WO2019080941A1 - Nouveaux composés tricycliques - Google Patents

Nouveaux composés tricycliques

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Publication number
WO2019080941A1
WO2019080941A1 PCT/CN2018/112386 CN2018112386W WO2019080941A1 WO 2019080941 A1 WO2019080941 A1 WO 2019080941A1 CN 2018112386 W CN2018112386 W CN 2018112386W WO 2019080941 A1 WO2019080941 A1 WO 2019080941A1
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WO
WIPO (PCT)
Prior art keywords
membered
heterocyclic
alkyl
alkylene
heteroaryl
Prior art date
Application number
PCT/CN2018/112386
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English (en)
Inventor
Haiquan Fang
Wenlai Zhou
Shaojing Hu
Mingming Chen
Guiqun YANG
Yanping Wang
Yuelei DU
Qinglong Li
Tong Wu
Lingjun WU
Haijun Li
Wei LONG
Original Assignee
Jacobio-Beta Pharmaceuticals Co., Ltd.
Jacobio-Alpha Pharmaceuticals Co., Ltd.
Jacobio Pharmaceuticals Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jacobio-Beta Pharmaceuticals Co., Ltd., Jacobio-Alpha Pharmaceuticals Co., Ltd., Jacobio Pharmaceuticals Co., Ltd. filed Critical Jacobio-Beta Pharmaceuticals Co., Ltd.
Priority to CN201880069871.5A priority Critical patent/CN111356695B/zh
Publication of WO2019080941A1 publication Critical patent/WO2019080941A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This invention relates to certain novel tricyclic compounds (Formula (1) ) as bromodomain and extra-terminal (BET) inhibitors which is shown as Formula (1) , their synthesis and their use for treating diseases. More particularly, this invention is directed to fused heterocyclic derivatives useful as inhibitors of BET, methods for producing such compounds and methods for treating diseases and conditions wherein inhibition of one or more BET bromodomains provides a benefit.
  • Epigenetics is used to describe heritable gene regulation or transcriptional silencing across generations of cells and even organism and the process of which is mediated through dynamic and reversible changes in chromatin accessibility and post-translational modifications (PTMs) of histone tails.
  • PTMs post-translational modifications
  • Several physiological processes might contribute to epigenetic regulation, including DNA methylation, non-coding RNA-mediated scaffolding and complex formation, and histone modification.
  • Histone modification is a process related to the post-translational covalent modification of histone proteins that markedly influences the ability of associated DNA to be transcribed. Lysine acetylation is a post-translational modification with broad relevance to cellular signaling and disease biology.
  • Enzymes that regulate lysine acetylation in histones are termed as ‘writers’ or histone acetyltransferaes (HATs) , and that regulating lysine deacetylation in histone as ‘erasers’ or histone deacetylases (HDACs) .
  • Bromodomains (BRDs) ‘readers’ of epigenetic marks, specifically recognize ⁇ -N-acetyl lysine (Kac) residues on histones tails.
  • BRDs BRDs, first described in 1992, contain approximately 110 amino acids. There are 46 known bromodomain containing proteins from humans which across eight families based on structure/sequence similarity. Among them, bromodomain and extra-terminal domain (BET) recognize acetylated lysine residues in histones H3 and H4. BET family, containing BRD2, BRD3, BRD4 and BRDT four members, share 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) : 1294145) .
  • 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.
  • the present invention relates to tricyclic compounds useful as BET inhibitors and for the treatment of conditions associated with BET.
  • the compounds of the invention have the general structure as Formula (1) , or a pharmaceutically acceptable salt thereof, or stereoisomer thereof:
  • one is a single bond and the other is a double bond;
  • X 1 is CR 1a , O, S, S (O) , S (O) 2 or NR 1b ;
  • X 2 is CR 2a , O, S or NR 2b ;
  • each R 1a or R 2a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) C 1-6 alkoxy, C 1-6 alkylene-C 1-6 alkoxy, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted;
  • each R 1b or R 2b is independently absent, H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-3 alkylene-C 5-6 aryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted;
  • R 3 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) NH 2 , C (O) NH-C 1-6 alkyl, C (O) N (C 1-6 alkyl) 2 , C (O) C 1-6 alkyl, C (O) OC 1-6 alkyl, S (O) C 1-6 alkyl, S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, -C l-6 alkylene-NH 2 , -C l-6 alkylene-NH-C 1-6 alkyl, -C l-6 alkylene-N (C 1-6 alkyl) 2 , C 2-6 alkenyl, C 2-6 alkenyl-OH, C 2-6 alkynyl, -C 2-6 alkenyl-OH, -C 2-6 al
  • s 0, 1, 2, 3, 4 or 5;
  • R 4 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) NH 2 , C (O) NH-C 1-6 alkyl, C (O) N (C 1-6 alkyl) 2 , C (O) C 1-6 alkyl, S (O) C 1-6 alkyl, S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, -C l-6 alkylene-NH 2 , C 5-6 heteroaryl, C 3-6 heterocyclic, C 3-6 carbocyclic; and each of which is independently optionally substituted;
  • W 1 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted;
  • W 2 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted;
  • Z is H, or deuterium.
  • the compounds of the invention have the general structure as Formula I or a pharmaceutically acceptable salt:
  • one is a single bond and the other is a double bond;
  • X 1 is CR 1a , O, S, S (O) , S (O) 2 or NR 1b ;
  • X 2 is CR 2a , O, S or NR 2b ;
  • each R 1a or R 2a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) C 1-6 alkoxy, C 1-6 alkylene-C 1-6 alkoxy, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted;
  • each R 1b or R 2b is independently absent, H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-3 alkylene-C 5-6 aryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted;
  • R 3 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) NH 2 , C (O) NH-C 1-6 alkyl, C (O) N (C 1-6 alkyl) 2 , C (O) C 1-6 alkyl, S (O) C 1-6 alkyl, S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, -C l-6 alkylene-NH 2 , -C l-6 alkylene-NH-C 1-6 alkyl, -C l-6 alkylene-N (C 1-6 alkyl) 2 , C 2-6 alkenyl, C 2-6 alkenyl-OH, C 2-6 alkynyl, -C 2-6 alkenyl-OH, -C 2-6 alkynyl-OH, -C l
  • s 0, 1, 2, 3, 4 or 5;
  • R 4 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) NH 2 , C (O) NH-C 1-6 alkyl, C (O) N (C 1-6 alkyl) 2 , C (O) C 1-6 alkyl, S (O) C 1-6 alkyl, S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, -C l-6 alkylene-NH 2 , C 5-6 heteroaryl, C 3-6 heterocyclic, C 3-6 carbocyclic; and each of which is independently optionally substituted;
  • W 1 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted;
  • W 2 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted.
  • the present invention further provides preferred technical solutions with regard to compound of Formula (1) , Formula (I) .
  • X 1 is CR 1a , O, S or NR 1b .
  • R 1a is H, F, Cl, Br, I, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S.
  • R 1a is H, F, Cl, Br, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 5-membered heteroayl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 1a is H, F, Cl, Br, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroayl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl or heterocyclic contains 1 or 2 heteroatoms selected from N, O or S
  • R 1a is H, F or methyl.
  • R 1b is absent, H, F, Cl, Br, I, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-3 alkylene-C 5-6 aryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S..
  • R 1b is absent, H, F, Cl, Br, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene-5-membered aryl, C 1-3 alkylene-6-membered-aryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 1b is absent, H, F, Cl, Br, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylene-5-membered aryl, methylene-6-membered-aryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, NH 2 , OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heterocyclic contains 1 or 2 heteroatoms selected from N, O or S.
  • R 1b is absent, H, methyl or benzyl.
  • X 2 is CR 2a , O, S or NR 2b .
  • R 2a is H, F, Cl, Br, I, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) C 1-6 alkoxy, C 1-6 alkylene-C 1-6 alkoxy, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S.
  • R 2a is H, F, Cl, Br, NH 2 , CN, OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C (O) C 1-3 alkoxy, C 1-3 alkylene-C 1-3 alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 2a is H, F, Cl, Br, NH 2 , CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) OCH 3 , C (O) OCH 2 CH 3 , C (O) OCH 2 CH 2 CH 3 , C (O) OCH (CH 3 ) 2 , CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 CH 2 OCH 2 CH 3 , CH 2 CH 2 OCH 3 , C (CH 3 ) 2 OCH 3 , C (CH 3 ) 2 OCH 2 CH 3 , C (CH 3 ) 2 OCH 2 CH 2 CH 3 , 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is
  • R 2a is H, F, Cl, CN, methyl, methoxy, CF 3 , C (O) OCH 2 CH 3 , CH 2 OH, CH 2 OCH 3 ,
  • R 2a is H, F, Cl, CN, methyl, CD 3 , ethyl, isopropyl, methoxy, CF 3 , C (O) OCH 2 CH 3 , CH 2 OH, CH 2 OCH 3 ,
  • R 2b is absent, H, F, Cl, Br, I, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S.
  • R 2b is absent, H, F, Cl, Br, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 2b is absent, H, F, Cl, Br, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, NH 2 , OH, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heterocyclic contains 1 or 2 heteroatoms selected from N, O or S.
  • R 2b is absent or H.
  • R 3 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C (O) NH 2 , C (O) NH-C 1-3 alkyl, C (O) N (C 1-3 alkyl) 2 , C (O) C 1-3 alkyl, S (O) C 1-3 alkyl, S (O) 2 C 1-3 alkyl, P (O) (C 1-3 alkyl) 2 , -C l-3 alkylene-OH, -C l-3 alkylene-NH 2 , -C l-3 alkylene-NH-C 1-3 alkyl, -C l-3 alkylene-N (C 1-3 alkyl) 2 , C 2-3 alkenyl, C 2-3 alkenyl-OH, C 2-3 alkynyl, -C 2-3 alkenyl-OH, -C 2-3 alkynyl-N (C 1-3 alkyl) 2 , C 2-3 al
  • R 3a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylene-OH; or
  • R 3 is H, F, Cl, Br, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) NH 2 , C (O) N (CH 3 ) 2 , C (O) CH 3 , S (O) 2 CH 3 , P (O) (CH 3 ) 2 , CH 2 OH, CH 2 CH 2 OH, C (CH 3 ) 2 OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C (CH 3 ) 2 NH 2 , CH 2 N (CH 3 ) 2 , CH 2 CH 2 N (CH 3 ) 2 , CH 2 N (CH 2 CH 3 ) 2 , C (CH 3 ) 2 N (CH 3 ) 2 , C (CH 3 ) 2 N (CH 2 CH 3 ) 2 , vinyl, propylene, ethyny
  • R 3 is H, F, Cl, NH 2 , OH, methyl, ethyl, isopropyl, methoxy, isopropoxy, C (O) NH 2 , C (O) CH 3 , S (O) 2 CH 3 , P (O) (CH 3 ) 2 , CH 2 OH, C (CH 3 ) 2 OH, CH 2 NH 2 , C (CH 3 ) 2 NH 2 , CH 2 N (CH 3 ) 2 , CH 2 CH 2 N (CH 3 ) 2 , C (CH 3 ) 2 N (CH 3 ) 2 , C (CH 3 ) 2 N (CH 2 CH 3 ) 2 , vinyl, ethynyl, -C l-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene- (O-C 1-3 alkylene) s -OH, -C 1-3 alkylene- (O-C 1-3 alkylene) s -OH, -C
  • s is 1, 2, 3 or 4.
  • each R 3a is independently H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylene-OH; or
  • each R 3a is independently H, F, Cl, Br, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 OH, CH 2 CH 2 OH, CH (CH 3 ) OH or C (CH 3 ) 2 OH; or
  • R 3 is H, CH 3 , C (O) NH 2 ,
  • R 3 is H, CH 3 , C (O) NH 2 , C (O) N (CH 3 ) 2 , C (O) CH 3 , C (O) OCH 3 ,
  • R 4 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C (O) NH 2 , C (O) NH-C 1-3 alkyl, C (O) N (C 1-3 alkyl) 2 , C (O) C 1-3 alkyl, S (O) C 1-3 alkyl, S (O) 2 C 1-3 alkyl, P (O) (C 1-3 alkyl) 2 , -C l-3 alkylene-OH, -C l-3 alkylene-NH 2 , C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • R 4a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 heterocyclic or C 3-6 carbocyclic; and wherein each of the heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S; or
  • R 4 is H, F, Cl, Br, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) NH 2 , C (O) N (CH 3 ) 2 , C (O) CH 3 , S (O) 2 CH 3 , P (O) (CH 3 ) 2 , CH 2 OH, CH 2 CH 2 OH, C (CH 3 ) 2 OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C (CH 3 ) 2 NH 2 , 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic
  • R 4 is H, F, Cl, NH 2 , OH, methyl, ethyl, isopropyl, methoxy, isopropoxy, C (O) NH 2 , C (O) CH 3 , S (O) 2 CH 3 , P (O) (CH 3 ) 2 , CH 2 OH, C (CH 3 ) 2 OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted one or more R 4a .
  • each R 4a is independently H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and wherein each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S; or
  • each R 4a is independently H, F, Cl, Br, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and wherein each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O; or
  • each R 4a is independently H, F, Cl, NH 2 , OH, methyl, ethyl, isopropyl, methoxy, isopropoxy,
  • W 1 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkylene-C 1-3 alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S.
  • W 1 is H, F, Cl, Br, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 OCH 2 CH 3 , 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • W 1 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, isopropoxy, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • W 1 is H, F, methyl, ethyl, propyl, isopropyl, methoxy, isopropoxy, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , and each of which is independently optionally substituted with F, Cl, NH 2 , OH, methyl or methoxy.
  • W 1 is H, F, methyl, ethyl, propyl, methoxy, CH 2 OCH 3 , CH 2 CH 2 OCH 3 ,
  • W 1 is H, F, methyl, ethyl, propyl, methoxy, CH 2 OCH 3 , CH 2 CH 2 CF 3 , CH 2 CH 2 OCH 3 ,
  • W 2 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S.
  • W 2 is H, F, Cl, Br, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • W 2 is H, F, Cl, NH 2 , OH, methyl, ethyl, isopropyl, methoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • W 2 is H, and each of which is independently optionally substituted with F, Cl, methyl or methoxy.
  • W 2 is H
  • the compound is of Formula (2) :
  • X 1 is O, S or NR 1b ;
  • R 1b is H halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-3 alkylene-C 5-6 aryl;
  • R 2 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) C 1-6 alkoxy, C 1-6 alkylene-C 1-6 alkoxy, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • R 3 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) NH 2 , C (O) N (C 1-6 alkyl) 2 , C (O) OC 1-6 alkyl, S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, -C l-6 alkylene-NH 2 , -C l-6 alkylene-N (C 1-6 alkyl) 2 , C 2-6 alkenyl, -C 2-6 alkynyl-OH, -C l-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene- (O-C 1-6 alkylene) s -OH, -C 1-6 alkylene- (O-C 1-6 alkylene) s -C 1-6 alkoxy, -C 1-6
  • s is 1, 2, 3 or 4;
  • each R 3a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylene-OH; or
  • R 4 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, C 5-6 heteroaryl, C 3-6 heterocyclic, C 3-6 carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • each R 4a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 heterocyclic or C 3-6 carbocyclic; and wherein each of the heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;or
  • W 1 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • W 2 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • Z is H, or deuterium.
  • the compound is of Formula II:
  • X 1 is O, S or NR 1b ;
  • R 1b is H halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-3 alkylene-C 5-6 aryl;
  • R 2 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) C 1-6 alkoxy, C 1-6 alkylene-C 1-6 alkoxy, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • R 3 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) NH 2 , S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, -C l-6 alkylene-NH 2 , -C l-6 alkylene-N (C 1-6 alkyl) 2 , C 2-6 alkenyl, -C 2-6 alkynyl-OH, -C l-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene- (O-C 1-6 alkylene) s -OH, -C 1-6 alkylene- (O-C 1-6 alkylene) s -C 1-6 alkoxy, -C 1-6 alkylene- (O-C 1-6 alkylene) s -N (C 1-6 alkyl)
  • s is 1, 2, 3 or 4;
  • each R 3a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylene-OH; or
  • R 4 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, C 5-6 heteroaryl, C 3-6 heterocyclic, C 3-6 carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • each R 4a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 heterocyclic or C 3-6 carbocyclic; and wherein each of the heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;or
  • W 1 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • W 2 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S.
  • the present invention further provides some preferred technical solutions with regard to compound of Formula (2) , or Formula (II) .
  • R 1b is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene-5-membered aryl or C 1-3 alkylene-6-membered-aryl.
  • R 1b is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylene-5-membered aryl or methylene-6-membered-aryl.
  • R 1b is H, methyl or benzyl.
  • R 2 is H, F, Cl, Br, I, NH 2 , CN, OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C (O) C 1-3 alkoxy, C 1-3 alkylene-C 1-3 alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , CN, OH, NO 2 , carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 2 is H, F, Cl, NH 2 , CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) OCH 3 , C (O) OCH 2 CH 3 , C (O) OCH 2 CH 2 CH 3 , C (O) OCH (CH 3 ) 2 , CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 CH 2 OCH 2 CH 3 , CH 2 CH 2 OCH 3 , C (CH 3 ) 2 OCH 3 , C (CH 3 ) 2 OCH 2 CH 3 , C (CH 3 ) 2 OCH 2 CH 2 CH 3 , 5-membered heteroaryl or 6-membered heteroaryl; and each of which is independently optionally substituted with F, Cl, NH 2 , OH, carboxyl, methyl, ethyl, propyl, is
  • R 2 is H, F, Cl, CN, methyl, methoxy, CF 3 , C (O) OCH 2 CH 3 , CH 2 OH, CH 2 OCH 3 ,
  • R 2 is H, F, Cl, CN, methyl, CD 3 , ethyl, isopropyl, methoxy, CF 3 , C (O) OCH 2 CH 3 , CH 2 OH, CH 2 OCH 3 ,
  • R 3 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C (O) NH 2 , S (O) 2 C 1-3 alkyl, P (O) (C 1-3 alkyl) 2 , -C l-3 alkylene-OH, -C l-3 alkylene-NH 2 , -C l-3 alkylene-N (C 1-3 alkyl) 2 , -C 2-3 alkynyl-OH, -C l-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene- (O-C 1-3 alkylene) s -OH, -C 1-3 alkylene- (O-C 1-3 alkylene) s -C 1-3 alkoxy, -C 1-3 alkylene- (O-C 1-3 alkylene) s -N (C 1-3 alkyl)
  • R 3 is H, F, Cl, Br, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C (O) NH 2 , S (O) 2 CH 3 , P (O) (CH 3 ) 2 , CH 2 OH, CH 2 CH 2 OH, C (CH 3 ) 2 OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C (CH 3 ) 2 NH 2 , CH 2 N (CH 3 ) 2 , CH 2 N (CH 2 CH 3 ) 2 , C (CH 3 ) 2 N (CH 3 ) 2 , C (CH 3 ) 2 N (CH 2 CH 3 ) 2 , ethynyl, propynyl, -C l-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene- (O-)
  • s is 1, 2, 3 or 4.
  • R 3 is H, F, Cl, NH 2 , OH, methyl, ethyl, isopropyl, methoxy, C (O) NH 2 , S (O) 2 CH 3 , P (O) (CH 3 ) 2 , CH 2 OH, C (CH 3 ) 2 OH, CH 2 NH 2 , C (CH 3 ) 2 NH 2 , CH 2 N (CH 3 ) 2 , C (CH 3 ) 2 N (CH 3 ) 2 , ethynyl, CH 2 OCH 3 , C (CH 3 ) 2 OCH 3 , CH 2 OCH 2 OH, C (CH 3 ) 2 OCH 2 OH, C (CH 3 ) 2 OCH 2 CH 2 OH, C (CH 3 ) 2 OCH 2 CH 2 OH, C (CH 3 ) 2 OCH 2 CH 2 OH, C (CH 3 ) 2 OCH 2 CH 2 CH 2 OH, C (CH 3 ) 2 - (OCH 2 ) 2
  • each R 3a is independently H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylene-OH; or
  • each R 3a is independently H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 OH, CH 2 CH 2 OH, CH (CH 3 ) OH; or
  • R 3 is H, F, Cl, NH 2 , OH, methyl, ethyl, isopropyl, methoxy, C (O) NH 2 , S (O) 2 CH 3 , P (O) (CH 3 ) 2 , CH 2 OH, C (CH 3 ) 2 OH, CH 2 NH 2 , C (CH 3 ) 2 NH 2 , CH 2 N (CH 3 ) 2 , C (CH 3 ) 2 N (CH 3 ) 2 ,
  • R 3 is H, F, Cl, NH 2 , OH, methyl, ethyl, isopropyl, methoxy, C (O) NH 2 , C (O) N (CH 3 ) 2 , C (O) CH 3 , C (O) OCH 3 , S (O) 2 CH 3 , P (O) (CH 3 ) 2 , CH 2 OH, C (CH 3 ) 2 OH, CH 2 NH 2 , C (CH 3 ) 2 NH 2 , CH 2 N (CH 3 ) 2 , C (CH 3 ) 2 N (CH 3 ) 2 ,
  • R 4 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, S (O) 2 C 1-3 alkyl, P (O) (C 1-3 alkyl) 2 , -C l-3 alkylene-OH, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carb ocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 4 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, S (O) 2 CH 3 , P (O) (CH 3 ) 2 , CH 2 OH, CH (CH 3 ) OH, C (CH 3 ) 2 OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with one or more R 4a .
  • each R 4a is independently H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and wherein each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S; or
  • each R 4a is independently H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 3-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and wherein each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O; or
  • each R 4a is independently H, F, Cl, NH 2 , OH, methyl,
  • R 4 is H, F, Cl, NH 2 , OH, methyl, ethyl, isopropyl, methoxy, S (O) 2 CH 3 , P (O) (CH 3 ) 2 , CH 2 OH, C (CH 3 ) 2 OH,
  • R 4 is H, F, Cl, NH 2 , OH, methyl, ethyl, isopropyl, methoxy, S (O) 2 CH 3 , P (O) (CH 3 ) 2 , CH 2 OH, C (CH 3 ) 2 OH,
  • W 1 is H, F, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkylene-C 1-3 alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • W 1 is H, F, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 OCH 2 CH 3 , CH (CH 3 ) OCH 3 , C (CH 3 ) 2 OCH 3 , 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • W 1 is H, F, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, CH 2 OCH 3 , CH 2 CH 2 OCH 3 ,
  • W 1 is H, F, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, CH 2 OCH 3 , CH 2 CH 2 CF 3 , CH 2 CH 2 OCH 3 ,
  • W 2 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • W 2 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • W 2 is H, F, Cl, methyl, methoxy
  • the compound is of Formula (3) :
  • X 2 is O, S or NR 2b ;
  • R 2b is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy;
  • R 1 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • R 3 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) NH 2 , S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, -C l-6 alkylene-NH 2 , -C l-6 alkylene-N (C 1-6 alkyl) 2 , C 2-6 alkenyl, -C 2-6 alkynyl-OH, -C l-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene- (O-C 1-6 alkylene) s -OH, -C 1-6 alkylene- (O-C 1-6 alkylene) s -C 1-6 alkoxy, -C 0-6 alkylene-NH-C 1-6 alkylene-C (O) -C 1-6 alkoxy, C
  • s is 1, 2, 3 or 4;
  • each R 3a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylene-OH; or
  • R 4 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, C 5-6 heteroaryl, C 3-6 heterocyclic, C 3-6 carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • each R 4a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 heterocyclic or C 3-6 carbocyclic; and wherein each of the heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;or
  • W 1 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • W 2 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • Z is H, or deuterium.
  • the compound is of Formula III:
  • X 2 is O, S or NR 2b ;
  • R 2b is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy;
  • R 1 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • R 3 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) NH 2 , S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, -C l-6 alkylene-NH 2 , -C l-6 alkylene-N (C 1-6 alkyl) 2 , C 2-6 alkenyl, -C 2-6 alkynyl-OH, -C l-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene- (O-C 1-6 alkylene) s -OH, -C 1-6 alkylene- (O-C 1-6 alkylene) s -C 1-6 alkoxy, -C 0-6 alkylene-NH-C 1-6 alkylene-C (O) -C 1-6 alkoxy, C
  • s is 1, 2, 3 or 4;
  • each R 3a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylene-OH; or
  • R 4 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, C 5-6 heteroaryl, C 3-6 heterocyclic, C 3-6 carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • each R 4a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 heterocyclic or C 3-6 carbocyclic; and wherein each of the heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;or
  • W 1 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • W 2 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S.
  • the present invention further provides some preferred technical solutions with regard to compound of Formula (3) , or Formula (III) .
  • R 2b is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy.
  • R 2b is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • X 2 is O, S or NH.
  • R 1 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 1 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • R 1 is H, F or methyl.
  • R 3 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, S (O) 2 CH 3 , P (O) (CH 3 ) 2 , C 1-3 alkylene-OH, CH 2 NH 2 , CH (CH 3 ) NH 2 , C (CH 3 ) 2 NH 2 , CH 2 N (CH 3 ) 2 , C (CH 3 ) 2 N ( (CH 3 ) 2 , 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with one or more R 3a ; and wherein each of the heteroaryl
  • R 3 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 OH, CH (CH 3 ) OH, C (CH 3 ) 2 OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with one or more R 3a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • R 3a is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylene-OH; or
  • R 3a is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R 3 is H, F, Cl, NH 2 , OH, methyl, methoxy, C (CH 3 ) 2 OH,
  • R 4 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, S (O) 2 CH 3 , P (O) (CH 3 ) 2 , -C l-3 alkylene-OH, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 4 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 OH, CH (CH 3 ) OH, C (CH 3 ) 2 OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • each R 4a is independently H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and wherein each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S; or
  • R 4a is independently H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and wherein each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • R 4 is H, F, Cl, NH 2 , OH, methyl, methoxy, CH 2 OH, C (CH 3 ) 2 OH, or
  • R 4 is H, F, Cl, NH 2 , OH, methyl, methoxy, CH 2 OH, C (CH 3 ) 2 OH,
  • W 1 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkylene-C 1-3 alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • W 1 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 CH 2 OCH 3 , C (CH 3 ) 2 OCH 3 , 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • W 1 is H, F, Cl, methyl, methoxy
  • W 1 is H, F, Cl, methyl, methoxy, CH 2 CH 2 CF 3 ,
  • W 2 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • W 2 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl or 6-membered heteroaryl; and each of which is independently optionally substituted with F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl contains 1, 2 or 3 heteroatoms selected from N or O.
  • W 2 is H, F, Cl, NH 2 , OH, methyl, methoxy,
  • the compound is of Formula (4) :
  • X 2 is O, S or NR 2b ;
  • R 2b is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy;
  • R 3 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) NH 2 , S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, -C l-6 alkylene-NH 2 , -C l-6 alkylene-N (C 1-6 alkyl) 2 , C 2-6 alkenyl, -C 2-6 alkynyl-OH, -C l-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene- (O-C 1-6 alkylene) s -OH, -C 1-6 alkylene- (O-C 1-6 alkylene) s -C 1-6 alkoxy, -C 0-6 alkylene-NH-C 1-6 alkylene-C (O) -C 1-6 alkoxy, C
  • s is 1, 2, 3 or 4;
  • each R 3a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylene-OH; or
  • R 4 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, C 5-6 heteroaryl, C 3-6 heterocyclic, C 3-6 carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • each R 4a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 heterocyclic or C 3-6 carbocyclic; and wherein each of the heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;or
  • W 1 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • W 2 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • Z is H, or deuterium.
  • the compound is of Formula IV:
  • X 2 is O, S or NR 2b ;
  • R 2b is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy;
  • R 3 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) NH 2 , S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, -C l-6 alkylene-NH 2 , -C l-6 alkylene-N (C 1-6 alkyl) 2 , C 2-6 alkenyl, -C 2-6 alkynyl-OH, -C l-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene- (O-C 1-6 alkylene) s -OH, -C 1-6 alkylene- (O-C 1-6 alkylene) s -C 1-6 alkoxy, -C 0-6 alkylene-NH-C 1-6 alkylene-C (O) -C 1-6 alkoxy, C
  • s is 1, 2, 3 or 4;
  • each R 3a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylene-OH; or
  • R 4 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, C 5-6 heteroaryl, C 3-6 heterocyclic, C 3-6 carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • each R 4a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 heterocyclic or C 3-6 carbocyclic; and wherein each of the heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;or
  • W 1 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • W 2 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S.
  • the present invention further provides some preferred technical solutions with regard to compound of Formula (4) , or Formula (IV) .
  • R 2b is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy.
  • R 2b is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • X 2 is S or NH.
  • R 3 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, S (O) 2 CH 3 , P (O) (CH 3 ) 2 , C 1-3 alkylene-OH, CH 2 NH 2 , CH (CH 3 ) NH 2 , C (CH 3 ) 2 NH 2 , CH 2 N (CH 3 ) 2 , C (CH 3 ) 2 N ( (CH 3 ) 2 , 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with one or more R 3a ; and wherein each of the heteroary
  • R 3 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 OH, CH (CH 3 ) OH, C (CH 3 ) 2 OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with one or more R 3a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • R 3a is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylene-OH; or
  • R 3a is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R 3 is H, F, Cl, NH 2 , OH, methyl, methoxy, C (CH 3 ) 2 OH or
  • R 4 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, S (O) 2 CH 3 , P (O) (CH 3 ) 2 , -C l-3 alkylene-OH, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 4 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 OH, CH (CH 3 ) OH, C (CH 3 ) 2 OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • each R 4a is independently H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and wherein each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S; or
  • R 4a is independently H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and wherein each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O.
  • R 4 is H, F, Cl, NH 2 , OH, methyl, methoxy, CH 2 OH, C (CH 3 ) 2 OH or
  • W 1 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkylene-C 1-3 alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • W 1 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 CH 2 OCH 3 , C (CH 3 ) 2 OCH 3 , 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • W 1 is H, F, Cl, methyl, methoxy
  • W 1 is H, F, Cl, methyl, methoxy, CH 2 CH 2 CF 3 ,
  • W 2 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • W 2 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl or 6-membered heteroaryl; and each of which is independently optionally substituted with F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • W 2 is H, F, Cl, NH 2 , OH, methyl, methoxy,
  • the compound is of Formula (5) :
  • X 1 is CR 1a , O, S or NR 1b ;
  • R 1a is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • R 1b is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • R 3 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) NH 2 , S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, -C l-6 alkylene-NH 2 , -C l-6 alkylene-N (C 1-6 alkyl) 2 , C 2-6 alkenyl, -C 2-6 alkynyl-OH, -C l-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene- (O-C 1-6 alkylene) s -OH, -C 1-6 alkylene- (O-C 1-6 alkylene) s -C 1-6 alkoxy, -C 0-6 alkylene-NH-C 1-6 alkylene-C (O) -C 1-6 alkoxy, C
  • s is 1, 2, 3 or 4;
  • each R 3a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylene-OH; or
  • R 4 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, C 5-6 heteroaryl, C 3-6 heterocyclic, C 3-6 carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • each R 4a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 heterocyclic or C 3-6 carbocyclic; and wherein each of the heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;or
  • W 1 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • W 2 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • Z is H, or deuterium.
  • the compound is of Formula V:
  • X 1 is CR 1a , O, S or NR 1b ;
  • R 1a is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • R 1b is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • R 3 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C (O) NH 2 , S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, -C l-6 alkylene-NH 2 , -C l-6 alkylene-N (C 1-6 alkyl) 2 , C 2-6 alkenyl, -C 2-6 alkynyl-OH, -C l-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene- (O-C 1-6 alkylene) s -OH, -C 1-6 alkylene- (O-C 1-6 alkylene) s -C 1-6 alkoxy, -C 0-6 alkylene-NH-C 1-6 alkylene-C (O) -C 1-6 alkoxy, C
  • s is 1, 2, 3 or 4;
  • each R 3a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylene-OH; or
  • R 4 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, S (O) 2 C 1-6 alkyl, P (O) (C 1-6 alkyl) 2 , -C l-6 alkylene-OH, C 5-6 heteroaryl, C 3-6 heterocyclic, C 3-6 carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • each R 4a is independently H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 heterocyclic or C 3-6 carbocyclic; and wherein each of the heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;or
  • W 1 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
  • W 2 is H, halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, 6-membered aryl, C 5-6 heteroaryl, C 3-6 heterocyclic or C 3-6 carbocyclic; and each of which is independently optionally substituted with halogen, NH 2 , CN, OH, NO 2 , carboxyl, C 1-6 alkyl or C 1-6 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2, 3 or 4 heteroatoms selected from N, O or S.
  • the present invention further provides some preferred technical solutions with regard to compound of Formula (5) , or Formula (V) .
  • R 1a is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 1a is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • R 1b is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 1b is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • X 1 is CH, O, S or NH.
  • R 3 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, S (O) 2 CH 3 , P (O) (CH 3 ) 2 , C 1-3 alkylene-OH, CH 2 NH 2 , CH (CH 3 ) NH 2 , C (CH 3 ) 2 NH 2 , CH 2 N (CH 3 ) 2 , C (CH 3 ) 2 N ( (CH 3 ) 2 , 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with one or more R 3a ; and wherein each of the heteroary
  • R 3 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 OH, CH (CH 3 ) OH, C (CH 3 ) 2 OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with one or more R 3a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • R 3a is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylene-OH; or
  • R 3a is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R 3 is H, F, Cl, NH 2 , OH, methyl, methoxy, C (CH 3 ) 2 OH or
  • R 4 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, S (O) 2 CH 3 , P (O) (CH 3 ) 2 , -C l-3 alkylene-OH, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • R 4 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 OH, CH (CH 3 ) OH, C (CH 3 ) 2 OH, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with one or more R 4a ; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • each R 4a is independently H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and wherein each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S; or
  • R 4a is independently H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 7-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and wherein each of the heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • R 4 is H, F, Cl, NH 2 , OH, methyl, methoxy, CH 2 OH, C (CH 3 ) 2 OH or
  • W 1 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkylene-C 1-3 alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • W 1 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 OCH 3 , CH 2 OCH 2 CH 3 , CH 2 CH 2 OCH 3 , C (CH 3 ) 2 OCH 3 , 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic, 6-membered heterocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • W 1 is H, F, Cl, methyl, methoxy
  • W 2 is H, F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 3-membered heterocyclic, 4-membered heterocyclic, 5-membered heterocyclic, 6-membered heterocyclic, 3-membered carbocyclic, 4-membered carbocyclic, 5-membered carbocyclic or 6-membered carbocyclic; and each of which is independently optionally substituted with F, Cl, Br, I, NH 2 , OH, carboxyl, C 1-3 alkyl or C 1-3 alkoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N, O or S.
  • W 2 is H, F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, 6-membered aryl, 5-membered heteroaryl or 6-membered heteroaryl; and each of which is independently optionally substituted with F, Cl, NH 2 , OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and wherein each of the heteroaryl or heterocyclic contains 1, 2 or 3 heteroatoms selected from N or O.
  • W 2 is H, F, Cl, NH 2 , OH, methyl, methoxy,
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound described herein and at least one pharmaceutically acceptable excipient.
  • the said compound in a weight ratio to the said excipient within the range from about 0.0001 to about 10.
  • the present invention also provides a combination pharmaceutical product comprising the compound described herein, together with one or more other therapeutically active agents.
  • the present invention additionally provided a use of a pharmaceutical composition of Formula (1) , Formula (I) , Formula (2) , Formula (II) , Formula (3) , Formula (III) , Formula (4) , Formula (IV) , Formula (5) , or Formula (V) .
  • the present invention additionally provided a use of the pharmaceutical composition of as described herein for the preparation of a medicament.
  • the diseases or conditions is cancer.
  • the cancer is small cell lung cancer, non small cell lung cancer, colorectal cancer, multiple myeloma, acute myeloid leukemia (AML) , acute lymphoblastic leukemia (ALL) , pancreatic cancer, liver cancer, hepatocellular cancer, neuroblastoma, other solid tumors or other hematological cancer.
  • the cancer is small cell lung cancer, non small cell lung cancer, colorectal cancer, multiple myeloma, acute myeloid leukemia (AML) .
  • the cancer is selected from 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;
  • the diseases or conditions is an acquired immunodeficiency syndrome (AIDS) , obesity, dyslipidemia, hypercholesterolemia, Alzheimer’s disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy, diabetic neuropathy, an acute kidney disease or condition, a chronic kidney disease or condition, contraception in a male.
  • AIDS acquired immunodeficiency syndrome
  • a medicament thus prepared can be used for the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, an immunological disorder or an ocular disorder.
  • the present invention additionally provided a use of at least one compound described herein to prepare of a medicament.
  • the diseases or conditions is cancer.
  • the cancer is small cell lung cancer, non small cell lung cancer, colorectal cancer, multiple myeloma, acute myeloid leukemia (AML) , acute lymphoblastic leukemia (ALL) , pancreatic cancer, liver cancer, hepatocellular cancer, neuroblastoma, other solid tumors or other hematological cancer.
  • the cancer is small cell lung cancer, non small cell lung cancer, colorectal cancer, multiple myeloma, acute myeloid leukemia (AML) .
  • the cancer is selected from 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;
  • the diseases or conditions is an acquired immunodeficiency syndrome (AIDS) , obesity, dyslipidemia, hypercholesterolemia, Alzheimer’s disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy, diabetic neuropathy, an acute kidney disease or condition, a chronic kidney disease or condition, contraception in a male.
  • AIDS acquired immunodeficiency syndrome
  • a medicament thus prepared can be used for the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, an immunological disorder or an ocular disorder.
  • At least one compound for use described herein which is for use in the treatment of cancer, the prevention of cancer metastasis or the treatment of cardiovascular disease, an immunological disorder or an ocular disorder.
  • a method of treating a patient having a condition which is mediated by the activity of BET comprising administering to the patient a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.
  • the condition mediated by the activity of BET is cancer.
  • the condition mediated by the activity of BET is noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, neuroblastoma, anaplastic large-cell lymphoma and glioblastoma.
  • the diseases or conditions is cancer.
  • the cancer is small cell lung cancer, non small cell lung cancer, colorectal cancer, multiple myeloma, acute myeloid leukemia (AML) , acute lymphoblastic leukemia (ALL) , pancreatic cancer, liver cancer, hepatocellular cancer, neuroblastoma, other solid tumors or other hematological cancer.
  • the cancer is small cell lung cancer, non small cell lung cancer, colorectal cancer, multiple myeloma, acute myeloid leukemia (AML) .
  • the cancer is selected from 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
  • the diseases or conditions is an acquired immunodeficiency syndrome (AIDS) , obesity, dyslipidemia, hypercholesterolemia, Alzheimer’s disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy, diabetic neuropathy, an acute kidney disease or condition, a chronic kidney disease or condition, contraception in a male.
  • AIDS acquired immunodeficiency syndrome
  • At least one compound described herein or a pharmaceutically acceptable salt thereof for use as a medicament At least one compound described herein or a pharmaceutically acceptable salt thereof for use as a medicament.
  • At least one compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of cancer At least one compound described herein or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
  • a method of treating cancer selected from the group consisting of noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemias, liver cancer, neuroblastoma, melanoma, squamous-cell carcinoma of the head and neck, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric carcinoma, neuroblastoma, anaplastic large-cell lymphoma and glioblastoma in a mammal comprising administering to a mammal in need of such treatment an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof.
  • halogen as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include F, Cl and Br.
  • alkyl includes saturated monovalent hydrocarbon radicals having straight or branched.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclcopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclcobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclcopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
  • C 1-6 as in C 1-6 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.
  • C 2-6 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-1-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.
  • C 2-6 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.
  • 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 pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • the pharmaceutically acceptable acidic/anionic salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid.
  • organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic.
  • Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
  • 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 1 H (hydrogen) , 2 H (deuterium) and 3 H (tritium) . They are also commonly denoted as D for deuterium and T for tritium.
  • CD 3 denoted a methyl group wherein all of the hyderogen atoms are deuterium.
  • the present invention includes any possible tautomers 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.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds of Formula are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
  • compositions of the present invention comprise a compound represented by Formula (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds represented by Formula, or a prodrug, or a metabolite, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous) .
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion.
  • the compound represented by Formula may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt, of Formula.
  • the compounds of Formula, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or l000mg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
  • dosage levels on the order of from about 0.01mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day.
  • inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
  • 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 7 can be generated from a displacement reaction between 4 and an alkylating agent 6, where L is a leaving group, such as a halide, mesylate or triflate, in the presence of a base, such as cessium carbonate.
  • Suzuki coupling of 7 with 8 (where M is a suitable coupling partner, such as boronic acid, bonic ester) can generate 9.
  • the intermediate 9 can be synthesized using a Stille reaction condition between 7 and 8 (where M is a stannane) . Bromination of 9 at the present of an appropriate reagent, such as NBS, can give 10 and subsequent treatment of 10 by a coupling reaction with 11 using a suitable coupling condition can generate compound II.
  • B 2 Pin 2 Bis (pinacolato) diboron; DAST: Diethylaminosulfur trifluoride; DCM: Dichloromethane; DIEA: N, N-Diisopropylethylamine; DMAC: Dimethylacetamide; DMF: N, N-Dimethylformamide; DMSO: Dimethyl sulfoxide; dmbpy: 4, 4'-dimethyl-2, 2'-bipyridine; dtbpy: 4, 4’-Di-tert-butylbipyridine ; EtOAc: Ethyl acetate; EtOH: Ethanol; h or hr: hour; KOAc: Potassium acetate; [Ir (COD) (OMe) ] 2: Bis (1, 5-cyclooctadiene) dimethoxydiiridium; MeMgBr: Methylmagnesium bromide; MeOH: Methol; NMP: N-methyl-2-
  • the crude compound was purified using a reverse phase chromatography eluting with 40 ⁇ 50 %MeCN in H 2 O to afford the racemic compound (52 g, 61 %yield) , which was separated by chiral prep SFC to give Enantiomer a, (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (Intermediate 1, 25.1 g, 29.6 %yield) and Enantiomer b, (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methanol (Intermediate 2, 25.3 g, 29.7 %) .
  • Step 1 Ethyl 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-2-carboxylate
  • Step 2 Ethyl 5- (5-bromo-3-nitropyridin-2-yl) thiophene-2-carboxylate
  • Step 4 Ethyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 5 Ethyl 4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 6 2- (4-Benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • MeMgBr (3M in THF, 3.0 mL, 9.00 mmol) was slowly dropwisely added to a solution of ethyl 4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate (400 mg , 0.93 mmol) in THF at -30 °C over 10 min under a N 2 atmosphere. After addition, the reaction was slowly warmed to room temperature and stirred for 2 h. The reaction was quenched with addition of sat. aqueous NH 4 Cl and extracted with EtOAc (120 mL) .
  • N-bromosuccinimide (15.2 g, 85.6 mmol) was slowly added in small batchs to a solution of 5-bromo-2- (1-ethoxyvinyl) -3-nitropyridine (19.1 g, 85.6 mmol) in THF (400 mL) and water (70mL) at room temperature over 10 min. After addition, the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with sat. aqueous NaHCO 3 and extracted with EtOAc (400 mL) . The resulting organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated.
  • Step 3 5- (5-Bromo-3-nitropyridin-2-yl) thiazol-2-amine
  • Step 4 N- (5- (5-bromo-3-nitropyridin-2-yl) thiazol-2-yl) acetamide
  • Step 5 N- (6-bromo-4H-thiazolo [5', 4': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) acetamide
  • Step 7 2, 6-Dibromo-4H-thiazolo [5', 4': 4, 5] pyrrolo [3, 2-b] pyridine
  • Step 8 4-Benzyl-2, 6-dibromo-4H-thiazolo [5', 4': 4, 5] pyrrolo [3, 2-b] pyridine
  • Step 9 4-Benzyl-6-bromo-2- (prop-1-en-2-yl) -4H-thiazolo [5', 4': 4, 5] pyrrolo [3, 2-b] pyridine
  • Step 10 4-Benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -2- (prop-1-en-2-yl) -4H-thiazolo [5', 4': 4, 5] pyrrolo [3, 2-b] pyridine
  • Step 11 1- (4-Benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thiazolo [5', 4': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) ethanone
  • Osmium tetroxide (3.0 ml, 0.1 mmol/ml, 0.3 mmol) was slowly dropwise added to a solution of 4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -2- (prop-1-en-2-yl) -4H-thiazolo [5', 4': 4, 5] pyrrolo [3, 2-b] pyridin e (80.2 mg, 0.200 mmol) in 1, 4-dioxane (10 ml) at room temperature. The mixture was stirred for 1 h under N 2 atmosphere.
  • Step 12 2- (4-Benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thiazolo [5', 4': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • MeMgBr (1.0 mL, 3.0 mmol, 3M in THF ) was slowly added to a solution of 1- (4-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thiazolo [5', 4': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) ethanone (120 mg, 0.298 mmol) at -30 °C in THF (10 mL) over 1 min. After addition, the reaction was stirred at room temperature for 2 h. The reaction was quenched with sat. aqeous NH 4 Cl and extracted with EtOAc (20 mL) .
  • Step 1 Ethyl 6-bromo-4- ( (5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 2 Ethyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step3 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) met hyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 4 6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3', 2': 4, 5] pyrrolo [3, 2-b] pyridine
  • N-bromosuccinimide (0.651 g, 3.66 mmol) was added in small batchs to a solution of 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -8 (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3', 2': 4, 5] pyrrol o [3, 2-b] pyridine (1.32 g, 2.98 mmol) in THF (10 mL) and water (6 mL) at room temperature over 10 min. After addition, the reaction mixture was stirred at room temperature for 2 hr. The reaction was quenched with sat.
  • Step 6 6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -2- (1-ethoxyvinyl) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3', 2': 4, 5] pyrrolo [3, 2-b] pyridine
  • Step 7 1- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3', 2': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) ethan-1-one
  • Step 8 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3', 2': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 1 1- (3-Methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) ethan-1-one
  • Step 2 1- (2-Bromo-3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) -methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) ethan-1-one
  • N-bromosuccinimide (169 mg, 0.955 mmol) was slowly added to a solution of 1- (3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) ethan-1-one (320 mg, 0.792 mmol) in THF (10 mL) and water (50 mL) at room temperature over 10 min. After addition, the reaction was stirred at room temperature for 2 hr. The reaction was quenched with sat. aq. NaHCO 3 and the mixture was extracted with EtOAc (50mL) .
  • Step 3 1- (2- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl- (tetrahydro-2H-pyran-4- yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) ethan-1-one
  • Step4 2- (2- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl- (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) propan-2-ol
  • Step 1 6-Bromo-4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine
  • Step 2 6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine
  • Step 4 1- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) ethan-1-one
  • Step 5 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) - (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 1 2-Methoxy-3-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine
  • Step 2 3-Methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one
  • Step 3 1, 3-Dimethyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one
  • Step 4 1, 3-Dimethyl-5- (4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) pyridin-2 (1H) -one
  • Step 5 5- (2-Bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) -1, 3-dimethylpyridin-2 (1H) -one
  • Step 6 5- (2-Acetyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) -1, 3-dimethylpyridin-2 (1H) -one
  • Step 7 5- (2- (2-Hydroxypropan-2-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) -1, 3-dimethylpyridin-2 (1H) -one
  • Step 1 5- (6-Acetyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) -1, 3-dimethylpyridin-2 (1H) -one
  • Step 2 5- (6- (2-Hydroxypropan-2-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) -1, 3-dimethylpyridin-2 (1H) -one
  • Step 4 6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine
  • N-bromosuccinimide (0.432 g, 2.43mmol) was added in small batchs to a solution of 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrro lo [3, 2-b] pyridine (0.722 g, 1.63 mmol) in THF (20 mL) and water (10 mL) at room temperature over 10 min. After addition, the reaction was stirred at room temperature for 2 hr. The reaction was quenched with sat. NaHCO 3 and extracted with EtOAc (100 mL) .
  • Step 6 1- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) ethan-1-one
  • Step 7 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 1 1- (4- (Phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) ethan-1-one
  • Step 2 1- (2-Bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) ethan-1-one
  • Step 3 1- (2- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) ethan-1-one
  • Step 4 2- (2- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) propan-2-ol
  • Step 1 6-Bromo-4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine
  • Step 2 6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine
  • Step 4 1- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) ethan-1-one
  • Step 5 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 3 6-Bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine
  • 6-bromo-4H-furo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine 1.2 g, 5.06mmol
  • phenyl (tetrahydro-2H-pyran-4-yl) methanol (1.92 g, 10.0mmol)
  • triphenylphosphane (1.92 g, 10.0mmol) in dry THF (20 mL) was added diisopropyl azodicarboxylate (2.02 g, 10.0 mmol) at room temperature under N 2 .
  • Step 4 6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine
  • Step 6 1- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) ethan-1-one
  • Step 7 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 1 1- (4- (Phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) ethan-1-one
  • Step 2 1- (2-Bromo-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) ethan-1-one
  • Step 3 1- (2- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) ethan-1-one
  • Step 4 2- (2- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-furo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) propan-2-ol
  • Step 1 3- ( (2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-yl) oxy) propan-1-ol
  • Step 2 3- ( (2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-yl) oxy) propyl 4-methylbenzenesulfonate
  • Step 3 3- ( (2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-yl) oxy) -N-methylpropan-1-amine
  • Step 4 N- (3- ( (2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-yl) oxy) propyl) -3-methoxy-N-methyl- [1, 2, 4] tria zolo [4, 3-b] pyridazin-6-amine
  • Step 1 1- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) ethan-1-ol
  • Step 2 1- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) ethyl methanesulfonate
  • Step 3 Isopropyl (2S, 3R) -2- ( (1- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) ethyl) amino) -3-hydroxybutanoate
  • Step 4 6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine
  • Step 6 1- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl- (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) ethan-1-one
  • Step 7 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (phenyl- (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 1 (4-Chloro-5- (methoxycarbonyl) thiophen-2-yl) boronic acid
  • Step 2 Methyl 5- (5-bromo-3-nitropyridin-2-yl) -3-chlorothiophene-2-carboxylate
  • Step 4 Methyl 6-bromo-3-chloro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 5 Methyl 3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 6 2- (3-Chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 1 Methyl 6-bromo-3-chloro-4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H- thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 2 Methyl 3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 3 2- (3-Chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 1 Methyl 6-bromo-3-chloro-4- ( (3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 2 Methyl 3-chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 3 2- (3-Chloro-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 1 Methyl 5- (dibutyl (pentyl) stannyl) -3-fluorothiophene-2-carboxylate
  • Step 2 Methyl 5- (5-bromo-3-nitropyridin-2-yl) -3-fluorothiophene-2-carboxylate
  • Step 3 Methyl 6-bromo-3-fluoro-4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 4 Methyl 6-bromo-3-fluoro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 5 Methyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 6 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 1 Methyl 6-bromo-3-fluoro-4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 2 Methyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ( (3-fluoropyridin-2-yl) (tetrahydro- 2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 3 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 1 Methyl 6-bromo-3-fluoro-4- ( (5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 2 Methyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ( (5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 3 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-4- ( (5-fluoropyridin-2-yl) (tetrahydro-2H- pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 1 (4-Methoxy-5- (methoxycarbonyl) thiophen-2-yl) boronic acid
  • Step 2 Methyl 5- (5-bromo-3-nitropyridin-2-yl) -3-methoxythiophene-2-carboxylate
  • Step 3 Methyl 6-bromo-3-methoxy-4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 4 Methyl 6-bromo-4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methoxy-4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 5 Methyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran- 4-yl) methyl) -3-methoxy-4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 6 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methoxy-4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • N-bromosuccinimide (6.53 g, 36.7 mmol) was slowly added to a solution of ethyl 2-methylthiophene-3-carboxylate (5.07 g, 32.5 mmol) in DMF (60 mL) and acetic acid (40 mL) at room temperature over 10 min. After addition, the reaction was stirred at room temperature for 12 h. The reaction was quenched with sat. aq. NaHCO 3 and extracted with EtOAc (100 mL) . The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated.
  • Step 2 Ethyl 2-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophene-3-carboxylate
  • Step 3 Ethyl 5- (5-bromo-3-nitropyridin-2-yl) -2-methylthiophene-3-carboxylate
  • Step 4 Ethyl 6-bromo-2-methyl-4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylate
  • Step 5 Ethyl 6-bromo-4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2-methyl-4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylate
  • Step 6 Ethyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -2-methyl-4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-3-carboxylate
  • Step 1 Methyl 5-nitro-6- (thiophen-2-yl) nicotinate
  • Step 4 Methyl 2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-6-carboxylate
  • Step 5 Methyl 2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-6-carboxylate
  • Step 6 2- (2- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) propan-2-ol
  • Step 1 Methyl 2- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-6-carboxylate
  • Step 2 2- (2- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (5-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-6-yl) propan-2-ol
  • Step 1 6-Bromo-3-methyl-4- ( (3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine
  • Step 2 6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- ( (3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine
  • Step 4 1- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- ( (3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) ethan-1-one
  • Step 5 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- ( (3-methylpyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 1 Methyl 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carboxylate
  • Step 4 Methyl 1-benzyl-6-bromo-1, 4-dihydropyrrolo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • methyl 1-benzyl-5- (5-bromo-3-nitropyridin-2-yl) -1H-pyrrole-2-carboxylate (669 mg, 1.60 mmol) was converted to the title compound (486 mg, 1.26 mmol, 79%yield) as a yellow solid.
  • LC-MS [M+H] + 386.
  • Step 5 Methyl 1-benzyl-6-bromo-4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrolo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 6 Methyl 1-benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrolo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 7 2- (1-Benzyl-6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1, 4-dihydropyrrolo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 1 (5- (Methoxycarbonyl) -4-methylthiophen-2-yl) boronic acid
  • Step 2 Methyl 5- (5-bromo-3-nitropyridin-2-yl) -3-methylthiophene-2-carboxylate
  • Step 4 Methyl 6-bromo-4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 5 Methyl 4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 6 2- (4- ( (3-Fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3-methyl-6- (1-methyl-4- (methyl-d3) -1H-1, 2, 3-triazol-5-yl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Example 35 was prepared following the same procedures described as Example 34 except using Intermediate 2 in step 4 to afford the other Enantiomer B as a white solid.
  • LC-MS [M+H] + 538.
  • Step 1 Methyl (S) -6-bromo-3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 2 Methyl (S) -6- (3, 5-dimethylisoxazol-4-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 3 (S) -2- (6- (3, 5-dimethylisoxazol-4-yl) -3-methyl-4- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Example 37 The compound of Example 37 was prepared using the same procedures as described for Example 36 excepting using Intermediate 1 in Step 1 to afford the title compound (32.0 mg) as an off-white solid.
  • LC-MS: [M+H + ] 535.
  • Step 1 Methyl 4- (5-bromo-3-nitropyridin-2-yl) -3-fluorothiophene-2-carboxylate
  • Step 2 Methyl 6-bromo-3-fluoro-8H-thieno [3', 2': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 3 Methyl (S) -6-bromo-3-fluoro-8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3', 2': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 4 Methyl (S) -6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3', 2': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 5 (S) -2- (6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-8- (phenyl (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3', 2': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Example 39 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -3-fluoro-8- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -8H-thieno [3', 2': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Example 39 The compound of Example 39 was prepared acccording to the procedures described for Example 38 excepting using Intermediate 1 in Step 3 to replace (R) -phenyl (tetrahydro-2H-pyran-4-yl) methanol to afford the title compound (56 mg) as an off-white solid.
  • LC-MS: [M+H] + 539.
  • Step 1 Methyl 6-bromo-3-methyl-4- (4, 4, 4-trifluoro-1- (3-fluoropyridin-2-yl) butyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 2 Methyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (4, 4, 4-trifluoro-1- (3-fluoropyridin-2-yl) butyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 3 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -3-methyl-4- (4, 4, 4-trifluoro-1- (3-fluoropyridin-2-yl) butyl) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 2 (5- (Methoxycarbonyl) -4- (methyl-d3) thiophen-2-yl) boronic acid
  • Step 4 Methyl 6-bromo-3- (methyl-d3) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 6 Methyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3- (methyl-d3) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 7 2- (6- (1, 4-Dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -3- (methyl-d3) -4H-thieno [2', 3': 4, 5] pyrrolo [3, 2-b] pyridin-2-yl) propan-2-ol
  • Step 2 Methyl 6-bromo-1-methyl-1, 4-dihydropyrrolo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 3 Methyl 6-bromo-4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1-methyl-1, 4-dihydropyrrolo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate
  • Step 4 Methyl 6- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -4- ( (3-fluoropyridin-2-yl) (tetrahydro-2H-pyran-4-yl) methyl) -1-methyl-1, 4-dihydropyrrolo [2', 3': 4, 5] pyrrolo [3, 2-b] pyridine-2-carboxylate

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Abstract

La présente invention concerne certains nouveaux composés tricycliques utilisés en tant qu'inhibiteurs de bromodomaines et extra-terminaux (BET), leur synthèse et leur utilisation dans le traitement de maladies. Plus particulièrement, la présente invention concerne des dérivés hétérocycliques fusionnés utiles en tant qu'inhibiteurs de BET, des procédés de production de tels composés et des méthodes de traitement de maladies et d'états dans lesquels l'inhibition d'un ou de plusieurs bromodomaines BET présente un avantage.
PCT/CN2018/112386 2017-10-27 2018-10-29 Nouveaux composés tricycliques WO2019080941A1 (fr)

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WO2020200284A1 (fr) * 2019-04-04 2020-10-08 上海华汇拓医药科技有限公司 Procédé de préparation de composé tricyclique et son utilisation dans le domaine de la médecine
JP2021530455A (ja) * 2018-06-25 2021-11-11 ジャコバイオ ファーマスーティカルズ カンパニー リミテッドJacobio Pharmaceuticals Co., Ltd. 三環式化合物
WO2022156757A1 (fr) * 2021-01-22 2022-07-28 Jingrui Biopharma Co., Ltd. Composés tricycliques en tant qu'agents anticancéreux
WO2022192481A1 (fr) * 2021-03-12 2022-09-15 Bristol-Myers Squibb Company Méthodes de traitement du cancer de la prostate

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