwise addition of SEM-Cl (0.600 g, 4.80 mmol) . The reaction mixture was warmed to rt and 2 h later, the reaction was completed based on LC/MS. The mixture was slowly poured into an ice-water (50 mL) . The two phases were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL) . The combined organic layers were washed with brine (50 mL) , dried under Na 2SO 4, and filtered. The solvent was taken off. The crude residue was purified on silica gel chromatography eluting with PE/EtOAc (20/1 ～ 10/1 volume ratio) to afford the title compound (1.33 g, 84%yield) as a yellow oil. ESI-MS: m/z = 357/359 (M+H)  +.
Step 2:
4-Bromo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1, 6-dihydro-7H-pyrrolo [2, 3-c] pyridin-7-one
Figure PCTCN2021105686-appb-000055
To a solution of 4-bromo-7-methoxy-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2, 3-c] pyridine in CH 3CN (50 mL) was added NaI (2.52 g, 16.8 mmol) . The mixture was cooled to 0 ℃ and followed dropwise addition of TMSCl (1.82 g, 16.8 mmol) . The reaction mixture was warmed to rt and stirred O/N. The mixture was slowly poured into an ice-water (50 mL) and extracted with EtOAc (3 x 50 mL) . The combined organic layers were washed with brine (50 mL) and dried over Na 2SO 4. After filtration, the collected organic phase was concentrated on a rotary evaporator and the residue was purified on a silica gel column eluting with PE/EtOAc (1/1 volume ratio) to afford the title compound (3.22 g, 85%yield) as a white solids. ESI-MS: m/z = 343/345 (M+H)  +.
Step 3:
4-Bromo-6-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1, 6-dihydro-7H-pyrrolo [2, 3-c] pyridin-7-one
Figure PCTCN2021105686-appb-000056
To a solution of
4-bromo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1, 6-dihydro-7H-pyrrolo [2, 3-c] pyridin-7-one (3.10 g, 9.02 mmol) in DMF (50 mL) was added Cs 2CO 3 (5.86 g, 18.0  mmol) in several portions at rt. The resulting mixture was stirred for 10 min, followed by addition of MeI (2.56 g, 18.0 mmol) at rt , and continued stirring O/N. The solvent was taken off on a rotary evaporator and the residue was purified using a liquid chromatography eluting with PE/EtOAc (3/1 volume ratio) to afford the title intermediate (1.88 g, 58 %yield) as a white solid. ESI-MS: m/z = 357/359 (M+H)  +.
Step 4:
6-Methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1, 6-dihydro-7H-pyrrolo [2, 3-c] pyridin-7-one
Figure PCTCN2021105686-appb-000057
To a solution of
4-bromo-6-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1, 6-dihydro-7H-pyrrolo [2, 3-c] pyridin-7-one (0.940 g, 2.63 mmol) in degassed 1, 4-dioxane (20 mL) was added 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (1.67 g, 6.58 mmol) , X-Phos (0.0630 g, 6.58 mmol) and KOAc (0.773 g, 7.89 mmol) respectively at rt under a N 2 stream. The resulting mixture was vacuumed, backfilled with N 2, and this sequence was repeated three times. PdCl 2 (dppf) (96.0 mg, 2.63 mmol) was added at rt under a N 2 stream. The resulting mixture was warmed to 65 ℃ and stirred O/N. Most of the solvent was taken off on a rotary evaporator and the residue was purified using liquid chromatography eluting with PE/EtOAc (8/1 ～ 6/1 volume ratio) to afford the title intermediate (0.701 g, 66%yield) as a white solid. ESI-MS: m/z = 405 (M+H)  +.
Step 5:
(6-Methyl-7-oxo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridin-4-yl) boronic acid
Figure PCTCN2021105686-appb-000058
To a solution of 6-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- ( (2- (trimethylsilyl) ethoxy) methyl) -1, 6-dihydro-7H-pyrrolo [2, 3-c] pyridin-7-one in acetone/H 2O (15 mL/15 mL) was added NH 4OAc (0.812 g, 10.5 mmol) and NaIO 4 (2.10 g, 10.5 mmol) respectively at rt. The resulting mixture was stirred for 2 h. The organic solvent was removed on a rotary evaporator. The remaining aqueous layer was extracted with EtOAc (2 x 15 mL) . The combined organic layers were washed with brine (10 mL) , dried under Na 2SO 4, and filtered. The filtrate was concentrated on a rotary evaporator. The residue was purified using liquid chromatography eluting with EtOAc to afford the expected title intermediate (0.340 g, 60%yield) as a white solids. ESI-MS: m/z = 323 (M+H)  +.
Step 6: Methyl 5-hydroxy-1H-pyrazole-3-carboxylate
Figure PCTCN2021105686-appb-000059
To a solution of dimethyl but-2-ynedioate (1.16 g, 8.13 mmol) in acetic acid/toluene (1.8 mL/3.0 mL) was added hydrazine (0.448 g, 8.95 mmol) at rt. The reaction mixture was stirred O/N at rt. The reaction mixture was poured into an ice-water (10 mL) . Solids came out from the solution, which was collected by filtration and washing with water (3 x 10 mL) and PE (3 x 10 mL) . The solids were dried in an oven under vacuum to afford the title intermediate (0.810 g, 70%yield) as a white solids. ESI-MS: m/z = 143 (M+H)  +.
Step 7: 1- (Tert-butyl) 3-methyl 5-hydroxy-1H-pyrazole-1, 3-dicarboxylate
Figure PCTCN2021105686-appb-000060
To a solution of methyl 5-hydroxy-1H-pyrazole-3-carboxylate (2.20 g, 15.5 mmol) in acetonitrile (40 mL) was added Et 3N (1.7 mL, 22.5 mmol) at 0 ℃. To the resulting cloudy mixture was dropwise added (Boc)  2 O (3.8 mL, 16.5 mmol) . The resulting reaction was warmed to rt and continued stirring O/N. The solvent was taken off and the residue was purified using liquid chromatography eluting with PE/EtOAc (3/1 volume ratio) to afford the title intermediate (2.18 g, 58%yield) as a white solids. ESI-MS: m/z = 243 (M+H)  +.
Step 8: 1- (Tert-butyl)
3-methyl-5- (2, 6-dimethylphenoxy) -1H-pyrazole-1, 3-dicarboxylate
Figure PCTCN2021105686-appb-000061
To a solution of 1- (tert-butyl) 3-methyl 5-hydroxy-1H-pyrazole-1, 3-dicarboxylate (0.432 g, 1.78 mmol) in DCM (40 mL) in a round bottom flask was added (2, 6-dimethylphenyl) boronic acid (1.47 g, 9.79 mmol) , CuO (0.225 g, 1.78 mmol) , pyridine (0.700 mL, 8.9 mmol) and a few active molecular sieve. The flask was sealed and the resulting reaction mixture was stirred for six days at rt. The solvent was taken off and the resulting residue was purified using a liquid chromatography eluting with PE/EtOAc (6: 1 volume ratio) to afford the expected title intermediate (0.230 g, 38%yield) as a yellow oil. ESI-MS: m/z = 347 (M+H)  +.
Step9: Methyl 5- (2, 6-dimethylphenoxy) -1H-pyrazole-3-carboxylate
Figure PCTCN2021105686-appb-000062
To a solution of 1- (tert-butyl) 3-methyl  5- (2, 6-dimethylphenoxy) -1H-pyrazole-1, 3 -dicarboxylate (1.01 g, 4.00 mmol) in DCM (3 mL) was dropwise added 2, 2, 2-trifluoroacetic acid (0.500 mL, 6.75 mmol) at 0 ℃. The reaction mixture was warmed to rt and stirred O/N. The solvent was taken off and the residue was purified using liquid chromatography eluting with PE/EtOAc (6: 1 volume ratio) to afford the title intermediate (0.101 g, 61%yield) as a white solids. ESI-MS: m/z = 247 (M+H)  +.
Step 10: Methyl
5- (2, 6-dimethylphenoxy) -1- (6-methyl-7-oxo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridin-4-yl) -1H-pyrazole-3-carboxylate
Figure PCTCN2021105686-appb-000063
To a solution of methyl 5- (2, 6-dimethylphenoxy) -1H-pyrazole-3-carboxylate (50 mg, 0.155 mmol) and (6-methyl-7-oxo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridin-4-yl) boronic acid (from Intermediate, Step 5, 25.0 mg, 0.100 mmol) in CH 3CN (2 mL) was added Cu (OAc)  2 (31.0 mg, 0.155 mmol) , followed by addition of pyridine (0.05 mL) and few active molecular sieve. The reaction mixture was flushed with N 2 gas, sealed, and stirred at rt for 3 days. The reaction mixture was concentrated to ～0.5 mL and the residue was purified on a thin layer silica gel plate developing with PE/EtOAc (2: 1 volume ratio) to afford the title intermediate (5 mg, 9%yield) as a brown oil. ESI-MS: m/z = 523 (M+H)  +.
Step 11:
4- (5- (2, 6-Dimethylphenoxy) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) -6-methyl-1- ( (2- (trimethylsilyl) ethoxy) methyl) -1, 6-dihydro-7H-pyrrolo [2, 3-c] pyridin-7-one
Figure PCTCN2021105686-appb-000064
To a solution of methyl
5- (2, 6-dimethylphenoxy) -1- (6-methyl-7-oxo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridin-4-yl) -1H-pyrazole-3-carboxylate (5.00 mg, 0.00958 mmol) in anhydrous THF (2 mL) was slowly dropwise added MeMgBr (1 M, 0.05 mL, 0.05 mmol) at 0 ℃ under N 2. The reaction mixture was warmed rt and continued stirring for 3 h. The reaction was completed based on LC/MS. The  reaction was quenched by addition of sat. aq. NH4Cl (2 mL) . The reaction mixture was extracted with EtOAc (3 x 5 mL) . The combined organic layers were washed with brine, dried under Na 2SO 4, and filtered. The filtrate was concentrated to afford the title crude intermediate (5 mg, 100%yield) as an light brown solids. ESI-MS: m/z = 523 (M+H)  +.
Step 12:
4- (5- (2, 6-Dimethylphenoxy) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2, 3-c] pyridin-7-one
Figure PCTCN2021105686-appb-000065
To a solution of methyl
5- (2, 6-dimethylphenoxy) -1- (6-methyl-7-oxo-1- ( (2- (trimethylsilyl) ethoxy) methyl) -6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridin-4-yl) -1H-pyrazole-3-carboxylat e (5 mg, 0.00958 mmol) in anhydrous THF (2 mL) was added TBAF (0.0125 mg, 0.0479 mmol) at rt. The resulting mixture was warmed to 75 ℃ and stirred for 5 h. The mixture was purified on a high pressure liquid chromatography to afford 0.54 mg, 14%yield) as a white solids. ESI-MS: m/z = 393 (M+H)  +.
Example 2
4- (4- (2, 6-Dimethylphenoxy) -1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
Figure PCTCN2021105686-appb-000066
Step 1: 1-Benzyl-1H-pyrazol-4-ol
Figure PCTCN2021105686-appb-000067
To a solution of
1-benzyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (5.00 g, 17.6 mmol) in THF (100 mL) was dropwise added NaOH (2M, 17.6 mL, 35.2 mmol) and hydrogen peroxide (30%, 3.75 mL, 35.2 mmol) at 0 ℃ respectively. The resulting mixture was warmed to rt and continued stirring for 16 h. A saturated aqueous solution of sodium thiosulfate was added (6.96 g, 44.0 mmol) with stirring. After 30 min, most of the organic solvent was taken off and water (100 ml) was added to  dissolve the residue. The aqueous solution was extracted with EtOAc (2 x 100 mL) . The combined organic layers were dried under anhydrous Na 2SO 4, filtered through a thin pad of celite with EtOAc. The collected organic phase was concentrated on a rotary evaporator to afford the title crude intermediate (3.00 g, 98%yield) as a yellow solids. ESI-MS: m/z = 175 (M+H)  +.
Step 2: 1-Benzyl-4- (2, 6-dimethyl-4-nitrophenoxy) -1H-pyrazole
Figure PCTCN2021105686-appb-000068
To a solution of 1-benzyl-1H-pyrazol-4-ol (3.00 g, 17.2 mmol) in CH 3CN (50 mL) in a pressure round bottom bottle was added 2-fluoro-1, 3-dimethyl-5-nitrobenzene (2.62 g, 15.5 mmol) and K 2CO 3 (4.76, 34.4 mmol) respectively at rt under N 2. The reaction vessel was sealed, the mixture was warmed to 85 ℃ and continued stirring O/N. After cooling to rt, most of the solvent was taken off and the residue was dissolved in water (50 mL) . The resulting aqueous layer was extracted with EtOAc (2 x 50 mL) . The combined organic layers were washed with brine (20 mL) , dried under Na 2SO 4, filtered through a thin pad of celite using EtOAc (20 mL) . The filtrate was concentrated on a rotary evaporator to afford the title crude intermediate (4.80 g, 96%yield) as a yellow solids. ESI-MS: m/z = 324 (M+H)  +.
Step 3: 4- ( (1-Benzyl-1H-pyrazol-4-yl) oxy) -3, 5-dimethylaniline
Figure PCTCN2021105686-appb-000069
To a solution of 1-benzyl-4- (2, 6-dimethyl-4-nitrophenoxy) -1H-pyrazole (3.50 g, 11.9 mmol) in DCM (100 mL) was added Zn powder (1.93 g, 29.8 mmol) in portions at 0 ℃, followed by dropwise addition of glacial acetic acid (1.78 g, 29.8 mmol) . The reaction temperature was raised to rt and continued stirring O/N. The reaction mixture was filtered through a thin pad of celite with DCM (30 mL) . The filtrate was neutralized with carefully addition of sat. NaHCO3 to pH 7～8. The two layers were separated, the organic phase was washed with brine (30 mL) , dried under Na2SO4, and filtered. The filtrate was concentrated on a rotary evaporator. The crude residue was purified on a silica gel column using liquid chromatography eluting with PE/EtOAc (1/1 volumetric ratio) to afford the expected title intermediate (3.50 g, 80%yield) as a yellow oil. ESI-MS: m/z = 294 (M+H)  +.
Step 4: 1-Benzyl-4- (2, 6-dimethylphenoxy) -1H-pyrazole
Figure PCTCN2021105686-appb-000070
To a solution of 4- ( (1-benzyl-1H-pyrazol-4-yl) oxy) -3, 5-dimethylaniline (3.50 g,  11.9 mmol) in EtOH/MeOH (20: 1 volume ratio, 100 mL) was added CuCl 2.2H 2O (2.42 g, 17.9 mmol) and followed by dropwise addition of tert-butyl nitrite (1.85 g, 17.9 mmol) at rt under N 2. The resulting mixture stirred at rt O/N. The reaction mixture was passed through a thin pad of celite with EtOH (50 mL) . The filtrate was concentrated on a rotary evaporator. The residue was partitioned between EtOAc (100 mL) and water (100 mL) . The two layers were separated and the organic phase was washed with brined, dried under Na 2SO 4, and filtered. The filtrate was concentrated and the residue was purified on a silica gel column using liquid chromatography eluting from PE to PE/EtOAc (3/1 volumetric ratio) to afford the expected title intermediate (2.54 g, 76%yield) as a yellow oil. ESI-MS: m/z = 279 (M+H)  +.
Step 5: 4- (2, 6-Dimethylphenoxy) -1H-pyrazole
Figure PCTCN2021105686-appb-000071
To a solution of 1-benzyl-4- (2, 6-dimethylphenoxy) -1H-pyrazole in MeOH (10 mL) was added Pd/C (130 mg) at rt under a N 2 stream. The mixture was vacuumed, backfilled with H 2, and this sequence was repeated three times. The resulting mixture was stirred at rt with a H 2 balloon O/N. The reaction mixture was cautiously passed through a thin pad of celite with MeOH (15 mL) . The collected organic phase was concentrated on a rotary evaporator to afford the crude expected title intermediate (825 mg, 98%yield) as an off-white solids. ESI-MS: m/z = 189 (M+H)  +.
Step 6: 1- (4- (2, 6-Dimethylphenoxy) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
Figure PCTCN2021105686-appb-000072
To a solution of 4- (2, 6-dimethylphenoxy) -1H-pyrazole in DMF (10 mL) was added 2, 2-dimethyloxirane (612 mg, 8.51 mmol) and Cs 2CO 3 (4.16 g, 12.7 mmol) respectively at rt. The resulting was warmed to 90 ℃ and continued stirring O/N. After cooling down to rt, water (100 mL) and EtOAc (100 mL) were added. The two layers were separated. The organic phase was washed with brine (2 x 50 mL) , dried under Na 2SO 4, and filtered. The filtrate was concentrated on a rotary evaporator to afford the expected crude title intermediate (830 mg, 75 %yield) as a light yellow oil. ESI-MS: m/z = 261 (M+H)  +.
Step 7:
1- (5-Bromo-4- (2, 6-dimethylphenoxy) -1H-pyrazol-1-yl) -2-methylpropan-2-ol
Figure PCTCN2021105686-appb-000073
To a solution of
1- (4- (2, 6-dimethylphenoxy) -1H-pyrazol-1-yl) -2-methylpropan-2-ol (600 mg, 2.31  mmol) in TFA (5 mL) was added NBS (493 mg, 2.77 mmoL) at 0 ℃ under N 2. The resulting mixture was stirred for 2 h and the reaction was completed based on TLC. The solvent was taken off and the residue was purified on a thin layer chromatography plate with a developing solvent PE/EtOAc (5/1 volumetric ratio) to afford the expected title intermediate (155 mg, 20 %yield) as a yellow solids. ESI-MS: m/z = 339/341 (M+H)  +.
Step 8:
4- (4- (2, 6-Dimethylphenoxy) -1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
Figure PCTCN2021105686-appb-000074
To a solution of
1- (5-bromo-4- (2, 6-dimethylphenoxy) -1H-pyrazol-1-yl) -2-methylpropan-2-ol (50.0 mg, 0.150 mmol) and N-ethyl-6-methyl-7-oxo-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Intermediate 1, 51.0 mg, 0.150 mmol) in degassed 1, 4-dioxane (5 mL) in a round bottom flask was added X-phos (7.10 mg, 0.0150 mmol) and KOAc (32.0 mg, 0.300 mmol) respectively. The reaction mixture was vacuumed, backfilled with N 2, and this sequence was repeated three times. Pd 2 (dba)  3 (6.90 mg, 0.00750 mmol) was added at rt under a N 2 steam. The round bottom flask with reaction mixture was sealed and the reaction mixture was warmed to 80 ℃, with stirring O/N. The reaction mixture was cooled to rt, filtered through a thin pad of celite with DCM (30 mL) . The solvent was taken off and the residue was purified on high pressure liquid chromatography eluting with CH 3CN in H 2O (0%to 85%) to afford the expected title compound (5.90 mg, 8%yield) as a white solids. ESI-MS: m/z = 478 (M+H)  +.
Example 3
4- (1-Benzyl-4- (2, 6-dimethylphenoxy) -1H-pyrazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
Figure PCTCN2021105686-appb-000075
Step 1:
1-Benzyl-4- (2, 6-Dimethylphenoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole
To a solution 1-benzyl-4- (2, 6-dimethylphenoxy) -1H-pyrazole (from Step 4 of Ex. 2, 1.25 g, 4.50 mmol) in n-heptane (30 mL) in a pressure tube was added In (COD)  2 (OMe)  2 (24.0 mg, 0.203 mmol) , 4, 4'-Di-tert-butyl-2, 2'-bipyridine (24.0 mg, 0.0900 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (1.73 g, 13.5 mmol) respectively at rt. The tube was flushed with a N 2 stream for 5 sec and sealed. The temperature of resulting reaction mixture was raised to 70 ℃ under N 2 and stirred O/N. The reaction mixture was cooled to rt and the solvent was taken off. The residue was purified using a high pressure liquid chromatography eluting with solvent? to afford the expected title intermediate (890 mg, 49%yield) as light yellow solids. ESI-MS: m/z = 405 (M+H)  +.
Step 2:
4- (1-Benzyl-4- (2, 6-dimethylphenoxy) -1H-pyrazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
To a solution of
1-benzyl-4- (2, 6-dimethylphenoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1 H-pyrazole (89.0 mg, 0.220 mmol) and
4-bromo-N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxam ide (Intermediate 1, 66.0 mg, 0.22 mmol) in degassed 1, 4-dioxane (5 mL) in a round bottom flask was added X-phos (9.50 mg, 0.0200 mmol) and KOAc (43.0 mg, 0.440 mmol) at rt under N 2. The flask was vacuumed, backfilled with N 2, and this sequence was repeated three times. Pd 2 (dba)  3 (9.20 mg, 0.0100 mmol) was added under N 2 and the reaction flask was flushed with N 2 for 5 sec and sealed. The reaction mixture was stirred at 80 ℃ under N 2 in a silica oil bath O/N. The reaction was completed based on LC/MS. The reaction mixture was cooled to rt and passed through a thin pad of celite. The collected solution was concentrated on a rotary evaporator and the residue was purified using reverse phase high pressure liquid chromatography to afford the expected title compound (1.00 mg, 1%yield) as a white solids. ESI-MS: m/z =496 (M+H)  +.
Example 4
4- (1- (2, 6-Dimethylbenzyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-4-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Region isomer 4A)
and
4- (1- (2, 6-Dimethylbenzyl) -5- (2-hydroxypropan-2-yl) -1H-pyrazol-4-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Region isomer 4B)
Figure PCTCN2021105686-appb-000076
Step 1: Methyl 4-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazole-3-carboxylate (region isomer 4-1A) and methyl
4-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazole-5-carboxylate (region isomer 4-1B)
Figure PCTCN2021105686-appb-000077
To a solution of methyl 4-bromo-1H-pyrazole-3-carboxylate (500 mg, 2.44 mmol) in CH 3CN (10 mL) in a round bottom flask was added 2- (bromomethyl) -1, 3-dimethylbenzene (485 mg, 2.44 mmol) and Cs 2CO 3 (1.59 g, 4.88 mmol) at rt. The reaction mixture was stirred at 75 ℃ in a preheated oil bath O/N. The reaction was completed based on TLC. The temperature of the reaction mixture was cooled to rt, diluted with EtOAc (50 mL) and water (50 mL) . The two layers were separated. The organic phase was washed with brine (50 mL) , dried under Na 2SO 4 and filtered. The solvent was taken off and the crude compound was purified using a thin layer chromatography with PE/EtOAc (5/1 volumetric ratio) to afford two region isomers: 4-1 A (less polar component, 315 mg, 40%yield) intermediate as a light yellow solids, RT = 3.03 min, ESI-MS: m/z =323/325 (M+H)  +; 4-1B (more polar component, 290 mg, 37%yield) as a light yellow solids, RT = 2.80 min, ESI-MS: m/z =323/325 (M+H)  +.
The following reactions were run in parallel.
Step 2: 2- (4-Bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazol-3-yl) propan-2-ol (region isomer 4-2A) and
2- (4-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazol-5-yl) propan-2-ol (region isomer 4-2B)
Figure PCTCN2021105686-appb-000078
To a solution of methyl
4-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazole-3-carboxylate (region isomer 4-1A, 150 mg, 0.460 mmol) in anhydrous THF (5 mL) was slowly dropwise added MeMgBr (3.0 M, 0.500 mL, 1.50 mmol) at -60 ℃ under N 2. The resulting reaction mixture was stirred for 1 h, then slowly warmed to rt and continued stirring for 1h. The reaction was completed based on LC/MS and quenched with addition of sat. aq. NH 4Cl (2 mL) solution. The solvent was taken off and the residue was purified using a high pressure reverse phase liquid chromatography to afford the expected title intermediate (region isomer 4-2A, 30.0 mg, 20%yield) as a white solids. ESI-MS: m/z =323/325 (M+H)  +.
The same procedure was followed to convert methyl 4-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazole-5-carboxylate (region isomer 4-1B) to 2- (4-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazol-5-yl) propan-2-ol (region isomer 4-2B, 40 mg, 27%yield) as a white solids. ESI-MS: m/z = 323/325 (M+H)  +.
Step 3:
4- (1- (2, 6-Dimethylbenzyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-4-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (region isomer 4A)
and
4- (1- (2, 6-dimethylbenzyl) -5- (2-hydroxypropan-2-yl) -1H-pyrazol-4-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (region isomer 4B)
To a solution of 2- (4-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazol-3-yl) propan-2-ol (region isomer 4-2A, 30.0 mg, 0.0929 mmol) and N-ethyl-6-methyl-7-oxo-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Intermediate 1 , 32.0 mg, 0.0929 mmol) in a degassed 1, 4-dioxane (5 mL) in a round bottom flask was charged with X-phos (4.4 mg, 0.00929 mmol) and KOAc (22.0 mg, 0.200 mmol) at rt under N 2. The round bottom flask was vacuumed, back filled with N 2, and this sequence was repeated three times. Pd 2 (dba)  3 (4.30 mg, 0.00465 mmol) was added, and the flask was flushed with N 2 for 5 sec and sealed. Then the reaction mixture was stirred at 80 ℃ in a pre-heated oil bath O/N. The reaction was completed based on LC/MS. The temperature was cooled to rt, and the reaction mixture was passed through a thin pad of celite with DCM (20 mL) . The solvent was taken off and the residue was purified using a high pressure reverse phase liquid chromatography to afford the expected title compound (regioisomer 4-3A, 2.30 mg, 5%yield) as a white solids. ESI-MS: m/z = 462 (M+H)  +.
The same procedure was followed to convert 2- (4-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazol-5-yl) propan-2-ol (region isomer 4-2B)  to 4- (1- (2, 6-dimethylbenzyl) -5- (2-hydroxypropan-2-yl) -1H-pyrazol-4-yl) -N-ethyl-6-met hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide region isomer 4-3B, 8.0 mg, 14%yield) as a white solids. ESI-MS: m/z = 462 (M+H)  +.
Example 5
N-ethyl-4- (5- (2-hydroxypropan-2-yl) -1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazol-3-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbo xamide (Region isomer 5A)
and
N-ethyl-4- (3- (2-hydroxypropan-2-yl) -1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-p yrazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (region isomer 5B)
Figure PCTCN2021105686-appb-000079
Step 1: Methyl
3-bromo-1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazole-5-carboxylate (Region isomer 5-1A)
and
Methyl
5-bromo-1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazole-3-carboxylate (Region isomer 5-1B)
Figure PCTCN2021105686-appb-000080
To a solution of methyl 5-bromo-1H-pyrazole-3-carboxylate (500 mg, 2.45 mmol) in CH 3CN (5 mL) in a round bottom flask was added 4- (bromomethyl) tetrahydro-2H-pyran (526 mg, 2.94 mmol) and K 2CO 3 at rt. The flask was flushed with N 2 and sealed. The reaction mixture was stirred at 80 ℃ in a preheated oil bath O/N. The reaction was completed based on TLC and cooled to rt. Most of the solvent was taken off and the residue was partitioned between EtOAc (50  mL) and H 2O (50 mL) . The two layers were separated and the aqueous phase was extracted with EtOAc (2x 50 mL) . The combined organic layers were washed with brine (50 mL) , dried under Na 2SO 4 and filtered. The filtrate was concentrated on a rotary evaporator. The resulted residue was purified using a chromatography eluting with PE/EtOAc (8/1 volume ratio) to afford the expected two title region isomers: 5-1A (less polar component, 430 mg, 58%yield) as an off-white solid, RT = 2.30 min, ESI-MS: m/z = 304.20 (M+H)  +, and 5-1B (more polar component, 300 mg, 40 %yield) as an off-white solid, RT = 1.94 min, ESI-MS: m/z = 303/305 (M+H) +..
The following reactions were run in parallel.
Step 2:
2- (3-Bromo-1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazol-5-yl) propan-2-ol (region isomer 5-2A)
and
2- (5-Bromo-1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazol-3-yl) propan-2-ol (region isomer 5-2B)
Figure PCTCN2021105686-appb-000081
To a solution of methyl 3-bromo-1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazole-5-carboxylate (Region isomer 5-1A, 330 mg, 1.09 mmol) in anhydrous THF (5 mL) was slowly dropwise added MeMgBr (1M, 10.9 mL, 10.9 mmol) at 0 ℃ under N 2. The resulting reaction mixture was slowly warmed to rt and continued stirring O/N. The reaction was completed based on LC/MS. The mixture was slowly poured into sat. aq. NH 4Cl (50 mL) and extracted with EtOAc (2 x 50 mL) . The combined organic layers were washed with brine (30 mL) , dried under Na 2SO 4, and collected by filtration. The filtrate was concentrated on a rotary evaporator and the residue was purified by a silica gel chromatography eluting with PE/EtOAc (4/1 volume ratio) to afford the expected intermediate (Region isomer 5-2A, 189 mg, 57%yield) as an off-white solids. ESI-MS: m/z = 303/305 (M+H)  +.
Region isomer 5-2B was made using the same procedure as above (165 mg, 61%yield) as an off-white solids. ESI-MS: m/z = 303/305 (M+H)  +.
Step 3:
N-ethyl-4- (5- (2-hydroxypropan-2-yl) -1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-p yrazol-3-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de (Region isomer 5A)
and
N-ethyl-4- (3- (2-hydroxypropan-2-yl) -1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-p yrazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de (region isomer 5B)
To a solution of 2- (3-Bromo-1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazol-5-yl) propan-2-ol (region isomer 5-2A, 142 mg, 0.470 mmol) in THF/H 2O (15 mL/1.5 mL) in a round bottom flask was charged with N-ethyl-6-methyl-7-oxo-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Intermediate1, 195 mg, 0.564 mmol) , X-Phos (22.4 mg, 0.0470 mmol) and K 3PO 4 (299 mg, 1.41 mmol) at rt under N 2. The flask was vacuumed, backfilled with N 2, and this sequence was repeated three times. Pd 2 (dba)  3 (21.5 mg, 0.0235 mmol) was added at rt in one portion under N 2. The flask was vacuumed, back filled with N 2, and sealed. Then the reaction mixture was warmed 65 ℃ and stirred O/N. The reaction was completed based on LC/MS. The reaction mixture was cooled to rt and passed through a thin pad of celite with EtOAc (50 mL) . The collected organic phase was washed with brine (30 mL) , dried under Na 2SO 4 and collected by filtration. The filtrate was concentrated on a rotary evaporator and the resulting residue was purified using a reverse phase high pressure liquid chromatography with CH 3CN (0%～ 75%) in H 2O to afford the expected product (Region isomer 5A, 51 mg, 25 %yield) as a white solids. ESI-MS: m/z =442 (M+H)  +;  1H NMR (400 MHz, DMSO-d 6) δ 12.22 (s, 1H) , 8.38 (t, J = 5.2 Hz, 1H) , 7.65 (s, 1H) , 7.41 (s, 1H) , 6.43 (s, 1H) , 5.33 (s, 1H) , 4.26 (d, J = 7.2 Hz, 2H) , 3.85 (dd, J = 11.2, 2.4 Hz, 2H) , 3.57 (s, 3H) , 3.32 –3.25 (m, 4H) , 2.40 –2.34 (m, 1H) , 1.56 (s, 6H) , 1.54 –1.52 (m, 2H) , 1.40 –1.30 (m, 2H) , 1.15 (t, J = 7.2 Hz, 3H) .
The region isome 5B was synthesized using the same procedure as above (Region isomer 5B, 9 mg, 6%yield) as a white solids. ESI-MS: m/z = 442 (M+H) +;  1H NMR (400 MHz, DMSO-d 6) δ 12.40 (s, 1H) , 8.43 (t, J = 4.2 Hz, 1H) , 7.38 (s, 1H) , 6.73 (s, 1H) , 6.27 (s, 1H) , 4.89 (s, 1H) , 3.89 (d, J = 7.2 Hz, 2H) , 3.69 (dd, J = 11.2, 2.4 Hz, 2H) , 3.56 (s, 3H) , 3.29 –3.25 (m, 4H) , 2.02 –1.93 (m, 1H) , 1.46 (s, 6H) , 1.29 –1.26 (m, 2H) , 1.11 (t, J = 7.2 Hz, 3H) , 1.05 –0.95 (m, 2H) .
Example 6
N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
Figure PCTCN2021105686-appb-000082
Step 1: Methyl
4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-2-carboxylate
Figure PCTCN2021105686-appb-000083
To a solution of methyl 4-bromothiophene-2-carboxylate (5.00 g, 22.6 mmol) in degassed 1, 4-dioxane (50 mL) in a round bottom flask was added 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (8.61 g, 33.9 mmol) and KOAc (6.65 g, 67.8 mmol) at rt under N 2. The flask with reagents was vacuumed, backfilled with N 2, and this sequence was repeated three times. PdCl 2 (DPPF) (496 mg, 0.698 mmol) was added at rt under N 2. The flask was flushed with N 2 for 10 sec, sealed, and the resulting reaction mixture was stirred in a 85 ℃ preheated oil bath O/N. The reaction was completed based on LC/MS. The reaction mixture was cooled to rt, partitioned between water (50 mL) and EtOAc (100 mL) . After separation, the aqueous layer was extracted with EtOAc (50 mL) . The combined organic layers were washed with H 2O (50 mL) , brine (50 mL) , dried under Na 2SO 4, and filtered. The filtrate was concentrated on a rotary evaporator and the residue was purified using a silica gel chromatography eluting with PE/EtOAc (20/1 volume ratio) to afford the title intermediate (5.32 g, 88%yield) as an off-white solids. ESI-MS: m/z = 269 (M+H)  +.
Step 2: (5- (Methoxycarbonyl) thiophen-3-yl) boronic acid
Figure PCTCN2021105686-appb-000084
To a solution of methyl
4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-2-carboxylate (4.10 g, 15.3 mmol) in acetone (41 mL) and water (41 mL) was added NH 4OAc (5.90 g, 76.5 mmol) and NaIO 4 (16.4 g, 76.5 mmol) respectively at 0 ℃. 10 min later, the temperature was slowly warm to rt and the reaction was continued until completion (～4h) based on LC/MS. The reaction mixture was passed through a thin pad of celite with EtOAc (2 x 15 mL) . To the filtrate was added water (50 mL) . The two layers were separated, and the aqueous layer was extracted with EtOAc (3 x 50 mL) . The combined organic layers were washed with water (50 mL) , brine (50 mL) , dried under Na 2SO 4 and collected by filtration. The solvent was taken off to afford the crude intermediate (1.88 g, 66%yield) as an off-white solids. ESI-MS: m/z = 187 (M+H)  +.
Step 3: Methyl 4-hydroxythiophene-2-carboxylate
Figure PCTCN2021105686-appb-000085
To a solution of (5- (methoxycarbonyl) thiophen-3-yl) boronic acid (2.50 g, 13.4  mmol) in THF (38 mL) was dropwise added H 2O 2 (50%, 4.56 g, 67.0 mmol) over 1 min at 0 ℃. The reaction mixture was warmed to rt and continued stirring until completion of the reaction (～ 2h) based on LC/MS. The reaction mixture was cooled to 0 ℃, quenched with sat. aq. Na 2S 2O 3 (100 mL) , and stirred for 30 min. The aq. layer was extracted with EtOAc (3 x 50 mL) . The combined organic phase were washed with water (50 mL) , brine (50 mL) , dried under Na 2SO 4, and collected by filtration. The solvent was taken off and the residue was purified using liquid chromatography on a silica gel column eluting with PE/EtOAc (5/1 volume ratio) to afford the title intermediate (1.32 g, 62 %yield) as a pink solids. ESI-MS: m/z = 159 (M+H)  +.
Step 4: Methyl 4- (2, 6-dimethyl-4-nitrophenoxy) thiophene-2-carboxylate
Figure PCTCN2021105686-appb-000086
To a solution of methyl 4-hydroxythiophene-2-carboxylate (730 mg, 4.61 mmol) in CH 3CN (10 mL) was added 2-fluoro-1, 3-dimethyl-5-nitrobenzene (935 mg, 5.53 mmol) and Cs 2CO 3 (3.00 g, 9.22 mmol) respectively at rt. The resulting reaction mixture was stirred at 85 ℃ in a pre-heated oil bath under N 2 O/N. The reaction was completed based on LC/MS. The reaction mixture was cooled to rt and the solvent was taken off. The residue was dissolved in EtOAc (15 mL) and water (15 mL) . The two layers were separated and the aq. layer was extracted with EtOAc (3 x 10 mL) . The combined organic layers were washed with water (10 mL) , brine (10 mL) , dried under Na 2SO 4, and collected by filtration. The filtrate was concentrated on a rotary evaporator and the residue was purified using a chromatography on a silica gel column eluting with PE/EtOAc (15/1 volume ratio) to afford the expected title intermediate (830 mg, 59%yield) as an off-white solids. ESI-MS: m/z = 308 (M+H)  +;  1H NMR (400 MHz, d 6-DMSO) δ 8.13 (s, 2H) , 7.48 (d, J = 4.0 Hz, 1H) , 6.89 (d, J = 4.0 Hz, 1H) , 3.81 (s, 3H) , 2.22 (s, 6H) .
Step 5: Methyl
5-bromo-4- (2, 6-dimethyl-4-nitrophenoxy) thiophene-2-carboxylate
Figure PCTCN2021105686-appb-000087
To a solution of methyl 4- (2, 6-dimethyl-4-nitrophenoxy) thiophene-2-carboxylate (746 mg, 2.43 mmol) in TFA (12.0 mL) was added NBS (520 mg, 2.92 mmol) in several portions at 0 ℃. The reaction mixture was slowly warmed to rt and stirred until completion of the reaction (～ 30 min) based on LC/MS. The reaction mixture was cooled to 0 ℃, quenched with water (10 mL) , and cautiously neutralized with sat. aq. NaHCO 3 to pH 9～10. The solution was extracted with EtOAc (3 x 10 mL) . The combined organic layers were washed with water (10 mL) , brine (10 mL) , dried under  Na 2SO 4, and collected by filtration. The filtrate was concentrated on a rotary evaporator and the residue was purified using a chromatography on a silica gel column eluting with PE/EtOAc (20/1 volume ratio) to afford the title intermediate (892 mg, 95 %yield) . ESI-MS: m/z = 386/388 (M+H)  +;  1H NMR (400 MHz, d 6-DMSO) δ 8.13 (s, 2H) , 6.92 (s, 1H) , 3.76 (s, 3H) , 2.21 (s, 6H) .
Step 6: Methyl
4- (4-amino-2, 6-dimethylphenoxy) -5-bromothiophene-2-carboxylate
Figure PCTCN2021105686-appb-000088
To a solution of methyl
5-bromo-4- (2, 6-dimethyl-4-nitrophenoxy) thiophene-2-carboxylate (890 mg, 2.30 mmol) in DCM (20 mL) was added AcOH (1.38 g, 23.0 mmol) and Zn powder (1.20 g, 18.4 mmol) at 0 ℃ under N 2. The reaction temperature was raised to rt and the reaction mixture was stirred for 4 h. The reaction mixture was diluted with DCM (15 mL) , passed through a thin pad of celite with DCM (2 x 5 mL) . The filtrated was added water (10 mL) , cooled to 0 ℃, and neutralized with sat. aq. NaHCO 3 to pH 9～10. The two phases were separated and the aq. layer was extracted with DCM (3 x 10 mL) . The combined organic layers were washed with water (10 mL) , brine (10 mL) , dried under Na 2SO 4, and collected by filtration. The filtrate was concentrated on a rotary evaporator and the residue was purified using chromatography on a silica gel column eluting wit PE/EtOAc (5/1 volume ratio) to afford the expected intermediate (620 mg, 76%yield) as a light yellow solids. ESI-MS: m/z = 356/358 (M+H)  +.
Step 7: Methyl
5-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) thiophene-2-carboxylate
Figure PCTCN2021105686-appb-000089
To a solution methyl
4- (4-amino-2, 6-dimethylphenoxy) -5-bromothiophene-2-carboxylate (540 mg, 1.52 mmol) in HOAc (2.5 mL) and H 2O (1 mL) was added NaNO 2 (126 mg, 1.82 mmol) in several portions at 0 ℃. The reaction was continued stirring at 0 ℃ for 5 min. BF 3 . HF (30%, 5 mL) was dropwise added at 0 ℃ and stirred for 30 min. The reaction temperature was raised to 100 ℃ and stirred until the completion of the reaction (～ 1h) based on LC/MS. The reaction mixture was cooled to rt and further cooled to 0 ℃. The reaction was quenched with dropwise addition of sat. aq. NaHCO 3 to pH 9～10 and extracted with EtOAc (3 x 50 mL) . The combined organic phases were washed with water (10 mL) , brine (10 mL) , dried under Na 2SO 4, and collected by filtration. The filtrate was concentrated on a rotary evaporator and the residue was purified on a  silica gel column eluting with PE/EtOAc (20/1 volume ratio) to afford the expected title intermediate (210 mg, 33%yield) as an off-white solids. ESI-MS: m/z = 359/361 (M+H)  +.
Step 8: 2- (5-Bromo-4- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) propan-2-ol
Figure PCTCN2021105686-appb-000090
To a solution of methyl
5-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) thiophene-2-carboxylate (210 mg, 0.585 mmol) in anhydrous THF (2 mL) was slowly dropwise addition of MeMgBr (3 M, 1.0 mL, 2.93 mmol) at 0 ℃ over 1 min. The reaction mixture was warmed to rt and continued stirring for 2 h and cooled to 0 ℃ again. The reaction was quenched with dropwise addition of sat. aq. NH 4Cl (5 mL) . The reaction mixture was extracted with EtOAc (3 x 10 mL) . The combined organic layers were washed with water (10 mL) , brine (10 mL) , dried under Na 2SO 4, and filtered with EtOAc (10 mL) . The filtrate was concentrated on a rotary evaporator and the residue was purified on a silica gel column eluting with PE/EtOAc (5/1 volume ratio) to afford the title intermediate (150 mg, 71 %yield) as an off-white solid. ESI-MS: m/z = 359/361 (M+H)  +.
Step 9:
N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
To a solution of
2- (5-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) propan-2-ol (86 mg, 0.240 mmol) in degassed THF (4 mL) in a round bottom flask was added N-ethyl-6-methyl-7-oxo-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Intermediate 1, 91.1 mg, 0.264 mmol) , KOAc (70.7 mg, 0.720 mmol) , X-phos (11.4 mg, 0.0240 mmol) and water (0.4 mL) . The flask was vacuumed, backfilled with N 2, and this sequence was repeated three times, and followed by addition of Pd 2 (dba)  3 (11.0 mg, 0.0120 mmol) under N 2. The flask was equipped with a condenser and a N 2 balloon, heated in a 65 ℃ oil bath with stirring O/N. The reaction mixture was cooled to rt, quenched with water (5 mL) , and extracted with EtOAc (3 x 10 mL) . The combined organic phases were washed with brine (10 mL) , dried under Na 2SO 4, and filtered. The filtrate was concentrated on a rotary evaporator and the residue was purified using a liquid chromatography eluting with DCM/MeOH (15/1 volumetric ratio) to afford the title final compound (50.0 mg, 42 %yield) as a white solids. ESI-MS: m/z = 498 (M+H) +;  1H NMR (400 MHz, d 6-DMSO) δ 12.36 (s, 1H) , 8.45 (t, J = 6.0 Hz, 1H) , 7.54 (s, 1H) , 7.16 (d, J = 4.0 Hz, 1H) , 6.98 (d, J = 8.0 Hz, 2H) , 6.16 (s, 1H) , 5.50 (s, 1H) , 3.57 (s, 3H) , 3.30 –3.26 (m, 2H) , 2.11 (s, 6H) , 1.42 (s, 6H) , 1.14 (t, J = 8.0 Hz, 3H) ;  19F NMR (377 MHz, d 6-DMSO) δ -118.39 (s, 1H) .
Example 7
4- (3- (4-Chloro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
Figure PCTCN2021105686-appb-000091
Step 1: Methyl
5-bromo-4- (4-chloro-2, 6-dimethylphenoxy) thiophene-2-carboxylate
Figure PCTCN2021105686-appb-000092
To a solution of methyl
4- (4-amino-2, 6-dimethylphenoxy) -5-bromothiophene-2-carboxylate (from Example 6 Step 6, 300 mg, 0.842 mmol) in concentrated aq. HCl (37%, 5 mL) was added NaNO 2 (116 mg, 1.68 mmol) at 0 ℃ and the mixture was stirred for 5 min. To the reaction mixture was added CuCl (83.4, 0.842 mmol) at 0 ℃. After stirring for 10 min, the reaction mixture was warmed to 100 ℃ and continued stirring for 1 h. The reaction mixture was cooled to 0 ℃, carefully neutralized with dropwise addition of sat. aq. NaHCO 3 to pH 9～10. The reaction mixture was extracted with EtOAc (3 x 10 mL) . The combined organic layers were washed with brine (10 mL) , dried under Na 2SO 4, and collected by filtration. The filtrate was purified using liquid chromatography eluting with PE/EtOAc (20/1 volumetric ratio) to afford the expected title intermediate (125 mg, 40 %yield) as an off-white solids. ESI-MS: m/z = 375/377 (M+H)  +.
Step 2: 2- (5-Bromo-4- (4-chloro-2, 6-dimethylphenoxy) thiophen-2-yl) propan-2-ol
Figure PCTCN2021105686-appb-000093
Following the same procedure as Example 6, Step 8 to convert methyl 5-bromo-4- (4-chloro-2, 6-dimethylphenoxy) thiophene-2-carboxylate (125 mg, 0.332 mmol) to the expected title intermediate 2- (5-bromo-4- (4-chloro-2, 6-dimethylphenoxy) thiophen-2-yl) propan-2-ol (65 mg, 52% yield) as an off-white solids. ESI-MS: m/z = 375/377 (M+H)  +.
Step 3:
4- (3- (4-Chloro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
Following the same procedure as Example 6, Step 9 to convert 2- (5-bromo-4- (4-chloro-2, 6-dimethylphenoxy) thiophen-2-yl) propan-2-ol (65 mg, 0.173 mmol) to the expected title final compound 4- (3- (4-chloro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethy l-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (10 mg, 11%yield) as a white solids. ESI-MS: m/z = 514 (M+H)  +.
Example 8
N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) -4-me thylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carb oxamide
Figure PCTCN2021105686-appb-000094
Step 1: Methyl
3-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-2-carboxylate
Figure PCTCN2021105686-appb-000095
Following the same procedure as Example 6, Step 1 to convert methyl 4-bromo-3-methylthiophene-2-carboxylate (2.00 g, 8.51 mmol) to the expected title intermediate methyl 3-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-2-carboxylate (2.40 g, 100%yield) . ESI-MS: m/z = 283 (M+H)  +.
Step 2: (5- (Methoxycarbonyl) -4-methylthiophen-3-yl) boronic acid
Figure PCTCN2021105686-appb-000096
Following the same procedure as Example 6, Step 2 to convert methyl 3-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-2-carboxylate (2.40 g, 8.51 mmol) to the expected title intermediate (5- (methoxycarbonyl) -4-methylthiophen-3-yl) boronic acid (1.70 g, 100%yield) as an off-white solids. ESI-MS: m/z = 201 (M+H) +.
Step 3: Methyl 4-hydroxy-3-methylthiophene-2-carboxylate
Figure PCTCN2021105686-appb-000097
Following the same procedure as Example 6, Step 3 to convert (5- (methoxycarbonyl) -4-methylthiophen-3-yl) boronic acid (1.70 g, 8.51 mmol) to the expected title intermediate methyl 4-hydroxy-3-methylthiophene-2-carboxylate (870 mg, 59%yield) as a light yellow solids. ESI-MS: m/z = 173 (M+H) +.
Step 4: Methyl
4- (2, 6-dimethyl-4-nitrophenoxy) -3-methylthiophene-2-carboxylate
Figure PCTCN2021105686-appb-000098
Following the same procedure as Example 6, Step 4 to convert methyl 4-hydroxy-3-methylthiophene-2-carboxylate (870 mg, 5.05 mmol) to the expected title intermediate methyl 4- (2, 6-dimethyl-4-nitrophenoxy) -3-methylthiophene-2-carboxylate (1.30 g, 80%yield) as an off-white solids. ESI-MS: m/z = 322 (M+H)  +.
Step 5: Methyl
4- (4-amino-2, 6-dimethylphenoxy) -3-methylthiophene-2-carboxylate
Figure PCTCN2021105686-appb-000099
Following the same procedure as Example 6, Step 5 to convert methyl 4- (2, 6-dimethyl-4-nitrophenoxy) -3-methylthiophene-2-carboxylate (770 mg, 2.40 mmol) to the expected title intermediate methyl 4- (4-amino-2, 6-dimethylphenoxy) -3-methylthiophene-2-carboxylate (660 mg, 95%yield) as a light yellow solids. ESI-MS: m/z = 292 (M+H)  +.
Step 6: Methyl
4- (4-fluoro-2, 6-dimethylphenoxy) -3-methylthiophene-2-carboxylate
Figure PCTCN2021105686-appb-000100
Following the same procedure as Example 6, Step 6 to convert methyl 4- (4-amino-2, 6-dimethylphenoxy) -3-methylthiophene-2-carboxylate (660 mg, 2.27 mmol) to the expected title intermediate methyl 4- (4-fluoro-2, 6-dimethylphenoxy) -3-methylthiophene-2-carboxylate (190 mg, 33%yield) as an off-white solids. ESI-MS: m/z = 295 (M+H)  +.
Step 7: Methyl
5-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) -3-methylthiophene-2-carboxylate
Figure PCTCN2021105686-appb-000101
Following the same procedure as Example 6, Step 7 to convert methyl 4- (4-fluoro-2, 6-dimethylphenoxy) -3-methylthiophene-2-carboxylate (190 mg, 0.646 mmol) to the expected title intermediate methyl 5-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) -3-methylthiophene-2-carboxylate (220 mg, 79%yield) as an off-white solids. ESI-MS: m/z = 373/375 (M+H)  +.
Step 8:
2- (5-Bromo-4- (4-fluoro-2, 6-dimethylphenoxy) -3-methylthiophen-2-yl) propan-2-ol
Figure PCTCN2021105686-appb-000102
Following the same procedure as Example 6, Step 8 to convert methyl 5-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) -3-methylthiophene-2-carboxylate (110 mg, 0.294 mmol) to the expected title intermediate 2- (5-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) -3-methylthiophen-2-yl) propan-2-ol (16 mg, 15%yield) as an off-white solids. ESI-MS: m/z = 373/375 (M+H)  +.
Step 9:
N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) -4-methyl thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide
Following the same procedure as Example 6, Step 9 to convert 2- (5-bromo-4- (4-fluoro-2, 6-dimethylphenoxy) -3-methylthiophen-2-yl) propan-2-ol (16 mg, 0.0429 mmol) to the expected title final compound N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) -4-methylthio phen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (5 mg, 16%yield) as a white solids. ESI-MS: m/z = 512 (M+H)  +.  1H-NMR (400 MHz, d 6-DMSO) δ 8.36-8.35 (m, 1H) , 6.71 (d, J = 8 Hz, 2H) , 6.54 (t, J =10 Hz, 2H) , 5.57 (s, 1H) , 3.31 (s, 3H) , 3.26-3.24 (m, 3H) , 2.20 (s, 3H) , 1.94 (s, 6H) , 1.56 (s, 6H) , 1.12 (t, J = 6 Hz, 3H) .
Example 9
4- (1- (2, 6-Dimethylbenzyl) -5- (2-hydroxypropan-2-yl) -1H-pyrazol-3-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Region isomer 9A)
And
4- (1- (2, 6-dimethylbenzyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Region isomer 9B)
Figure PCTCN2021105686-appb-000103
Step 1: Methyl 3-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazole-5-carboxylate (Region isomer 9-1A)
and
Methyl 5-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazole-3-carboxylate (Region isomer 9-1B)
Figure PCTCN2021105686-appb-000104
To a solution of methyl 5-bromo-1H-pyrazole-3-carboxylate (500 mg, 2.44 mmol) and 2- (bromomethyl) -1, 3-dimethylbenzene (485 mg, 2.44 mmol) in CH 3CN (10 mL) was added Cs 2CO 3 (1.59 g, 4.88 mmol) at rt. The reaction mixture was warmed to 75  ℃ and stirred O/N. The reaction was completed based on TLC. The reaction mixture was concentrated on a rotary evaporator, diluted with EtOAc (50 mL) and H 2O (50 mL) . The two layers were separated. The organic phase was washed with brine (30 mL) , dried under Na 2SO 4, and filtered. The filtrate was concentrated in vacuo and the resulted residue was purified using thin layer chromatography with PE/EtOAc (3/1 volumetric ratio) to afford two region isomers: 9-1A (less polar component, 300 mg, 38%yield) as a light yellow solids, LC/MS RT = 2.72 min, ESI-MS: m/z = 323, 32 (M+H)  +; 9-1B (more polar component, 311 mg, 39%yield) as a light yellow solids, LC/MS RT = 2.65 min, ESI-MS: m/z = 323, 325 (M+H)  +.
The following reactions were run in parallel.
Step 2: 2- (3-Bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazol-5-yl) propan-2-ol (Regioisomer 9-2A)
and
2- (5-Bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazol-3-yl) propan-2-ol (Regioisomer 9-2B)
Figure PCTCN2021105686-appb-000105
To a solution of methyl 3-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazole-5-carboxylate (Region isomer 9-1A, 150 mg, 0.460 mmol) in anhydrous THF (5 mL) was slowly dropwise added MeMgBr (3 M, 0.500 mL, 1.5 mmol) over 30 sec at -60 ℃ under N 2. The reaction mixture was stirred for 1h at -60 ℃, then warm to rt and continued stirring for 60 min. The reaction was completed based on LC/MS and quenched with addition of sat. aq. NH 4Cl (2 mL) . The solvent was taken off and the residue was purified using high pressure liquid chromatography to afford the expected title intermediate (Regioisomer-9-2A, 85.0 mg, 56%yield ) as an off-white solids. ESI-MS: m/z = 323, 325 (M+H)  +.
Following the same procedure as for synthesis of Region isomer-9-2A , methyl 5-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazole-3-carboxylate (Region isomer 9-1B, 150 mg, 0.460 mmol) was converted to the title intermediate 2- (5-Bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazol-3-yl) propan-2-ol (Region isomer 9-2B, 57.0 mg, 38%yield ) as an off-white solids. ESI-MS: m/z = 323, 325 (M+H)  +.
Step 3:
4- (1- (2, 6-Dimethylbenzyl) -5- (2-hydroxypropan-2-yl) -1H-pyrazol-3-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Region isomer 9A)
and
4- (1- (2, 6-Dimethylbenzyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Region isomer 9B)
To a solution of 2- (3-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazol-5-yl) propan-2-ol (Region isomer 9-2A, 81.0 mg, 0.250 mmol) in degassed 1, 4-dioxane (8 mL) in a round bottom flask was charged with N-ethyl-6-methyl-7-oxo-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Intermediate 1 , 86.5 mg, 0.250 mmol) , X-phos (11.0 mg, 0.0250 mmol) and KOAc (50.0 mg, 0.500 mmol) respectively at rt under N 2. The flask was vacuumed, backfilled with N 2, and this sequence was repeated three times. To it was added Pd 2 (dba)  3 (11.9 mg, 0.130 mmol) under N 2. The reaction vessel was equipped with a condenser and a N 2 balloon, then put in a preheated 80 ℃ oil bath and stirred O/N. The reaction was completed based on LC/MS. The reaction mixture was cooled to rt, passed through a thin pad of celite with DCM (20 mL) . The filtrate was concentrated on a rotary evaporator and the residue was purified using high pressure liquid chromatography to afford the expected final product 4- (1- (2, 6-dimethylbenzyl) -5- (2-hydroxypropan-2-yl) -1H-pyrazol-3-yl) -N-ethyl-6-met hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Region isomer 9A, 27.0 mg, 23%yield) as a white solids. ESI-MS: m/z =462 (M+H) +;  1H NMR (400 MHz, d 6-DMSO) δ 12.15 (s, 1H) , 8.07 (t, J = 4.2 Hz, 1H) , 7.54 (s, 1H) , 7.11 (dd, J = 8.4 Hz, 6.0 Hz, 1H) , 7.05 (d, J = 7.2 Hz, 2H) , 7.00 (d, J = 2.0 Hz, 1H) , 6.50 (s, 1H) , 5.54 (s, 2H) , 5.48 (s, 1H) , 3.53 (s, 3H) , 3.31 –3.26 (m, 2H) , 2.33 (s, 6H) , 1.64 (s, 6H) , 1.15 (t, J = 7.2 Hz, 3H) .
Follow the same procedure as described Region isomer-9A, 2- (5-bromo-1- (2, 6-dimethylbenzyl) -1H-pyrazol-3-yl) propan-2-ol (Region isomer 9-2B, 57.0 mg, 0.180 mmol) was converted to the title compound 4- (1- (2, 6-dimethylbenzyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -N-ethyl-6-met hyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Region isomer 9B, 10.0 mg, 12 %yield) as a white solids. ESI-MS: m/z = 462 (M+H)  +;  1H NMR (400 MHz, d 6-DMSO) δ 12.35 (s, 1H) , 8.41 (t, J = 4.8 Hz, 1H) , 7.34 (s, 1H) , 6.98 (dd, J = 8.0 Hz, 6.8 Hz, 1H) , 6.88 (d, J = 7.6 Hz, 2H) , 6.77 (d, J = 2.0 Hz, 1H) , 6.29 (s, 1H) , 5.24 (s, 2H) , 4.83 (s, 1H) , 3.52 (s, 3H) , 3.30 –3.25 (m, 2H) , 2.08 (s, 6H) , 1.39 (s, 6H) , 1.12 (t, J = 7.2 Hz, 3H) .
Example 10
N-ethyl-4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carbo xamide
Figure PCTCN2021105686-appb-000106
Step 1: Methyl 4, 5-dibromo-3-fluorothiophene-2-carboxylate
Figure PCTCN2021105686-appb-000107
To a solution of methyl 3-fluorothiophene-2-carboxylate (4.00 g, 25.0 mmol) in CCl 4 (80.0 mL) was added FeBr 3 (739 mg, 2.50 mmol) in several portions at 0 ℃, followed by slowly dropwise addition of Br 2 (40.0 g, 250 mmol) under N 2. After addition, the reaction temperature was warmed to 60 ℃, and continued stirring 24 h. The reaction temperature was cooled to 0 ℃, quenched with slowly addition of sat. aq. NaHSO 3, and extracted with DCM (3 x 100 mL) . The combined organic layers were washed with water (100 mL) , dried under Na 2SO 4, and collected with filtration. The filtrate was concentrated on a rotary evaporator to afford the expected crude title intermediate (7.95 g, 100%yield) as a light yellow solids ESI-MS: m/z = 319/321 (M+H)  +.
Step 2: Methyl 4-bromo-3-fluorothiophene-2-carboxylate
Figure PCTCN2021105686-appb-000108
To a solution of methyl 4, 5-dibromo-3-fluorothiophene-2-carboxylate (7.95 g, 25.0 mmol) in DCM (80 mL) was added glacial acetic acid at 0 ℃ and followed by addition of Zn powder in several portions. The reaction mixture was warmed to rt and continued stirring for 4.5 h. The reaction mixture was passed through a thin pad of celite with DCM (3 x 40 mL) . The filtrate was concentrated on a rotary evaporator to afford a white solids. The solids were partitioned between H 2O/PE (200 mL/200 mL) and separated. The aq. layer was extracted with PE (3 x 200 mL) . The combined organic layers were washed with H 2O (100 mL) , brine (100 mL) , and dried under Na 2SO 4, and collected by filtration. The filtrate was concentrated on a rotary evaporator to afford the crude title intermediate (5.98 g, 100%yield) as an off-white solids. ESI-MS: m/z = 239/241 (M+H)  +.
Step 3: Methyl
3-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-2-carboxylate
Figure PCTCN2021105686-appb-000109
To a solution of methyl 4-bromo-3-fluorothiophene-2-carboxylate (6.07 g, 25.4 mmol) in 1, 4-dioxane (120 mL) was added 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (16.1 g, 63.5 mmol) , KOAc  (10.0 g, 102 mmol) and PdCl 2 (dppf) (929 mg, 1.27 mmol) respectively under N 2. The vial was vacuumed, backfilled with N 2, and this sequence was repeated three times. The reaction mixture was stirred in a preheated oil bath at 85 ℃ under N 2 for 14 h. The reaction mixture was cooled to rt and filtered through a thin pad of celite. To the filtrate was added water (100 mL) , extracted with EtOAc (3 x 100 mL) . The combined organic layers were washed with water (100 mL) , brine (100 mL) , dried under Na 2SO 4, and filtered. The filtrate was concentrated on a rotary evaporator to afford the crude intermediate (7.27 g, 100%yield) as a black oil. ESI-MS: m/z = 287 (M+H)  +.
Step 4: (4-Fluoro-5- (methoxycarbonyl) thiophen-3-yl) boronic acid
Figure PCTCN2021105686-appb-000110
Following the same procedure as Example 6, Step 2 to convert methyl 3-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-2-carboxylate (7.27 g, 25.4 mmol) to the expected crude intermediate (4-fluoro-5- (methoxycarbonyl) thiophen-3-yl) boronic acid (5.18, 100%yield) as a black oil. ESI-MS: m/z = 205 (M+H)  +.
Step 5: Methyl 3-fluoro-4-hydroxythiophene-2-carboxylate
Figure PCTCN2021105686-appb-000111
Following the same procedure as Example 6, Step 3 to convert (4-fluoro-5- (methoxycarbonyl) thiophen-3-yl) boronic acid (5.18 g, 25.4 mmol) to the expected title intermediate methyl 3-fluoro-4-hydroxythiophene-2-carboxylate (3.00g, 67%yield) as a yellow solids. ESI-MS: m/z = 177 (M+H)  +.
Step 6: Methyl 4- (2, 6-dimethyl-4-nitrophenoxy) -3-fluorothiophene-2-carboxylate
Figure PCTCN2021105686-appb-000112
Following the same procedure as Example 6, Step 4 to convert methyl 3-fluoro-4-hydroxythiophene-2-carboxylate (2.00 g, 11.4 mmol) to the expected title intermediate methyl 4- (2, 6-dimethyl-4-nitrophenoxy) -3-fluorothiophene-2-carboxylate (289 mg, 8%yield) as an off-white solids. ESI-MS: m/z = 326 (M+H)  +.
Step 7: Methyl
4- (4-amino-2, 6-dimethylphenoxy) -3-fluorothiophene-2-carboxylate
Figure PCTCN2021105686-appb-000113
Following the same procedure as Example 6, Step 5 to convert methyl 4- (2, 6-dimethyl-4-nitrophenoxy) -3-fluorothiophene-2-carboxylate (289 mg, 0.888 mmol) to the expected title intermediate methyl 4- (4-amino-2, 6-dimethylphenoxy) -3-fluorothiophene-2-carboxylate (197 mg, 75%yield) as a yellow oil. ESI-MS: m/z = 296 (M+H) +.
Step 8: Methyl
3-fluoro-4- (4-fluoro-2, 6-dimethylphenoxy) thiophene-2-carboxylate
Figure PCTCN2021105686-appb-000114
Following the same procedure as Example 6, Step 6 to convert methyl 4- (4-amino-2, 6-dimethylphenoxy) -3-fluorothiophene-2-carboxylate (197 mg, 0.677 mmol) to the expected crude intermediate methyl 3-fluoro-4- (4-fluoro-2, 6-dimethylphenoxy) thiophene-2-carboxylate (199 mg, 100%yield) as a black oil. ESI-MS: m/z = 299 (M+H) +.
Step 9: Methyl
5-bromo-3-fluoro-4- (4-fluoro-2, 6-dimethylphenoxy) thiophene-2-carboxylate
Figure PCTCN2021105686-appb-000115
Following the same procedure as Example 6, Step 7 to convert methyl 3-fluoro-4- (4-fluoro-2, 6-dimethylphenoxy) thiophene-2-carboxylate (199 mg, 0.677 mmol) to the expected crude intermediate methyl 5-bromo-3-fluoro-4- (4-fluoro-2, 6-dimethylphenoxy) thiophene-2-carboxylate (110 mg, 44%yield) as a light yellow oil. ESI-MS: m/z = 377/379 (M+H) +.
Step 10:
2- (5-Bromo-3-fluoro-4- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) propan-2-ol
Figure PCTCN2021105686-appb-000116
Following the same procedure as Example 6, Step 8 to convert methyl 5-bromo-3-fluoro-4- (4-fluoro-2, 6-dimethylphenoxy) thiophene-2-carboxylate (110 mg, 0.677 mmol) to the expected intermediate 2- (5-bromo-3-fluoro-4- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) propan-2-ol (38.0 mg, 35%yield) as a light yellow oil. ESI-MS: m/z = 377/379 (M+H) +.
Step 11:
N-ethyl-4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxa mide
Following the same procedure as Example 6, Step 9 to convert 2- (5-bromo-3-fluoro-4- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) propan-2-ol (38.0 mg, 0.101 mmol) to the expected final product (13.7 mg, 26%yield) as an off-white solids. ESI-MS: m/z = 516 (M+H)  +.  1H NMR (400 MHz, d 6-DMSO) δ 12.34 (s, 1H) , 8.30 -8.28 (m, 1H) , 7.25 (s, 1H) , 7.20 (d, J = 9.6 Hz, 1H) , 6.50 (s, 1H) , 6.04 (d, J = 4.0 Hz, 1H) , 5.70 (s, 1H) , 3.56 (s, 3H) , 3.27 –3.23 (m, 2H) , 2.21 (s, 3H) , 1.96 (s, 3H) , 1.53 (s, 6H) , 1.11 (t, J = 7.2 Hz, 3H) .  19F NMR (376 MHz, DMSO) δ -116.62 (s, 1H) , -139.04 (s, 1H) .
Example 11A/B
N-ethyl-4- (3- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (11A)
and
N-ethyl-4- (3- ( (2-fluoro-4, 6-dimethylbenzyl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (11B)
Figure PCTCN2021105686-appb-000117
Step 1: 2- (Bromomethyl) -5-fluoro-1, 3-dimethylbenzene (11-1a)
and
2- (Bromomethyl) -1-fluoro-3, 5-dimethylbenzene (11-1b)
Figure PCTCN2021105686-appb-000118
To HOAc (25 mL) in a round bottom flask was added 1-fluoro-3, 5-dimethylbenzene (5.00 g, 40.3 mmol) , paraformaldehyde, and HBr (35%in HOAc, 35 ml) respectively at rt. The resulting mixture was stirred at rt for 4 h. The reaction was completed based on TLC. The reaction mixture was diluted with water (30 mL) and extracted with PE (3 x 40 mL) . The combined organic layers were washed with brine (30 mL) , dried under Na2SO4, and collected by filtration. The filtrate was concentrated on a rotary evaporator. The residue was purified using liquid phase chromatography eluting PE/EtOAc (9/1 volumetric ratio) to afford the expected unseparated region isomeric mixture 11-1a and 11-1b (2.40 g, 27%overall yield) as a white solids. ESI-MS: m/z = 217/219 (M+H)  +.
Step 2: Methyl 4- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) thiophene-2-carboxylate (11-2a)
and
Methyl 4- ( (2-fluoro-4, 6-dimethylbenzyl) oxy) thiophene-2-carboxylate (11-2b)
Figure PCTCN2021105686-appb-000119
To a solution of methyl 4-hydroxythiophene-2-carboxylate (from Ex. 6, Step 3, 300 mg, 1.90 mmol) in CH 3CN (3 mL) was added Cs 2CO 3 (1.24 g, 3.80 mmol) and a regioisomeric mixture (456 mg, 209 mmol) of 2- (bromomethyl) -5-fluoro-1, 3-dimethylbenzene (11-2a) and 2- (bromomethyl) -1-fluoro-3, 5-dimethylbenzene (11-1b) at rt. The resulting mixture was stirred at 80 ℃ for 2.5 h. The reaction mixture was cooled to rt, the solvent was taken off. The residue was partitioned between water (10 mL) and EtOAc (10 mL) . After separation, the aq. layer was extracted with EtOAc (3 x 10 mL) . The combined organic layers were washed with water (10 mL) , brine (10 mL) , dried under Na 2SO 4, and filtered. The filtrate was concentrated on an evaporator. The residue was purified by a chromatography eluting with PE/EtOAc (10/1 volumetric ratio) to afford the expected unseparated region isomeric mixture (537 mg, 96%overall yield) of methyl 4- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) thiophene-2-carboxylate (11-2a) and methyl 4- ( (2-fluoro-4, 6-dimethylbenzyl) oxy) thiophene-2-carboxylate (11-2b) as an off-white solids. ESI-MS: m/z = 295 (M+H)  +.
Step 3: Methyl
5-bromo-4- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) thiophene-2-carboxylate (11-3a)
and
Methyl 5-bromo-4- ( (2-fluoro-4, 6-dimethylbenzyl) oxy) thiophene-2-carboxylate (11-3b)
Figure PCTCN2021105686-appb-000120
To a solution of the region isomeric mixture (520 mg, 1.77 mmol) of methyl 4- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) thiophene-2-carboxylate (11-2a) and methyl 4- ( (2-fluoro-4, 6-dimethylbenzyl) oxy) thiophene-2-carboxylate (11-2b) in DCM/HOAc (6 mL/6 mL) was added NBS (347 mg, 1.95 mmol) in several portions at 0 ℃. The resulting reaction mixture was warmed to rt and continued stirring for 6 h. The reaction was quenched with addition of water (10 mL) and carefully dropwise added sat. aq. NaHCO to adjust pH 9～10. The two layers were separated and aq. layer was extracted with EtOAc (3 x 10 mL) . The combined organic layers were washed with water (10 mL) , brine (10 mL) , dried under Na 2SO 4, and filtered. The filtrate was concentrated on a rotary evaporator and the residue was purified using liquid chromatography eluting with PE/EtOAc (20/1 volumetric ratio) to afford a unseparate region isomeric mixture (548 mg, 83%yield) of methyl 5-bromo-4- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) thiophene-2-carboxylate (11-3a) and methyl 5-bromo-4- ( (2-fluoro-4, 6-dimethylbenzyl) oxy) thiophene-2-carboxylate (11-3b) as a red solids. ESI-MS: m/z = 373/375 (M+H)  +.
Step 4:
2- (5-Bromo-4- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) thiophen-2-yl) propan-2-ol (11-4a)
and
2- (5-Bromo-4- ( (2-fluoro-4, 6-dimethylbenzyl) oxy) thiophen-2-yl) propan-2-ol (11-4b)
Figure PCTCN2021105686-appb-000121
To a solution of the region isomeric mixture (584 mg, 1.56 mmol) of methyl 5-bromo-4- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) thiophene-2-carboxylate (11-3a) and  methyl 5-bromo-4- ( (2-fluoro-4, 6-dimethylbenzyl) oxy) thiophene-2-carboxylate (11-3b) in anhydrous THF (6 mL) was slowly dropwise added MeMgBr (3M, 2.60 mL, 7.80 mmol) at 0 ℃. The reaction mixture was slowly warmed to rt and continued stirring for 2 h. The reaction mixture was cooled to 0 ℃ and the reaction was quenched with addition of sat. aq. NH 4Cl (10 mL) . The two layers were separated and the aq. layer was extracted with EtOAc (3 x 10 mL) . The combined organic layers were washed with water (10 mL) , brine (10 mL) , dried under Na 2SO 4, and collected by filtration. The filtrate was concentrated and the residue was purified on a silica gel column eluting with PE/EtOAc (10/1 volumetric ratio) afford one of the region isomer, 2- (5-bromo-4- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) thiophen-2-yl) propan-2-ol (11-4a, 218 mg, 37%yield) as an red oil. LC/MS RT = 2.948 min , ESI-MS: m/z = 373/375 (M+H)  +; and a second region isomer 2- (5-bromo-4- ( (2-fluoro-4, 6-dimethylbenzyl) oxy) thiophen-2-yl) propan-2-ol (11-4b, 68 mg, 12%yield) as a yellow oil. LC/MS RT = 2.958 min, ESI-MS: m/z = 373/375 (M+H)  +.
The following reaction, Step 4, was run in parallel for compounds, 11A and 11B.
Step 5:
N-ethyl-4- (3- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) -5- (2-hydroxypropan-2-yl) thioph en-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (11A)
and
N-ethyl-4- (3- ( (2-fluoro-4, 6-dimethylbenzyl) oxy) -5- (2-hydroxypropan-2-yl) thioph en-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (11B)
To a solution of 2- (5-bromo-4- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) thiophen-2-yl) propan-2-ol (11-3a, 86.0 mg, 0.230 mmol) in degassed THF (3.0 mL) was added N-ethyl-6-methyl-7-oxo-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide (Intermediate 1, 87.3 mg, 0.253 mmol) , KOAc (67.7 mg, 0.690 mmol) , X-Phos (11.0 mg, 0.0230 mmol) , and water (0.300 mL) under N2. The reaction flask was vacuumed, back-filed with N 2, and this sequence was repeated three times. To the resulting mixture was added Pd 2 (dba)  3 (10.5 mg, 0.0115 mmol) under N 2. The flask was sealed and stirred at 65 ℃ O/N. The reaction mixture was cooled to rt and followed by addition of water (5 mL) . After separation of the two layers, the aq. layer was extracted with EtOAc (3 x 5 mL) . The combined organic layers were washed with brine, dried under Na 2SO 4, and concentrated on a rotary evaporator. The residue was purified by silica gel chromatography eluting with DCM/MeOH (15/1 volumetric ratio) to afford the title compound, 11A, (31.1 mg, 26%yield) as an off-white solids. LC/MS RT = 2.362 min; ESI-MS: m/z = 512 (M+H)  +;  1H NMR (400 MHz, d 6-DMSO) δ 12.25 (s, 1H) , 8.40 (t, J = 5.2 Hz, 1H) , 7.24 (s, 1H) , 7.09 (s, 1H) , 6.97 (s, 1H) , 6.82 (s, 1H) , 6.79 (s, 1H) , 5.53 (s, 1H) , 4.99 (s, 2H) , 3.43 (s, 3H) , 3.29-3.26 (m, 2H) , 2.22 (s, 6H) , 1.54 (s, 6H) , 1.12 (t, J = 7.2 Hz, 3H) ;  19F NMR (376 MHz, d 6-DMSO) δ -114.61 (s, 1H) .
The same procedure was applied to convert 2- (3-Bromo-4- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) thiophen-2-yl) propan-2-ol (11-3b, 68 mg, 0.0182 mmol) to the title compound, 11B, (11.1 mg, 9%yield) as an off-white solids. LC/MS RT = 2.414 min; ESI-MS: m/z = 512 (M+H)  +;  1H NMR (400 MHz, d 6-DMSO) δ 12.25 (s, 1H) , 8.41 (t, J = 4.8 Hz, 1H) , 7.29 (s, 1H) , 7.07 (s, 1H) , 6.99 (d,  J = 2.0 Hz, 1H) , 6.80 (t, J = 4.4 Hz, 2H) , 5.53 (s, 1H) , 5.04 (s, 2H) , 3.46 (s, 3H) , 3.30-3.25 (m, 2H) , 2.23 (s, 3H) , 2.21 (s, 3H) , 1.54 (s, 6H) , 1.14 (t, J = 7.2 Hz, 3H) .  19F NMR (376 MHz, d 6-DMSO) δ -119.37 (s, 1H) .
Anti-cell proliferation activity assay
AML cell line MV4-11 from ATCC was used to determine anti-proliferation of the compounds of Example. MV4-11 cells were growth in IMDM medium supplemented with 10%FBS and 1%penicillin/streptomycin at 37℃ with 5%CO2 in a humidified atmosphere. For cell proliferation assays, cells were plated in 96-well plates at density of 1×104/well in 100ul of culture medium. Compound dilution series were prepared in DMSO via a 5-fold serial dilution from 2mM to 0.512nM. The DMSO dilution series were then diluted 3: 200 in culture medium, and 50 L of the resulted solution were added to the appropriate wells of the MV4-11 cell plate. Compounds treatment for 72h, then add 50 ul CCK8 to each well, incubate for 1h. read the absorbance value at 450nm with a microplate reader. Calculate the antiproliferation IC50 of compounds with Graphpad Prism8.0.
Table 1: Compounds anti-cell proliferation activity IC 50
Figure PCTCN2021105686-appb-000122
Pharmacokinetic testing
SD rats were administered a single oral dose of 2mg/kg compound dissolved in 20%β-cyclodextrin. Blood samples were collected at 0min, 5min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h, 5h、 6h、 7h、 8h、 9h、 24h after dosing. Compounds were measured by LC-MS/MS.
Anti-tumor effect of compounds in MV-411 cell xenografts tumor in mice
6-8 week old male NOD-SCID mice were used to establish MV-411 cell xenograft tumor models to evaluate the anti-tumor efficacy of the compounds. 5E6 MV-411 cells were implanted subcutaneously into NOD-SCID mice. When the tumor reached approximately 200 mm 3, animals were divided into 2 groups, including vehicle group and treatment group. The compounds was administered by oral gavage in 20%β-cyclodextrin at a dose of 5 mg/kg once daily for 14 days. Weigh and measure the diameter of tumor twice a week and volume calculated as V = 1/2·d1·d2 2.  Euthanize the mice at the end of the experiment.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims (41)

  1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021105686-appb-100001
    wherein:
    for
    Figure PCTCN2021105686-appb-100002
    two of
    Figure PCTCN2021105686-appb-100003
    are double bond and the other three
    Figure PCTCN2021105686-appb-100004
    are single bond to form a 5-membered heteroaromatic ring system;
    L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
    R 0 is hydrogen, halogen or C 1-C 3 alkyl;
    R 1 is C 1-C 3 alkyl;
    R 2 is hydrogen or methyl;
    R 3 is hydrogen, -C (O) NHR 3a;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    X 0 is C or N;
    X 1 is O, S, S (O) , S (O)  2, CR 8or NR 8;
    X 2 is CR 9or NR 9;
    X 3 is CR 10, N or NR 10;
    R 5and R 6 are each independently hydrogen, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
    R 7 is hydrogen, C 1-C 6 alkyl;
    R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
    R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2, -CO (C 1-C 6 alkyl) or -CH 2R 9c;
    R 10 is absent, hydrogen, halogen, C 1-C 6 alkyl, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
    R 3a is hydrogen, CD 2CD 3, C 1-C 3 alkyl, C 1-C 6 haloalkyl, a C 3-C 6 cycloalkyl, a phenyl, or a 5-6 membered monocyclic heteroaryl; wherein the C 3-C 6 cycloalkyl, the phenyl, or the 5-6 membered monocyclic heteroaryl are each optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
    R 3b is halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
    R 4a, R 4b, R 8c, R 9c, R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8  membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1-C 3 alkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkyl, C 1-C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered cyclyl alkoxy, 3-6 membered heterocyclyl alkoxy, -S (C 1-C 6 alkyl) , -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2 or – (C 1-C 6 alkylenyl) -OH;
    R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl;
    R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
    R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a, R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
    R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
  2. A compound according to claim 1 of formula (II) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021105686-appb-100005
    for
    Figure PCTCN2021105686-appb-100006
    two of
    Figure PCTCN2021105686-appb-100007
    are double bond and the other three
    Figure PCTCN2021105686-appb-100008
    are single bond to form a 5-membered heteroaromatic ring system;
    L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
    R 0 is hydrogen, halogen or C 1-C 3 alkyl;
    R 1 is C 1-C 3 alkyl;
    R 2 is hydrogen or methyl;
    R 3 is hydrogen, -C (O) NHR 3a;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    X 0 is C or N;
    X 1 is O, S, S (O) , S (O)  2, CR 8or NR 8;
    X 2 is CR 9or NR 9;
    X 3 is CR 10, N or NR 10;
    R 5and R 6 are each independently hydrogen, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
    R 7 is hydrogen, C 1-C 6 alkyl;
    R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
    R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2, -CO (C 1-C 6 alkyl) or -CH 2R 9c;
    R 10 is absent, hydrogen, halogen, C 1-C 6 alkyl, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
    R 3a is hydrogen, CD 2CD 3, C 1-C 3 alkyl, C 1-C 6 haloalkyl, a C 3-C 6 cycloalkyl, a phenyl, or a 5-6 membered monocyclic heteroaryl; wherein the C 3-C 6 cycloalkyl, the phenyl, or the 5-6 membered monocyclic heteroaryl are each optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
    R 3b is halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, or C 1-C 6 haloalkoxy;
    R 4a, R 4b, R 8c, R 9c, R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1-C 3 alkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkyl, C 1-C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered cyclyl alkoxy, 3-6 membered heterocyclyl alkoxy, -S (C 1-C 6 alkyl) , -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2 or – (C 1-C 6 alkylenyl) -OH;
    R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl;
    R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
    R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a, R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
    R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
  3. A compound according to claim 2 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    R 0 is hydrogen.
  4. A compound according to claim 2 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    R 1 is methyl.
  5. A compound according to claim 2 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    R 2 is hydrogen.
  6. A compound according to claim 2 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    R 3 is hydrogen, -C (O) NHR 3a;
    R 3a is hydrogen, CD 2CD 3, C 1-C 3 alkyl, C 1-C 6 haloalkyl, a C 3-C 6 cycloalkyl; wherein the C 3-C 6 cycloalkyl is optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
    R 3b is halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy.
  7. A compound according to claim 6 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    R 3 is hydrogen, -C (O) NHR 3a;
    R 3a is methyl, ethyl, isopropyl, cyclcopropyl.
  8. A compound according to claim 2 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    R 4a, R 4b are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4b is
    Figure PCTCN2021105686-appb-100009
    wherein
    Figure PCTCN2021105686-appb-100010
    are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium.
  9. A compound according to claim 2 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
    R 5and R 6 are each independently hydrogen, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkoxy;
    R 7 is hydrogen, C 1-C 3 alkyl.
  10. A compound according to claim 9 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
    R 5and R 6 are each independently hydrogen, halogen, or methyl;
    R 7 is hydrogen, or methyl.
  11. A compound according to claim 10 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
    R 5, R 6 and R 7 are hydrogen.
  12. A compound according to claim 2 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
    R 8c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl.
  13. A compound according to claim 2 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2, -CO (C 1-C 6 alkyl) or -CH 2R 9c;
    R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl.
  14. A compound according to claim 2 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    R 10 is absent, halogen, C 1-C 6 alkyl, hydrogen, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
    R 10c and R 10d are each independently phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
  15. A compound according to claim 2 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    R 0 is hydrogen;
    R 1 is methyl;
    R 2 is hydrogen;
    R 3 is hydrogen, -C (O) NHR 3a;
    R 3a is hydrogen, CD 2CD 3, C 1-C 3 alkyl, C 1-C 6 haloalkyl, a C 3-C 6 cycloalkyl; wherein the C 3-C 6 cycloalkyl is optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
    R 3b is halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    R 4a, R 4b are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4b is
    Figure PCTCN2021105686-appb-100011
    wherein
    Figure PCTCN2021105686-appb-100012
    are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
    L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
    R 5and R 6 are each independently hydrogen, halogen, C 1-C 3 alkyl, C 1-C 3 haloalkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkoxy;
    R 7 is hydrogen, C 1-C 3 alkyl;
    R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
    R 8c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
    R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2, -CO (C 1-C 6 alkyl) or -CH 2R 9c;
    R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
    R 10 is absent, hydrogen, halogen, C 1-C 6 alkyl, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
    R 10c and R 10d are each independently phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
  16. A compound according to claim 15 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    R 3 is hydrogen, -C (O) NHR 3a;
    R 3a is methyl, ethyl, isopropyl, cyclcopropyl;
    L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
    R 5and R 6 are each independently hydrogen, halogen, or methyl;
    R 7 is hydrogen, or methyl.
  17. A compound according to claim 16 of formula (II) or a pharmaceutically acceptable salt thereof,
    wherein:
    L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
    R 5, R 6 and R 7 are hydrogen.
  18. A compound according to claim 2 of formula (III) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021105686-appb-100013
    wherein:
    L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
    R 0 is hydrogen, halogen or C 1-C 3 alkyl;
    R 1 is C 1-C 3 alkyl;
    R 2 is hydrogen or methyl;
    R 3 is hydrogen, -C (O) NHR 3a;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    X 1 is O, S, S (O) , S (O)  2, CR 8or NR 8;
    X 3 is CR 10, N or NR 10;
    R 5and R 6 are each independently hydrogen, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
    R 7 is hydrogen, C 1-C 6 alkyl;
    R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
    R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2, -CO (C 1-C 6 alkyl) or -CH 2R 9c;
    R 10 is absent, hydrogen, halogen, C 1-C 6 alkyl, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
    R 3a is hydrogen, CD 2CD 3, C 1-C 3 alkyl, C 1-C 6 haloalkyl, a C 3-C 6 cycloalkyl, a phenyl, or a 5-6 membered monocyclic heteroaryl; wherein the C 3-C 6 cycloalkyl, the phenyl, or the 5-6 membered monocyclic heteroaryl are each optionally substituted with 1, 2, 3, or 4 indenpendently selected by R 3b groups;
    R 3b is halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
    R 4a, R 4b, R 8c, R 9c, R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1-C 3 alkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkyl, C 1-C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered cyclyl alkoxy, 3-6 membered heterocyclyl alkoxy, -S (C 1-C 6 alkyl) , -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2 or – (C 1-C 6 alkylenyl) -OH;
    R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl;
    R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
    R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a, R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
    R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl.
  19. A compound according to claim 18 of formula (III) or a pharmaceutically acceptable salt thereof,
    wherein:
    X 1 is S or O;
    X 3 is CR 10 or N;
    L is hydrogen, O or NR 7;
    R 7 is hydrogen;
    R 0 is hydrogen;
    R 1 is methyl;
    R 2 is hydrogen;
    R 3 is hydrogen, -C (O) NHR 3a;
    R 3a is methyl, ethyl, isopropyl, cyclcopropyl;
    R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) ,  -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2, or -CO (C 1-C 6 alkyl) ;
    R 10 is absent, hydrogen, methyl, halogen, OR 10d;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    R 4a and R 10d are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4b is
    Figure PCTCN2021105686-appb-100014
    wherein
    Figure PCTCN2021105686-appb-100015
    are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
    R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
    R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
  20. A compound according to claim 18 of formula (III) or a pharmaceutically acceptable salt thereof,
    wherein:
    X 1 is S, X 3 is N, R 10 is absent.
  21. A compound according to claim 18 of formula (III) or a pharmaceutically acceptable salt thereof,
    wherein:
    X 1 is S, X 3 is CH.
  22. A compound according to claim 21 of formula (III) or a pharmaceutically acceptable salt thereof,
    wherein:
    X 1 is S, X 3 is CH;
    L is hydrogen, O or NR 7;
    R 7 is hydrogen;
    R 0 is hydrogen;
    R 1 is methyl;
    R 2 is hydrogen;
    R 3 is hydrogen, -C (O) NHR 3a;
    R 3a is methyl, ethyl, isopropyl, cyclcopropyl;
    R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2, or -CO (C 1-C 6 alkyl) ;
    R 10 is absent, hydrogen, methyl, halogen, OR 10d;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    R 4a and R 10d are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4b is
    Figure PCTCN2021105686-appb-100016
    wherein
    Figure PCTCN2021105686-appb-100017
    are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
    R 9a and R 9b are each independently hydrogen, halogen, C 1-C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
    R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
  23. A compound according to claim 18 of formula (III) or a pharmaceutically acceptable salt thereof,
    wherein:
    X 1 is O, X 3 is N, R 10 is absent.
  24. A compound according to claim 2 of formula (IV) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021105686-appb-100018
    wherein:
    L is hydrogen, O or NH;
    R 0 is hydrogen;
    R 1 is methyl;
    R 2 is hydrogen;
    R 3 is hydrogen, -C (O) NHR 3a;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    R 8 is hydrogen, -C (CH 3)  2OH;
    R 10 is hydrogen;
    R 3a is methyl, ethyl, isopropyl, cyclcopropyl;
    R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4b is
    Figure PCTCN2021105686-appb-100019
    wherein
    Figure PCTCN2021105686-appb-100020
    are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium.
  25. A compound according to claim 2 of formula (V) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021105686-appb-100021
    wherein:
    for
    Figure PCTCN2021105686-appb-100022
    two of
    Figure PCTCN2021105686-appb-100023
    are double bond and the other two
    Figure PCTCN2021105686-appb-100024
    are single bond to form a 5-membered heteroaromatic ring system;
    L is hydrogen, O or NH;
    R 0 is hydrogen;
    R 1 is methyl;
    R 2 is hydrogen;
    R 3 is hydrogen, -C (O) NHR 3a;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    R 8 is absent, hydrogen, -CH 2C (CH 3)  2OH, or -CH 2R 8c;
    R 9 is absent, or -CH 2R 9c;
    R 10 is hydrogen, -C (CH 3)  2OH;
    R 3a is methyl, ethyl, isopropyl, cyclcopropyl;
    R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4b is
    Figure PCTCN2021105686-appb-100025
    wherein
    Figure PCTCN2021105686-appb-100026
    are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
    R 8c and R 9c are each independently phenyl, tetrahydropyranyl, wherein phenyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
  26. A compound according to claim 1 of formula (VI) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021105686-appb-100027
    Wherein:
    L is O or NH;
    R 0 is hydrogen;
    R 1 is methyl;
    R 2 is hydrogen;
    R 3 is hydrogen, -C (O) NHR 3a;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    R 8 is absent, hydrogen, -CH 2C (CH 3)  2OH, or -CH 2R 8c;
    R 9 is absent, -C (CH 3)  2OH or -CH 2R 9c;
    R 10 is hydrogen;
    R 3a is methyl, ethyl, isopropyl, cyclcopropyl;
    R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4b is
    Figure PCTCN2021105686-appb-100028
    wherein
    Figure PCTCN2021105686-appb-100029
    are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
    R 8c and R 9c are each independently phenyl, tetrahydropyranyl, wherein phenyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
  27. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the conmpound is selected from the group consisting of
    4- (3- (2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- (2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5-carbamoyl-3- (2, 6-dimethylphenoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (4-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5-acetyl-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5-acetyl-3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5-acetyl-3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5-acetyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5-acetyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5-acetyl-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5-acetyl-3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5-acetyl-3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5-acetyl-3- ( (4-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5-acetyl-3- ( (2, 4-dimethylpyridin-3-yl) amino) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-6-methyl-4- (3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-6-methyl-4- (3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-6-methyl-4- (3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N, 6-dimethyl-4- (3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N, 6-dimethyl-4- (3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N, 6-dimethyl-4- (3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2- yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-isopropyl-6-methyl-4- (3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-isopropyl-6-methyl-4- (3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-isopropyl-6-methyl-4- (3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5-sulfamoylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-6-methyl-4- (3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-6-methyl-4- (3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-6-methyl-4- (3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiophen-2-yl) -N, 6-dime thyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) thiophen -2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxami de;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-met hylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (2-hydroxypropan-2-yl) -4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2 -carboxamide;
    N-cyclopropyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N -isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2- yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-6-methyl-4- (4-methyl-3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-6-methyl-4- (4-methyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-6-methyl-4- (4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -4-methyl-5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-methyl-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N, 6-dimethyl-4- (4-methyl-3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N, 6-dimethyl-4- (4-methyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N, 6-dimethyl-4- (4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (4-fluoro-2, 6-dimethylphenoxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-methyl-5-sulfamoylthiophen-2-yl) -N, 6-dim ethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5-sulfamoylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5-sulfamoylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-3- ( (3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-3- ( (1-methylpyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5-sulfamoylthiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -4-methyl-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-i sopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -4-methyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- (4-fluoro-2, 6-dimethylphenoxy) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
    4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-methylthiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-methyl-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-methyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- (4-fluoro-2, 6-dimethylphenoxy) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluorothiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluorothiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluorothiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluorothiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluorothiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluorothiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluorothiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluorothiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluorothiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (dimethylphosphoryl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluorothiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-5- (2-hydroxypropan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-cyclopropyl-4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen-2-yl) -N-isopropyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- (4-fluoro-2, 6-dimethylphenoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (1-fluoro-2-hydroxy-2-methylpropyl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (1-methylpyrrolidin-2-yl)  methoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- (4-fluoro-2, 6-dimethylphenoxy) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (1, 1-difluoro-2-hydroxy-2-methylpropyl) -3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methyl-3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (1-fluoro-2-hydroxy-2-methylpropyl) -3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-meth ylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -5- (1-fluoro-2-hydroxy-2-methylpropyl) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5- (3-hydroxy-2, 3-dimethylbutan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) -3- ( (3-methylpyridin-2-yl) oxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) oxy) -4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) -3- ( (1-methylpyrrolidin-2-yl) m ethoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) -3- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -5- (3-hydroxy-3-methylbutan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- (4-fluoro-2, 6-dimethylphenoxy) -5- (3-hydroxy-3-methylbutan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) oxy) -4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4, 6-dimethylpyridin-2-yl) oxy) -4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) amino) -4-fluoro-5- (3-hydroxy-3-methylbutan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) methoxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (5-fluoro-3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (2-hydroxypropan-2-yl) -3- ( (5-methylpyridin-2-yl) methoxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( ( (2, 4-dimethylpyridin-3-yl) methyl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (3-methylpyridin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- ( (5-fluoro-3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- ( (5-methylpyridin-2-yl) methoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( ( (2, 4-dimethylpyridin-3-yl) methyl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (2-hydroxypropan-2-yl) -3- (1- (3-methylpyridin-2-yl) ethoxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (1- (3, 5-dimethylpyridin-2-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (1- (3, 5-dimethylpyridin-4-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (difluoro (mesityl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (1- (5-fluoro-3-methylpyridin-2-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (1- (4-fluoro-2, 6-dimethylphenyl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (1- (2, 4-dimethylpyridin-3-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (2-hydroxypropan-2-yl) -3- (1- (5-methylpyridin-2-yl) ethoxy) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (1- (2, 4-dimethylpyridin-3-yl) ethyl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- (1- (3-methylpyridin-2-yl) ethoxy) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (1- (3, 5-dimethylpyridin-2-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (1- (3, 5-dimethylpyridin-4-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (d2 (mesityl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (difluoro (mesityl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- (1- (5-fluoro-3-methylpyridin-2-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- (1- (4-fluoro-2, 6-dimethylphenyl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (1- (2, 4-dimethylpyridin-3-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (2-hydroxypropan-2-yl) -3- (1- (5-methylpyridin-2-yl) ethoxy) thiophen-2-y l) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (1- (2, 4-dimethylpyridin-3-yl) ethyl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (fluoro (3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) fluoromethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) fluoromethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4- (fluoro (4-fluoro-2, 6-dimethylphenyl) methoxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide
    4- (4- (d2 (4-fluoro-2, 6-dimethylphenyl) methoxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (fluoro (5-fluoro-3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (fluoro (4-fluoro-2, 6-dimethylphenyl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) fluoromethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (fluoro (5-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( ( (2, 4-dimethylpyridin-3-yl) fluoromethyl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- (fluoro (3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-2-yl) fluoromethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (3, 5-dimethylpyridin-4-yl) fluoromethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4- (1- (4-fluoro-2, 6-dimethylphenyl) ethoxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- (fluoro (5-fluoro-3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- (fluoro (4-fluoro-2, 6-dimethylphenyl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( (2, 4-dimethylpyridin-3-yl) fluoromethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- (fluoro (5-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- ( ( (2, 4-dimethylpyridin-3-yl) fluoromethyl) amino) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (2- (2-hydroxypropan-2-yl) -4- ( (3-methylpyridin-2-yl) oxy) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (3, 5-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (3, 5-dimethylpyridin-4-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methylpyrrolidin-2-yl) methoxy) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (2, 4-dimethylpyridin-3-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (4, 6-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (2, 4-dimethylpyridin-3-yl) amino) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (2- (2-hydroxypropan-2-yl) -4- ( (3-methylpyridin-2-yl) oxy) thiazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (3, 5-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (3, 5-dimethylpyridin-4-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methylpyrrolidin-2-yl) methoxy) thiazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) thiazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (2, 4-dimethylpyridin-3-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (4, 6-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (2, 4-dimethylpyridin-3-yl) amino) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (2- (2-hydroxypropan-2-yl) -4- ( (3-methylpyridin-2-yl) oxy) oxazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (3, 5-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (3, 5-dimethylpyridin-4-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methylpyrrolidin-2-yl) methoxy) oxazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) oxazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (2, 4-dimethylpyridin-3-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (4, 6-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (2, 4-dimethylpyridin-3-yl) amino) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (2- (2-hydroxypropan-2-yl) -4- ( (3-methylpyridin-2-yl) oxy) oxazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (3, 5-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (3, 5-dimethylpyridin-4-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methylpyrrolidin-2-yl) methoxy) oxazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (2- (2-hydroxypropan-2-yl) -4- ( (1-methyl-5-oxopyrrolidin-2-yl) methoxy) oxazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (5-fluoro-3-methylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- (4-fluoro-2, 6-dimethylphenoxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (2, 4-dimethylpyridin-3-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (4, 6-dimethylpyridin-2-yl) oxy) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- ( (2, 4-dimethylpyridin-3-yl) amino) -2- (2-hydroxypropan-2-yl) oxazol-5-yl) -N, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- (2, 6-dimethylphenoxy) -1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (1-benzyl-4- (2, 6-dimethylphenoxy) -1H-pyrazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7- dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (5- (2-hydroxypropan-2-yl) -1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazol-3-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (1- (2, 6-dimethylbenzyl) -5- (2-hydroxypropan-2-yl) -1H-pyrazol-3-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (1- (2, 6-dimethylbenzyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-4-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (1- (2, 6-dimethylbenzyl) -5- (2-hydroxypropan-2-yl) -1H-pyrazol-4-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- (2-hydroxypropan-2-yl) -1- ( (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (1- (2, 6-dimethylbenzyl) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (5- (2, 6-dimethylphenoxy) -3- (2-hydroxypropan-2-yl) -1H-pyrazol-1-yl) -6-methyl-1H-pyrrolo [2, 3-c] pyridin-7 (6H) -one;
    4- (3- (4-chloro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (4-chloro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (4-chloro-2, 6-dimethylphenoxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (3- (4-fluoro-2, 6-dimethylphenoxy) -5- (2-hydroxypropan-2-yl) -4-methylthiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4- ( (2- (4-fluoro-2, 6-dimethylphenyl) propan-2-yl) oxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (4- (difluoro (4-fluoro-2, 6-dimethylphenyl) methoxy) -2- (2-hydroxypropan-2-yl) thiazol-5-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- ( (4-fluoro-2, 6-dimethylbenzyl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- (1- (4-fluoro-2, 6-dimethylphenyl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- (fluoro (4-fluoro-2, 6-dimethylphenyl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- ( (2- (4-fluoro-2, 6-dimethylphenyl) propan-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (difluoro (4-fluoro-2, 6-dimethylphenyl) methoxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- ( (5-fluoro-3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan -2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- (1- (5-fluoro-3-methylpyridin-2-yl) ethoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- (fluoro (5-fluoro-3-methylpyridin-2-yl) methoxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    N-ethyl-4- (4-fluoro-3- ( (2- (5-fluoro-3-methylpyridin-2-yl) propan-2-yl) oxy) -5- (2-hydroxypropan-2-yl) thiophen-2-yl) -6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide;
    4- (3- (difluoro (5-fluoro-3-methylpyridin-2-yl) methoxy) -4-fluoro-5- (2-hydroxypropan-2-yl) thiophen-2-yl) -N-ethyl-6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2, 3-c] pyridine-2-carboxamide.
  28. An intermediate compound of the formula (VII) ,
    Figure PCTCN2021105686-appb-100030
    wherein:
    L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    X 1 is O, S, S (O) , S (O)  2, CR 8or NR 8;
    X 3 is CR 10, N or NR 10;
    R 5and R 6 are each independently hydrogen, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
    R 7 is hydrogen, C 1-C 6 alkyl;
    R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
    R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2, -CO (C 1-C 6 alkyl) or -CH 2R 9c;
    R 10 is absent, hydrogen, halogen, C 1-C 6 alkyl, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
    R 4a, R 4b, R 8c, R 9c, R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1-C 3 alkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkyl, C 1-C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered cyclyl alkoxy, 3-6 membered heterocyclyl alkoxy,  -S (C 1-C 6 alkyl) , -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2 or – (C 1-C 6 alkylenyl) -OH;
    R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl;
    R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
    R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a, R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
    R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl;
    X is halide.
  29. An intermediate compound according to claim 28 of formula (VII) ,
    wherein:
    X 1 is S or O;
    X 3 is CR 10 or N;
    L is hydrogen, O or NR 7;
    R 7 is hydrogen;
    R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2, or -CO (C 1-C 6 alkyl) ;
    R 10 is absent, hydrogen, methyl, halogen, OR 10d;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    R 4a and R 10d are each independently phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4b is
    Figure PCTCN2021105686-appb-100031
    wherein
    Figure PCTCN2021105686-appb-100032
    are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
    R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a and R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
    R 9c is phenyl, or pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    X is CI, Br, I or triflate.
  30. An intermediate compound of the formula (VIII) ,
    Figure PCTCN2021105686-appb-100033
    wherein:
    L is hydrogen, O, S, CR 5R 6, -C (CH 3)  2OH or NR 7;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    X 1 is O, S, S (O) , S (O)  2, CR 8or NR 8;
    X 3 is CR 10, N or NR 10;
    R 5and R 6 are each independently hydrogen, halogen, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 1-C 6 alkoxy, C 1-C 6 haloalkoxy;
    R 7 is hydrogen, C 1-C 6 alkyl;
    R 8 is absent, hydrogen, -C (CH 3)  2OH, -CR 8aR 8bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, or -CH 2R 8c;
    R 9 is absent, hydrogen, -C (CH 3)  2OH, -CR 9aR 9bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CONH 2, -CO (C 1-C 6 alkyl) or -CH 2R 9c;
    R 10 is absent, hydrogen, halogen, C 1-C 6 alkyl, -C (CH 3)  2OH, -CR 10aR 10bC (CH 3)  2OH, -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2, -S (O)  2NH 2, -CH 2R 10c or -OR10 d;
    R 4a, R 4b, R 8c, R 9c, R 10c and R 10d are each independently 6-8 membered aryl, 5-8 membered heteroaryl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 6-8 membered arylalkyl, 5-8 membered heteroarylalkyl, 3-6 membered cyclylalkyl, 3-6 membered heterocyclylalkyl, wherein each 6-8 membered aryl, 5-8 membered heteroaryl, 4-6 membered cyclyl, 4-6 membered heterocyclyl is optionally substituted with 1, 2, 3, 4 independently selected groups from a halogen, -CN, C 1-C 3 alkyl, C 1-C 3 alkoxy, C 1-C 3 haloalkyl, C 1-C 3 haloalkoxy, 3-6 membered cyclyl, 3-6 membered heterocyclyl, 3-6 membered cyclyl alkoxy, 3-6 membered heterocyclyl alkoxy, -S (C 1-C 6 alkyl) , -S (O)  2 (C 1-C 6 alkyl) , -P (O) (C 1-C 2 alkyl)  2 or – (C 1-C 6 alkylenyl) -OH;
    R 4c and R 4d are each independently hydrogen, halogen, C1-C6 alkyl;
    R 8a and R 8b are hydrogen, halogen, C 1-C 2 alkyl, or R 8a, R 8b and the C atom to which R 8a and R 8b are attached to form a cyclopropyl;
    R 9a and R 9b are hydrogen, halogen, C 1-C 2 alkyl, or R 9a, R 9b and the C atom to which R 9a and R 9b are attached to form a cyclopropyl;
    R 10a and R 10b are hydrogen, halogen, C 1-C 2 alkyl, or R 10a, R 10b and the C atom to which R 10a and R 10b are attached to form a cyclopropyl;
    R is C 1-C 6 alkyl.
  31. An intermediate compound of the formula (IX) ,
    Figure PCTCN2021105686-appb-100034
    wherein:
    L is hydrogen, O or NH;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    R 8 is hydrogen, -C (CH 3)  2OH;
    R 10 is hydrogen;
    R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4b is
    Figure PCTCN2021105686-appb-100035
    wherein
    Figure PCTCN2021105686-appb-100036
    are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
    X is CI, Br, I or triflate.
  32. An intermediate compound of the formula (X) ,
    Figure PCTCN2021105686-appb-100037
    wherein:
    for
    Figure PCTCN2021105686-appb-100038
    two of
    Figure PCTCN2021105686-appb-100039
    are double bond and the other two
    Figure PCTCN2021105686-appb-100040
    are single bond to form a 5-membered heteroaromatic ring system;
    L is hydrogen, O or NH;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    R 8 is absent, hydrogen, -CH 2C (CH 3)  2OH, or -CH 2R 8c;
    R 9 is absent, or -CH 2R 9c;
    R 10 is hydrogen, -C (CH 3)  2OH;
    R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4b is
    Figure PCTCN2021105686-appb-100041
    wherein
    Figure PCTCN2021105686-appb-100042
    are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
    R 8c and R 9c are each independently phenyl, tetrahydropyranyl, wherein phenyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    X is CI, Br, I or triflate.
  33. An intermediate compound of the formula (XI) ,
    Figure PCTCN2021105686-appb-100043
    wherein:
    L is O or NH;
    R 4 is absent, R 4a or –CR 4bR 4cR 4d;
    R 9 is absent, -C (CH 3)  2OH or -CH 2R 9c;
    R 10 is hydrogen;
    R 4a is phenyl, pyridinyl; wherein phenyl and pyridinyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4b is
    Figure PCTCN2021105686-appb-100044
    wherein
    Figure PCTCN2021105686-appb-100045
    are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen;
    R 4c and R 4d are each independently hydrogen, methyl, halogen, deuterium;
    R 9c is phenyl, tetrahydropyranyl, wherein phenyl and tetrahydropyranyl are optionally substituted with 1, 2, 3, 4 independently selected groups from a methyl or halogen.
  34. A process of preparation of compounds of Formula (III) according to claim 18, the process comprising reacting Formula (XII) and Formula (VII) ; X is CI, Br, I or triflate; R is C 1-C 6 alkyl; R 0, R 1, R 2, R 3, R 4, L, X 0, X 1, X 2 and X 3 are defined as in claim 18;
    Figure PCTCN2021105686-appb-100046
  35. A process of preparation of compounds of Formula (III) according to claim 18, the process comprising reacting Formula (XIV) and Formula (VIII) ; X is CI, Br, I or triflate; R is C 1-C 6 alkyl; R 0, R 1, R 2, R 3, R 4, L, X 0, X 1, X 2 and X 3 are defined as in claim 18;
    Figure PCTCN2021105686-appb-100047
  36. A process of preparation of compounds of Formula (IV) according to claim 24, the process comprising reacting Formula (XII) and Formula (IX) ; X is CI, Br, I or triflate; R is C 1-C 6 alkyl; R 0, R 1, R 2, R 3, R 4, L, R 8 and R 10 are defined as in claim 24;
    Figure PCTCN2021105686-appb-100048
  37. A process of preparation of compounds of Formula (V) according to claim 25, the process comprising reacting Formula (XII) and Formula (X) ; X is CI, Br, I or triflate; R is C 1-C 6 alkyl; R 0, R 1, R 2, R 3, R 4, L, R 8, R 9 and R 10 are defined as in claim 25;
    Figure PCTCN2021105686-appb-100049
  38. A process of preparation of compounds of Formula (VI) according to claim 26, the process comprising reacting Formula (XV) and Formula (XI) ; R 0, R 1, R 2, R 3, R 4, L, R 9 and R 10 are defined as in claim 26;
    Figure PCTCN2021105686-appb-100050
  39. A method for inhibiting a bromodomain which comprises contacting the bromodomain with a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  40. A method of treating cancer comprising administering a therapeutically effective amount of one or more compounds according to claim 1 or a pharmaceutically acceptable salt thereof.
  41. The method of claim 14 wherein the cancer is selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic) , acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias) , embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin’s and non-Hodgkin’s) , malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC) , non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas) , small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom’s macroglobulinemia, testicular tumors, uterine cancer, and Wilms’ tumor.
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