WO2021147974A1 - Novel heterocyclic compounds useful as aurora a selective inhibitors - Google Patents

Novel heterocyclic compounds useful as aurora a selective inhibitors Download PDF

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Publication number
WO2021147974A1
WO2021147974A1 PCT/CN2021/073169 CN2021073169W WO2021147974A1 WO 2021147974 A1 WO2021147974 A1 WO 2021147974A1 CN 2021073169 W CN2021073169 W CN 2021073169W WO 2021147974 A1 WO2021147974 A1 WO 2021147974A1
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Prior art keywords
alkyl
membered
heterocyclic ring
deuterium
ring
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PCT/CN2021/073169
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English (en)
French (fr)
Inventor
Dai Cheng
Mingming Chen
Amin LI
Haijun Li
Guiqun YANG
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Jacobio Pharmaceuticals Co Ltd
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Jacobio Pharmaceuticals Co Ltd
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Priority to MX2022009059A priority Critical patent/MX2022009059A/es
Priority to JP2022544153A priority patent/JP7688646B2/ja
Priority to AU2021209744A priority patent/AU2021209744B2/en
Priority to KR1020227021336A priority patent/KR102828343B1/ko
Priority to PH1/2022/551858A priority patent/PH12022551858A1/en
Priority to CN202180003823.8A priority patent/CN114423751B/zh
Priority to CA3161268A priority patent/CA3161268C/en
Priority to CN202310353468.8A priority patent/CN116354936A/zh
Priority to EP21743926.4A priority patent/EP4093736A4/en
Application filed by Jacobio Pharmaceuticals Co Ltd filed Critical Jacobio Pharmaceuticals Co Ltd
Priority to IL294247A priority patent/IL294247B2/en
Priority to US17/794,641 priority patent/US20230128198A1/en
Publication of WO2021147974A1 publication Critical patent/WO2021147974A1/en
Priority to US17/484,456 priority patent/US11384066B1/en
Priority to ZA2022/07498A priority patent/ZA202207498B/en
Anticipated expiration legal-status Critical
Priority to CONC2022/0010878A priority patent/CO2022010878A2/es
Ceased legal-status Critical Current

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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to novel heterocyclic compounds useful as an Aurora A selective inhibitor, their synthesis, pharmaceutical compositions thereof, and use of compounds and pharmaceutical compositions for the treatment of cancer and cancer occurrence-related diseases.
  • Aurora kinases are a family of serine/threonine kinases and are key regulators of mitosis. There are three human homologs of Aurora kinases, A, B, and C, of which Aurora A has been implicated in cancers of diverse histological origin and may possess oncogenic properties when overexpressed.
  • Aurora-A localizes to centrosomes/spindle poles and is required for spindle assembly
  • Aurora-B is a chromosome passenger protein required for phosphorylation of histone H3, chromosome segregation and cytokinesis.
  • Aurora-A and -B are both overexpressed in a wide range of different human tumours.
  • certain Aurora B inhibitors and Aurora A/B dual inhibitors in clinical development have been reported as presenting neutropenia and bone marrow cytotoxicity in patients while certain relatively selective Aurora A inhibitors in clinical development did not show these disorders. Therefore, it is desirable to selectively inhibit Aurora A and reduce or avoid Aurora B or Aurora A/B dual inhibition. As such, selective Aurora A inhibition may be useful for cancer therapy.
  • the present invention provides certain inhibitors of Aurora A which may be useful for treating cancer.
  • the compounds of the present invention fulfill the need of small molecules in order to inhibit the activity of Aurora A.
  • the present invention relates to novel heterocyclic compounds useful as Aurora A selective inhibitors and for the treatment of conditions mediated by Aurora A.
  • the compounds of the invention have the general structure as Formula I or a pharmaceutically acceptable salt thereof:
  • L 1 and L 2 is independently O, CR 2a R 2b , or NR 2a ;
  • Y 1 is independently CH, CR Y1 or N;
  • Y 2 is independently CH, CR Y2 or N;
  • Y 3 is independently CH, CR Y3 or N; provided, however Y 1 , Y 2 , Y 3 are not all N;
  • W 1 is CR w or N
  • W 2 is CR w or N
  • R w is independently -H; halogen; -NH 2 ; -CN; -OH; -NO 2 ; carboxyl; -C 1-6 alkyl; -C 1-6 alkoxy; -C 1-6 alkyl or -C 1-6 alkoxy substituted with deuterium, halogen, -NH 2 , -CN, -OH, -NO 2 , carboxyl, -C 1-6 alkyl or -C 1-6 alkoxy;
  • Each X 1 and X 2 is independently -H, deuterium, -CN, -OH, -NH 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-NR 2 R 3 , -C 1-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene-CO-OR 2 , -C 1-6 alkylene-CO-NR 2 R 3 , -C 1-6 alkylene-NR 2 CO-NR 2 R 3 , -C 1-6 alkylene-NR 2 -COC 1-6 alkyl, -C 1-6 alkylene-C 3-10 heterocyclic ring, -C 1-6 alkylene-C 5-10 heteroaryl, -CO-C 1-6 alkylene-NR 2 R 3 , -CO-NR 2 -C 3-10 heterocyclic ring, -CO-C 3-10 heterocyclic ring, -O-C 1-6 alkylene-CO-OR 2 ,
  • p 0, 1, 2, 3 or 4;
  • Y is O, S, SO, - (CH 2 ) m CO- (CH 2 ) m -, - (CH 2 ) m SO 2 - (CH 2 ) m -, or - (CH 2 ) m CR 4 R 5 - (CH 2 ) m -, and m is independently 0, 1, 2 or 3;
  • Z is -H, deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -N 3 , -NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 6-membered aryl, 7-membered aryl, 8-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, or 8-membered carbocyclic ring, and each of the heteroaryl and heterocyclic ring, and each
  • Z is -H, deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -N 3 , -NO 2 , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, ethylene, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 5-membered carbocyclic ring, or 6-membered carbocyclic ring, and each of the heteroaryl and heterocyclic ring contains 1 or 2 heteroatoms selected from N or O; and each of which is independently optionally substituted with deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -NO 2 , carbonyl,
  • Z is –H, deuterium, methyl, -CHD 2 , -CH 2 D, -CD 3 , ethyl, -CHF 2 , -CH 2 F, -CF 3 or carboxyl.
  • L 1 and L 2 is independently CR 2a R 2b or NR 2a .
  • each of R 2a and R 2b is independently -H, deuterium, methyl, -CHD 2 , -CH 2 D, -CD 3 , ethyl, -CHF 2 , -CH 2 F, -CF 3 , or carboxyl.
  • each of R 2a and R 2b is independently -H or deuterium.
  • L 1 is -CH 2 -, -CH (COOH) -, or -NH-
  • L 2 is -NH-or -CH 2 -.
  • L 1 is -CH 2 -, and L 2 is -NH-.
  • R Y1 , R Y2 and R Y3 is independently deuterium, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , -NO 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -COOH, -CONH 2 , -CO-C 1-6 alkyl, -S-C 1-6 alkyl, -SO-C 1-6 alkyl, -SO 2 , -SO 2 C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, -CO-C 3-8 heterocyclic ring, C 3-8 carbocyclic ring, C 5-6 aryl, C 3-8 heterocyclic ring, or C 5-6 heteroaryl, and each of the heterocyclic ring and heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of which is independently optionally substitute
  • R Y1 , R Y2 and R Y3 is independently deuterium, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , -NO 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , -COOH, -CONH 2 , -CO-C 1-3 alkyl, -S-C 1-3 alkyl, -SO-C 1-3 alkyl, -SO 2 , -SO 2 C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkoxy, -CO-C 3-8 heterocyclic ring, 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, 8-membered carbocyclic ring, 5-membered
  • R Y1 , R Y2 and R Y3 is independently deuterium, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , -NO 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , -COOH, -CONH 2 , -CO-C 1-3 alkyl, -S-C 1-3 alkyl, -SO-C 1-3 alkyl, -SO 2 , -SO 2 C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkoxy, -CO-4-membered heterocyclic ring, -CO-5-membered heterocyclic ring, -CO-6-membered heterocyclic ring, 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 3-membered carbo
  • R Y1 , R Y2 and R Y3 is independently deuterium, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , -NO 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl, -N (CH 3 ) 2 , -COOH, -CONH 2 , -COCH 3 , -COCH 2 CH 3 , -CO-C (CH 3 ) 2 , -SCH 3 , -SOCH 3 , -SO 2 , -SO 2 CH 3 , -CO-4-membered heterocyclic ring, -CO-5-membered heterocyclic ring, -CO-6-membered heterocyclic ring, 3-member
  • R Y1 , R Y2 and R Y3 is independently deuterium, -F, -Cl, -CN, -OH, methyl, ethyl, isopropyl, -NHmethyl, -COOH, -CON (CH 3 ) 2 , -COCH 3 , -COCH 2 CH 3 , -CO-CH (CH 3 ) 2 , -CO-C (CH 3 ) 3 , -COCF 3 , -CO-C (CH 3 ) 2 , -SOCH 3 , -SO 2 , -SO 2 CH 3 , -CHF 2 , -CF 3 , -CH (F) CH 3 , -C (F) 2 CH 3 , -OCH 3 , -OCF 3 , -CH 2 OH, -CH 2 CH 2 OH, -CHOHCH 3, -CH 2 F, -CH 2 D, CHD 2 , -CD
  • W 1 is CR w
  • W 2 is CR w
  • R w is independently -H; -F; -Cl; -Br; -I; -NH 2 ; -CN; -OH; -NO 2 ; carboxyl; -C 1-3 alkyl; -C 1-3 alkoxy; -C 1-6 alkyl or -C 1-6 alkoxy substituted with deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -NO 2 , carboxyl, -C 1-3 alkyl or -C 1-3 alkoxy.
  • R w is independently -H; -F; -Cl; -Br; -NH 2 ; -CN; -OH; -NO 2 ; carboxyl; methyl; ethyl; propyl; isopropyl; methoxy; ethoxy; propoxy; isopropoxy; -C 1-3 alkyl or -C 1-3 alkoxy substituted with deuterium, -F, -Cl, -Br, -NH 2 , -CN, -OH, -NO 2 , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R w is independently -H, deuterium, -F, -CN or methyl.
  • R w is –H, -F or -CN.
  • W 1 is CH or N
  • W 2 is CH, CF or N.
  • W 1 is N
  • W 2 is N
  • each X 1 and X 2 is independently -H, deuterium, -CN, -OH, -NH 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-NR 2 R 3 , -C 1-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene-CO-OR 2 , -C 1-6 alkylene-CO-NR 2 R 3 , -C 1-6 alkylene-NR 2 CO-NR 2 R 3 , -C 1-6 alkylene-NR 2 -COC 1-6 alkyl, -C 1-6 alkylene-C 3-10 heterocyclic ring, -C 1-6 alkylene-C 5-10 heteroaryl, -CO-C 1-6 alkylene-NR 2 R 3 , -CO-C 3-10 heterocyclic ring, -O-C 1-6 alkylene-CO-OR 2 , -O-C 1-6 alkylene-CO-OR 2 ,
  • each X 1 and X 2 is independently -H, deuterium, -CN, -OH, -NH 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-NR 2 R 3 , -C 1-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene-CO-OR 2 , -C 1-6 alkylene-CO-NR 2 R 3 , -C 1-6 alkylene-NR 2 CO-NR 2 R 3 , -C 1-6 alkylene-C 3-8 heterocyclic ring, -C 1-6 alkylene-C 5-10 heteroaryl, -CO-C 3-8 heterocyclic ring, -O-C 3-10 heterocyclic ring, -O-C 3-8 carbocyclic ring, -NR 2 -C 1-6 alkylene-NR 2 R 3 , -NR 2 -C 1-6 alkylene-C 3-8 heterocyclic ring
  • each X 1 and X 2 is independently -H, deuterium, -CN, -OH, -NH 2 , carboxyl, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkylene-NR 2 R 3 , -C 1-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene-CO-OR 2 , -C 1-3 alkylene-CO-NR 2 R 3 , -C 1-3 alkylene-NR 2 CO-NR 2 R 3 , -C 1-3 alkylene-C 3-6 heterocyclic ring, -C 1-3 alkylene-C 5-6 heteroaryl, -CO-C 3-6 heterocyclic ring, -O-C 3-6 carbocyclic ring, -NR 2 -C 1-3 alkylene-NR 2 R 3 , -NR 2 -C 1-3 alkylene-C 3-6 heterocyclic ring, -CO-OR 2 , -CO-OR 2 , -
  • each X 1 and X 2 is independently -H, deuterium, -CN, -OH, -NH 2 , C 1-3 alkyl, or C 1-3 alkoxy; and each of which is independently optionally substituted with one or more substituent R a ; and each of R a is independently deuterium, -F, -Cl, -Br, -CN, -OH, -NH 2 , oxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or carboxyl.
  • each X 1 and X 2 is independently -H, deuterium, -CN, -OH, -NH 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; and each of which is independently optionally substituted with R a ; and each R a is independently deuterium, -F, -Cl, -CN, -OH, -NH 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or carboxyl.
  • each X 1 and X 2 is independently -H, deuterium, methyl, -CHD 2 , -CH 2 D, -CD 3 , ethyl, or methyl substituted with one or more F.
  • each X 1 and X 2 is independently -H, methyl, ethyl, or -CF 3 .
  • X 1 and X 2 are both -H.
  • X 1 combines with X 2 , to form a 3-membered carbocyclic ring, 4-membered carbocyclic ring, or 5-membered carbocyclic ring, wherein the ring systems is optionally substituted with deuterium, -F, -Cl, methyl or ethyl.
  • X 1 combines with X 2 , to form a 5-membered bridge ring.
  • two X 1 can be joined together to form a cyclopropyl, cyclobutyl, or cyclopentyl, and each of which is independently optionally substituted with deuterium, -F, -Cl, -NH 2 , -CN, -OH, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
  • two X 1 can be joined together to form a cyclopropyl or cyclobutyl.
  • each of R 2 and R 3 is independently -H, deuterium, -F, -Cl, -Br, -I, -CN, -OH, -N 3 , -NO 2 , C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , -NH-O-C 1-3 alkyl, -NH-C 1-3 alkylene-O-C 1-3 alkylene, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 9-membered heterocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, 8-membered carbocyclic ring, or 9-membered carbocyclic ring
  • each of R 2 and R 3 is independently -H, deuterium, -F, -Cl, -Br, -I, -CN, -OH, -N 3 , -NO 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl, -NHOCH 3 , -NHOCH 2 CH 3 , -NHCH 2 OCH 3 , -NHOCH 2 CH 2 CH 3 , -NHCH 2 OCH 2 CH 3 , -NHCH 2 CH 2 OCH 3 , -NHOCH (CH 3 ) 2 , 5-membered heterocyclic ring, 6-membered heterocyclic ring, 5-membered carbocyclic ring, or 6-membered carbocyclic ring, and each of the heterocyclic
  • each of R 2 and R 3 is independently -H, deuterium, -F, -Cl, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl, -N (CH 3 ) 2 , -SCH 3 , -SO 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 D, CHD 2 , -CD 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CD 3 , -CH 2 CF 3 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N (CH 3 ) 2 , -CH 2 CH 2 CH 2 F, -CH 2 CH
  • q is 0, 1 or 2.
  • p is 0, 1, 2 or 3.
  • Y is O, S, SO, - (CH 2 ) m CO- (CH 2 ) m -, - (CH 2 ) m SO 2 - (CH 2 ) m -, or - (CH 2 ) m CR 4 R 5 - (CH 2 ) m -.
  • Y is O, - (CH 2 ) m CO- (CH 2 ) m -, - (CH 2 ) m SO 2 - (CH 2 ) m -, or - (CH 2 ) m CR 4 R 5 - (CH 2 ) m -.
  • m is 0, 1 or 2.
  • R 4 and R 5 is independently selected from –H, deuterium, -F, methyl, -CH 2 D, -CHF 2 , -CH 2 F, -CD 2 H, -CD 3 , -CF 3 , or
  • R 4 combines with R 5 , to form cyclopropyl, cyclobutyl, or
  • Y is independently selected from O, -CH 2 -, -CH 2 -CH 2 -, -CH 2 CF 2 -, -CF 2 -, -CF 2 CH 2 -, -CH (CH 3 ) -, -C (CH 3 ) 2 -, -CH (CF 3 ) -, -CO-, -SO 2 -, -CH 2 -CO-, -CH 2 -SO 2 -, -CO-CH 2 -, -SO 2 -CH 2 -, -SO 2 -CH 2 -, -SO 2 -CH 2 -,
  • Ar 2 is a 6-membered aryl, 7-membered aryl, 8-membered aryl, 9-membered aryl, 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, 8-membered carbocyclic ring, 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, or 9-membered heteroaryl; each of the heterocyclic ring and heteroaryl contains 1, 2, 3 heteroatoms selected from N, O or S; and each of which is independently
  • Ar 2 is a 6-membered aryl, 7-membered aryl, 8-membered aryl, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, 8-membered carbocyclic ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl; each of the heterocyclic ring and heteroaryl contains 1, 2 heteroatoms selected from N, O or S; and each of which is independently optionally substituted with one or more of deuterium; -F; -Cl; -Br; -I; -CN; -OH; -NH 2 ; -NO 2 ; carbony
  • Ar 2 is
  • Ar 1 is 6-membered aryl, 7-membered aryl, 8-membered aryl, 9-membered aryl, 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, 8-membered carbocyclic ring, 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 5-membered heteroaryl 6-membered heteroaryl, 7-membered heteroaryl, or 8-membered heteroaryl; each of the heterocyclic ring and heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of which is independently optionally substituted with one or more of deuter
  • Ar 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is of Formula II:
  • the compound is of Formula III, IV or V:
  • Z, L 1 , L 2 , Y 1 , Y 2 , X 1 , X 2 , Y, Ar 1 , Ar 2 , and p are as defined herein.
  • the compound is of Formula VI:
  • Y 2 is independently CH, CR Y2 or N;
  • each X and X 2 is independently -H, deuterium, halogen, -CN, -OH, -NH 2 , -NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-NR 2 R 3 , -C 1-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene-CO-OR 2 , -C 1-6 alkylene-CO-NR 2 R 3 , -C 1-6 alkylene-NR 2 CO-NR 2 R 3 , -C 1-6 alkylene-NR 2 -COC 1-6 alkyl, -C 1-6 alkylene-C 3-10 heterocyclic ring, -C 1-6 alkylene-C 5-10 heteroaryl, -CO-C 1-6 alkylene-NR 2 R 3 , -CO-NR 2 -C 3-10 heterocyclic ring, -CO-C 3-10 heterocyclic ring, -O-C 1-6 alky
  • X 1 combines with X 2 , to form a C 3-10 carbocyclic ring or a C 3-10 heterocyclic ring which contains 1, 2 or 3 heteroatoms selected from N, O or S, wherein the ring systems is optionally substituted with deuterium, halogen, -CN, -OH, C 1-6 alkoxy, or C 1-6 alkyl; or
  • Y is O, S, SO, - (CH 2 ) m CO- (CH 2 ) m -, - (CH 2 ) m SO 2 - (CH 2 ) m -, or - (CH 2 ) m CR 4 R 5 - (CH 2 ) m -, and m is independently 0, 1, 2 or 3;
  • R Y2 is independently deuterium, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , -NO 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , -CO-C 1-3 alkyl, -S-C 1-3 alkyl, -SO-C 1-3 alkyl, -SO 2 , -SO 2 C 1-3 alkyl, C 1-3 lkyl, C 1-3 alkoxy, 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, 8-membered carbocyclic ring, 5-membered aryl, 6-membered aryl, 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered
  • R Y2 is independently deuterium, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , -NO 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl, -N (CH 3 ) 2 , -COCH 3 , -COCH 2 CH 3 , -CO-C (CH 3 ) 2 , -SCH 3 , -SOCH 3 , -SO 2 , -SO 2 CH 3 , 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered aryl, 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring, 5-membere
  • R Y2 is independently deuterium, -F, -Cl, -CN, methyl, ethyl, isopropyl, -NHmethyl, -COCH 3 , -COCH 2 CH 3 , -CO-C (CH 3 ) 2 , -SOCH 3 , -SO 2 , -SO 2 CH 3 , -CHF 2 , -CF 3 , -CH (F) CH 3 , -C (F) 2 CH 3 , -OCH 3 , -OCF 3 , -CH 2 OH, -CH 2 CH 2 OH, -CHOHCH 3, -CH 2 F, -CH 2 D, CHD 2 , -CD 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CD 3 , -CH 2 CF 3 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHCH 3 , -CH 2
  • each X 1 and X 2 is independently -H, deuterium, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , -NO 2 , carboxyl, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkylene-NR 2 R 3 , -C 1-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene-CO-OR 2 , -C 1-3 alkylene-CO-NR 2 R 3 , -C 1-3 alkylene-NR 2 CO-NR 2 R 3 , -C 1-3 alkylene-C 3-6 heterocyclic ring, -C 1-3 alkylene-C 5-6 heteroaryl, -CO-C 3-6 heterocyclic ring, -O-C 3-6 carbocyclic ring, -NR 2 -C 1-3 alkylene-NR 2 R 3 , -NR 2 -C 1-3 1-3 alkylene-NR
  • each X 1 and X 2 is independently -H, deuterium, -F, -Cl, -CN, -OH, -NH 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; and each of which is independently optionally substituted with R a ; and R a is independently deuterium, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , -NO 2 , oxo, -CONH 2 , -SO 2 NH 2 , -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or carboxyl.
  • each X 1 and X 2 is independently -H, methyl, ethyl, or -CF 3 .
  • X 1 and X 2 are both -H.
  • X 1 combines with X 2 , to form a 3-membered carbocyclic ring, 4-membered carbocyclic ring, or 5-membered carbocyclic ring, wherein the ring systems is optionally substituted with deuterium, -F, -Cl, methyl or ethyl.
  • X 1 combines with X 2 , to form a 5-membered bridge ring.
  • two X 1 can be joined together to form a cyclopropyl, cyclobutyl, or cyclopentyl, and each of which is independently optionally substituted with deuterium, -F, -Cl, -NH 2 , -CN, -OH, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
  • two X 1 can be joined together to form a cyclopropyl or cyclobutyl.
  • each of R 2 and R 3 is independently -H, deuterium, -F, -Cl, -Br, -I, -CN, -OH, -N 3 , -NO 2 , C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , -NH-O-C 1-3 alkyl, -NH-C 1-3 alkylene-O-C 1-3 alkylene, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 9-membered heterocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, 8-membered carbocyclic ring, or 9-membered carbocyclic ring
  • each of R 2 and R 3 is independently -H, deuterium, -F, -Cl, -Br, -I, -CN, -OH, -N 3 , -NO 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl, -NHOCH 3 , -NHOCH 2 CH 3 , -NHCH 2 OCH 3 , -NHOCH 2 CH 2 CH 3 , -NHCH 2 OCH 2 CH 3 , -NHCH 2 CH 2 OCH 3 , -NHOCH (CH 3 ) 2 , 5-membered heterocyclic ring, 6-membered heterocyclic ring, 5-membered carbocyclic ring, or 6-membered carbocyclic ring, and each of the heterocyclic
  • each of R 2 and R 3 is independently -H, deuterium, -F, -Cl, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl, -N (CH 3 ) 2 , -SCH 3 , -SO 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 D, CHD 2 , -CD 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CD 3 , -CH 2 CF 3 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N (CH 3 ) 2 , -CH 2 CH 2 CH 2 F, -CH 2 CH
  • q is 0 or 1.
  • Y is O, - (CH 2 ) m CO- (CH 2 ) m -, - (CH 2 ) m SO 2 - (CH 2 ) m -, or - (CH 2 ) m CR 4 R 5 - (CH 2 ) m -.
  • m is 0 or 1.
  • R 4 and R 5 is independently selected from –H, deuterium, -F, methyl, -CH 2 D, -CHF 2 , -CH 2 F, -CD 2 H, -CD 3 , -CF 3 , or
  • R 4 combines with R 5 , to form cyclopropyl, cyclobutyl, or
  • Y is independently selected from O, -CH 2 -, -CH 2 -CH 2 -, -CH 2 CF 2 -, -CF 2 -, -CF 2 CH 2 -, -CH (CH 3 ) -, -C (CH 3 ) 2 -, -CH (CF 3 ) -, -CO-, -SO 2 -, -CH 2 -CO-, -CH 2 -SO 2 -, -CO-CH 2 -, -SO 2 -CH 2 -, -SO 2 -CH 2 -, -SO 2 -CH 2 -,
  • Ar 2 is a phenyl, and each of which is independently optionally substituted with one or more of deuterium, -F, -Cl, -Br, -CN, -OH, -NH 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 D, CHD 2 , -CD 3 .
  • Ar 2 is
  • Ar 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is of Formula VII:
  • Y 1 is independently CH or CR Y1 ;
  • Y 2 is independently CH or CR Y2 ;
  • each X 1 and X 2 is independently selected from -H, deuterium, halogen, -CN, -OH, -NH 2 , -NO 2 , carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkylene-NR 2 R 3 , -C 1-6 alkylene-O-C 1-6 alkyl, -C 1-6 alkylene-CO-OR 2 , -C 1-6 alkylene-CO-NR 2 R 3 , -C 1-6 alkylene-NR 2 CO-NR 2 R 3 , -C 1-6 alkylene-NR 2 -COC 1-6 alkyl, -C 1-6 alkylene-C 3-10 heterocyclic ring, -C 1-6 alkylene-C 5-10 heteroaryl, -CO-C 1-6 alkylene-NR 2 R 3 , -CO-NR 2 -C 3-10 heterocyclic ring, -CO-C 3-10 heterocyclic ring, -O-C
  • X 1 combines with X 2 , to form a C 3-10 carbocyclic ring or a C 3-10 heterocyclic ring which contains 1, 2 or 3 heteroatoms selected from N, O or S, wherein each of the ring systems is independently optionally substituted with deuterium, halogen, -CN, -OH, C 1-6 alkoxy, or C 1-6 alkyl; or
  • Y is selected from O, S, SO, - (CH 2 ) m CO- (CH 2 ) m -, - (CH 2 ) m SO 2 - (CH 2 ) m -, or - (CH 2 ) m -CR 4 R 5 - (CH 2 ) m -, and m is independently 0, 1, 2 or 3;
  • R Y1 and R Y2 is independently selected from deuterium, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , -NO 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , -CO-C 1-3 alkyl, -S-C 1-3 alkyl, -SO-C 1-3 alkyl, -SO 2 , -SO 2 C 1-3 alkyl, C 1-3 lkyl, C 1-3 alkoxy, 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, 8-membered carbocyclic ring, 5-membered aryl, 6-membered aryl, 3-membered heterocyclic ring, 4-membered heterocycl
  • R Y1 and R Y2 is independently selected from deuterium, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , -NO 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl, -N (CH 3 ) 2 , -COCH 3 , -COCH 2 CH 3 , -CO-C (CH 3 ) 2 , -SCH 3 , -SOCH 3 , -SO 2 , -SO 2 CH 3 , 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 6-membered aryl, 3-membered heterocyclic ring, 4-membered heterocyclic ring
  • R Y1 and R Y2 is independently selected from deuterium, -F, -Cl, -CN, methyl, ethyl, isopropyl, -NHmethyl, -COCH 3 , -SOCH 3 , -SO 2 , -SO 2 CH 3 , -CHF 2 , -CF 3 , -COCH 3 , -COCH 2 CH 3 , -CO-C (CH 3 ) 2 , -CH (F) CH 3 , -C (F) 2 CH 3 , -OCH 3 , -OCF 3 , -CH 2 OH, -CH 2 CH 2 OH, -CHOHCH 3, -CH 2 F, -CH 2 D, CHD 2 , -CD 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CD 3 , -CH 2 CF 3 , -CH 2 CH 2 NH 2 , -
  • each X 1 and X 2 is independently selected from -H, deuterium, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , -NO 2 , carboxyl, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkylene-NR 2 R 3 , -C 1-3 alkylene-O-C 1-3 alkyl, -C 1-3 alkylene-CO-OR 2 , -C 1-3 alkylene-CO-NR 2 R 3 , -C 1-3 alkylene-NR 2 CO-NR 2 R 3 , -C 1-3 alkylene-C 3-6 heterocyclic ring, -C 1-3 alkylene-C 5-6 heteroaryl, -CO-C 3-6 heterocyclic ring, -O-C 3-6 carbocyclic ring, -NR 2 -C 1-3 alkylene-NR 2 R 3 , -NR 2 -C
  • each X 1 and X 2 is independently selected from -H, deuterium, -F, -Cl, -CN, -OH, -NH 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy; and each of which is independently optionally substituted with R a ; and R a is independently deuterium, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , -NO 2 , oxo, -CONH 2 , -SO 2 NH 2 , -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or carboxyl.
  • X 1 and X 2 is independently selected from -H, methyl, ethyl, or -CF 3 .
  • X 1 and X 2 are both -H.
  • X 1 combines with X 2 , to form a 3-membered carbocyclic ring, 4-membered carbocyclic ring, or 5-membered carbocyclic ring, wherein each of the ring systems is independently optionally substituted with deuterium, -F, -Cl, methyl or ethyl.
  • X 1 combines with X 2 , to form a 5-membered bridge ring.
  • each of R 2 and R 3 is independently selected from -H, deuterium, -F, -Cl, -Br, -I, -CN, -OH, -N 3 , -NO 2 , C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , -NH-O-C 1-3 alkyl, -NH-C 1-3 alkylene-O-C 1-3 alkylene, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 9-membered heterocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-
  • each of R 2 and R 3 is independently selected from -H, deuterium, -F, -Cl, -Br, -I, -CN, -OH, -N 3 , -NO 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl, -NHOCH 3 , -NHOCH 2 CH 3 , -NHCH 2 OCH 3 , -NHOCH 2 CH 2 CH 3 , -NHCH 2 OCH 2 CH 3 , -NHCH 2 CH 2 OCH 3 , -NHOCH (CH 3 ) 2 , 5-membered heterocyclic ring, 6-membered heterocyclic ring, 5-membered carbocyclic ring, or 6-membered carbocyclic ring, and each of the heterocyclic ring, and each
  • each of R 2 and R 3 is independently selected from -H, deuterium, -F, -Cl, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl, -N (CH 3 ) 2 , -SCH 3 , -SO 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 D, CHD 2 , -CD 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CD 3 , -CH 2 CF 3 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N (CH 3 ) 2 , -CH 2 CH 2 CH 2 F, -CH -CH
  • q is 0 or 1.
  • Y is selected from O, - (CH 2 ) m CO- (CH 2 ) m -, - (CH 2 ) m SO 2 - (CH 2 ) m -, or - (CH 2 ) m -CR 4 R 5 - (CH 2 ) m -.
  • m is 0 or 1.
  • R 4 and R 5 is independently selected from –H, deuterium, -F, methyl, -CH 2 D, -CHF 2 , -CH 2 F, -CD 2 H, -CD 3 , -CF 3 , or
  • R 4 combines with R 5 , to form cyclopropyl, cyclobutyl, or
  • Y is selected from O, -CH 2 -, -CH 2 -CH 2 -, -CH 2 CF 2 -, -CF 2 -, -CF 2 CH 2 -, -CH (CH 3 ) -, -C (CH 3 ) 2 -, -CH (CF 3 ) -, -CO-, -SO 2 -, -CH 2 -CO-, -CH 2 -SO 2 -, -CO-CH 2 -, -SO 2 -CH 2 -, -SO 2 -CH 2 -,
  • Ar 2 is a phenyl, and each of which is independently optionally substituted with one or more of deuterium, -F, -Cl, -Br, -CN, -OH, -NH 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 D, CHD 2 , -CD 3 .
  • Ar 2 is
  • Ar 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the present invention further provides some preferred technical solution with regard to a compound of Formula I, II, III, IV, V, VI or VII, or pharmaceutically acceptable salt thereof, and the compound includes the group consisting of:
  • the compounds of the present invention can be prepared in a number ways well known to one skilled in the art of organic synthesis using the methods described below or variations thereon as appreciated by those skilled in the art.
  • the references cited herein are hereby incorporated by reference in their entirety.
  • Schemes 1, 2 and 3 show a general synthetic method for preparing the compounds described herein.
  • Schemes 1, 2 and 3 show a general synthetic method for preparing the compounds described herein.
  • Examples section below For a more detailed description of the individual reaction steps, see the Examples section below.
  • Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds.
  • many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known those skilled in the art.
  • Nucleophilic substitution or condensation reaction of 6 with 7 can be required to obtain the final product 8.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one compound or pharmaceutically acceptable salt thereof of Formula I, II, III, IV, V, VI or VII, and at least one pharmaceutically acceptable excipient.
  • the said compound or pharmaceutically acceptable salt thereof of Formula I, II, III, IV, V, VI or VII in a weight ratio to the said excipient within the range from about 0.0001 to about 10.
  • the present invention additionally provides a use of at least one compound or pharmaceutically acceptable salt thereof of Formula I, II, III, IV, V, VI or VII, and/or a pharmaceutical composition described herein for the manufacture of a medicament.
  • a medicament thus prepared can be used for the treatment or prevention of cancer or cancer metastasis.
  • a medicament thus prepared can be used as an Aurora A selective inhibitor.
  • the cancer is selected from the group consisting of small cell lung cancer, colorectal cancer, gastric cancer, prostate cancer, breast cancer, triple-negative breast cancer, cervical cancer, head and neck cancer, esophageal cancer, ovarian cancer, non-small cell lung cancer, non-Hodgkin lymphoma, or any of combination thereof.
  • the cancer is selected from small cell lung cancer, prostate cancer, triple-negative breast cancer, cervical cancer, or head and neck cancer.
  • the cancer is selected from the group consisting of small cell lung cancer, colorectal cancer, gastric cancer, prostate cancer, breast cancer, triple-negative breast cancer, cervical cancer, head and neck cancer, esophageal cancer, ovarian cancer, non-small cell lung cancer, non-Hodgkin lymphoma, or any of combination thereof.
  • the cancer is selected from small cell lung cancer, prostate cancer, triple-negative breast cancer, cervical cancer, or head and neck cancer.
  • the present invention additionally provides a method of treating a patient having a condition which is mediated by the activity of Aurora A, said method comprising administering to the patient a therapeutically effective amount of at least one compound or pharmaceutically acceptable salt thereof of Formula I, II, III, IV, V, VI or VII, and/or a pharmaceutical composition described above.
  • the condition mediated by the activity of Aurora A is cancer.
  • the condition mediated by the activity of Aurora A is small cell lung cancer, colorectal cancer, gastric cancer, prostate cancer, breast cancer, triple-negative breast cancer, cervical cancer, head and neck cancer, esophageal cancer, ovarian cancer, non-small cell lung cancer, non-Hodgkin lymphoma, or any of combination thereof.
  • the cancer is selected from small cell lung cancer, prostate cancer, triple-negative breast cancer, cervical cancer, or head and neck cancer.
  • the present invention additionally provides a method of treating cancer selected from the group consisting of small cell lung cancer, colorectal cancer, gastric cancer, prostate cancer, breast cancer, triple-negative breast cancer, cervical cancer, head and neck cancer, esophageal cancer, ovarian cancer, non-small cell lung cancer, or non-Hodgkin lymphoma in a mammal comprising administering to a mammal in need of such treatment an effective amount of at least one compound or pharmaceutically acceptable salt of Formula I, II, III, IV, V, VI or VII, and/or a pharmaceutical composition of described above.
  • halogen means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include F, Cl and Br.
  • haloC 1-6 alkyl means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include F, Cl and Br.
  • haloC 1-6 alkyl means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include F, Cl and Br.
  • haloC 1-6 alkyl , “haloC 2-6 alkenyl” , “haloC 2-6 alkynyl” and “haloC 1-6 alkoxy” mean a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms.
  • fluoroC 1-6 alkyl, fluoroC 2-6 alkenyl, fluoroC 2-6 alkynyl and fluoroC 1-6 alkoxy groups in particular fluoroC 1-3 alkyl, for example, CF 3 , CHF 2 , CH 2 F, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 and fluoroC 1-3 alkoxy groups, for example, OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH 2 CF 3 , and most especially CF 3 , OCF 3 and OCHF 2 .
  • fluoroC 1-3 alkyl for example, CF 3 , CHF 2 , CH 2 F, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 and fluoroC 1-3 alkoxy groups, for example, OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH
  • alkyl includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
  • C 1-8 as in C 1-8 alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched arrangement.
  • 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 and alkynyl groups include straight, branched chain or cyclic alkenes and alkynes.
  • C 2-8 alkenyl and “C 2-8 alkynyl” means an alkenyl or alkynyl radicals having 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or brached arrangement.
  • Alkoxy radicals are oxygen ethers formed from the previously described straight, branched chain or cyclic alkyl groups.
  • aryl refers to an unsubstituted or substituted mono-or polycyclic 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 ring or “heterocyclyl” , as used herein, unless otherwise indicated, refers to unsubstituted and substituted mono-or polycyclic non-aromatic ring system containing one or more heteroatoms.
  • Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
  • 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.
  • cycloalkyl 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.
  • alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., aralky or dialkylamino) it shall be interpreted as including those limitations given above for “alkyl” and “aryl” .
  • Designated numbers of carbon atoms e.g., C l - 6 ) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
  • substituted refers to a group mentioned above in which one or more (preferably 1-6, more preferably 1-3) hydrogen atoms are each independently replaced with the same or different substituent (s) .
  • the substituent (s) is independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluromethoxy, ethoxy, propyloxy, iso-propyloxy, n-butyloxy, isobutyloxy, t-butyloxy, -SCH 3 , -SC 2 H 5 , formaldehyde group, -C (OCH 3 ) , cyano, nitro, CF 3 , -OCF 3 , amino, dimethylamino, methyl thio, sulfonyl and acetyl.
  • Particularly preferred substituent (s) is -F, -Cl or -Br.
  • Compounds described herein, such as certain compounds of Formula I, II, III, IV, V, VI or VII may contain asymmetrically substituted carbon atoms (or chiral centers) in the R or S configuration.
  • the present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
  • enriched R- or S-designated isomer can be substantially free (e.g., with less than 5%, less than 1%, or non-detectable, as determined by chiral HPLC) of the other isomer for the respective chiral center.
  • the enriched R-or S-isomers can be prepared by methods exemplified in this application, such as by using a chiral auxiliary such as R-or S-tert-butylsulfinamide in the synthetic process.
  • chiral HPLC purifications of a stereoisomeric mixture such as a racemic mixture.
  • General methods for separating stereoisomers (such as enantiomers and/or diastereomers) using HPLC are known in the art.
  • Isotopes can be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl, and 125I.
  • Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
  • one or more hydrogen atoms of any of the compounds described herein can be substituted with deuterium to provide the corresponding deterium-labeled or -enriched compounds.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • Compounds of Formula I, II, III, IV, V, VI or VII may have different isomeric forms.
  • any asymmetric carbon atom may be present in the (R) -, (S) -or (R, S) -configuration, preferably in the (R) -or (S) -configuration.
  • the compounds may thus be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.
  • 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 I, II, III, IV, V, VI or VII are shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of Formula I, II, III, IV, V, VI or VII 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 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 I, II, III, IV, V, VI or VII 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 I, II, III, IV, V, VI or VII (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 I, II, III, IV, V, VI or VII, 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 I, II, III, IV, V, VI or VII, or a pharmaceutically acceptable salt thereof 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. In general, 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 I, II, III, IV, V, VI or VII.
  • a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt, of Formula I, II, III, IV, V, VI or VII.
  • the compounds of Formula I, II, III, IV, V, VI or VII, 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 I, II, III, IV, V, VI or VII 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 described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art.
  • synthetic procedures known in the art.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated.
  • the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed.
  • Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated.
  • the starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.
  • Step 1 (6-chloro-3, 5-dimethylpyrazin-2-yl) methanol
  • Ethyl 6-chloro-3, 5-dimethylpyrazine-2-carboxylate (0.846 g, 3.941 mmol) was dissolved in anhydrous THF under nitrogen.
  • a solution of DIBAH (3.9 mL, 3.900 mmol) 1M in THF was added slowly at -30 °C ⁇ -50 °C under nitrogen.
  • the resulting mixture was allowed to warm to room temperature.
  • the reaction was quenched with saturated ammonium chloride aqueous solution (20 mL) at 0 ⁇ 10 °C.
  • the resulting solution was diluted with brine and extracted with 50 mL of EtOAc washed with.
  • Step 2 2- (bromomethyl) -6-chloro-3, 5-dimethylpyrazine
  • Step 3 2- (bromomethyl) -6-chloro-4-cyclopropyl-3-fluoropyridine
  • Step 4 (6-chloro-3-fluoro-5-methylpyridin-2-yl) methanol
  • Step 5 2- (bromomethyl) -6-chloro-3-fluoro-5-methylpyridine
  • Step 4 (3, 5-difluoropyridin-2-yl) methanol
  • Step 2 di-tert-butyl piperidine-1, 4-dicarboxylate
  • Step 2 methyl-1- (4-methoxybenzyl) -2-methylpiperidine-4-carboxylate
  • Step 3 methyl (2R, 4R) -1- (4-methoxybenzyl) -2-methylpiperidine-4-carboxylate
  • Step 4 methyl- (2R, 4R) -2-methylpiperidine-4-carboxylate-hydrochloride
  • Step 5 1- (tert-butyl) -4-methyl (2R, 4R) -2-methylpiperidine-1, 4-dicarboxylate
  • Step 7 di-tert-butyl- (2R, 4R) -2-methylpiperidine-1, 4-dicarboxylate
  • Step 3 methyl 1- (3-chloro-2-fluorobenzyl) -2-ethylpiperidine-4-carboxylate
  • Step 2 methyl 1- (3-chloro-2-fluorobenzyl) -2, 6-dimethylpiperidine-4-carboxylate
  • Step 1 di-tert-butyl- (2R, 4R) -4- ( (3, 5-difluoropyridin-2-yl) methyl) -2-methyl-piperidine-1, 4-dicarboxylate
  • Step 2 2- ( ( (2R, 4R) -1, 4-bis (tert-butoxycarbonyl) -2-methylpiperidin-4-yl) methyl) -3, 5-difluoropyridine-1-oxide
  • Step 3 di-tert-butyl- (2R, 4R) -4- ( (6-chloro-3, 5-difluoropyridin-2-yl) methyl) -2-methylpiperidine-1, 4-dicarboxylate
  • Step 1 methyl 1- (3-chloro-2-fluorobenzyl) piperidine-4-carboxylate
  • Step 2 methyl 4- ( (6-bromo-3-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluoro-benzyl) piperidine-4-carboxylate
  • Step 3 methyl 4- ( (6- ( (1- (tert-butoxycarbonyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) piperidine-4-carboxylate
  • Step 4 methyl 1- (3-chloro-2-fluorobenzyl) -4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) piperidine-4-carboxylate
  • Step 5 1- (3-chloro-2-fluorobenzyl) -4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) piperidine-4-carboxylic acid
  • Step 1 methyl 4- ( (6-bromo-3-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluoro-benzyl) -2-ethyl piperidine-4-carboxylate
  • Step 2 methyl 4- ( (6- ( (1- (tert-butoxycarbonyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-ethylpiperidine-4-carboxylate
  • Step 3 methyl 1- (3-chloro-2-fluorobenzyl) -2-ethyl-4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) piperidine-4-carboxylate
  • Step 4 1- (3-chloro-2-fluorobenzyl) -2-ethyl-4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) piperidine-4-carboxylic acid
  • Step 1 methyl-4- ( (6-bromo-3-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2, 6-dimethylpiperidine-4-carboxylate
  • Step 2 Methyl 1- (3-chloro-2-fluorobenzyl) -4- ( (3-fluoro-6- ( (5-methyl-1- ( (2- (trimethylsilyl) -ethoxy) methyl) -1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2, 6-dimethylpiperidine-4-carboxylate
  • Step 3 methyl-1- (3-chloro-2-fluorobenzyl) -4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2, 6-dimethylpiperidine-4-carboxylate
  • Step 4 1- (3-chloro-2-fluorobenzyl) -4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2, 6-dimethylpiperidine-4-carboxylic acid
  • Step 1 methyl 4- ( (6-bromo-3-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidine-4-carboxylate
  • Step 2 methyl 1- (3-chloro-2-fluorobenzyl) -4- ( (3-fluoro-6- (thiazol-2-ylamino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 3 1- (3-chloro-2-fluorobenzyl) -4- ( (3-fluoro-6- (thiazol-2-ylamino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 1 di-tert-butyl- (2R, 4R) -4- ( (6-chloro-5-fluoropyridin-2-yl) methyl) -2-methylpiperidine-1, 4-dicarboxylate
  • Step 2 di-tert-butyl- (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -3-methyl-1H-pyrazol-5-yl) amino) -5-fluoropyridin-2-yl) methyl) -2-methylpiperidine-1, 4-dicarboxylate
  • Step 3 tert-butyl- (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -3-methyl-1H-pyrazol-5-yl) amino) -5-fluoro pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 4 tert-butyl- (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -3-methyl-1H-pyrazol-5-yl) amino) -5-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidine-4-carboxylate
  • Step 5 (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (5-fluoro-6- ( (3-methyl-1H-pyrazol-5-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 1 methyl (2R, 4R) -4- ( (6-bromo-3-fluoropyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate trifluoroacetate
  • Step 2 methyl- (2R, 4R) -4- ( (6-bromo-3-fluoropyridin-2-yl) methyl) -2-methyl-1- (2- (trifluoromethyl) benzoyl) piperidine-4-carboxylate
  • Step 3 methyl- (2R, 4R) -4- ( (6- ( (1- (tert-butoxycarbonyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoropyridin-2-yl) methyl) -2-methyl-1- (2- (trifluoromethyl) benzoyl) piperidine-4-carboxylate
  • Step 4 methyl- (2R, 4R) -4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methyl-1- (2- (trifluoromethyl) benzoyl) piperidine-4-carboxylate
  • Step 5 (2R, 4R) -4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methyl-1- (2- (trifluoromethyl) benzoyl) piperidine-4-carboxylic acid
  • Step 1 methyl (2R, 4R) -4- ( (6-bromo-3-fluoropyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate trifluoroacetate
  • Step 2 methyl (2R, 4R) -4- ( (6-bromo-3-fluoropyridin-2-yl) methyl) -2-methyl-1- ( (2- (trifluoromethyl) phenyl) sulfonyl) piperidine-4-carboxylate
  • Step 3 methyl (2R, 4R) -4- ( (6- ( (1- (tert-butoxycarbonyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoropyridin-2-yl) methyl) -2-methyl-1- ( (2- (trifluoromethyl) phenyl) sulfonyl) piperidine-4-carbox ylate
  • Step 4 methyl (2R, 4R) -4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methyl-1- ( (2- (trifluoromethyl) phenyl) sulfonyl) piperidine-4-carboxylate
  • Step 5 (2R, 4R) -4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methyl-1- ( (2- (trifluoromethyl) phenyl) sulfonyl) piperidine-4-carboxylic acid
  • Step 1 1- (3-chloro-2-fluorophenyl) ethan-1-ol
  • Step 2 1- (1-bromoethyl) -3-chloro-2-fluorobenzene
  • Step 3 methyl (2R, 4R) -4- ( (6-bromo-3-fluoropyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate hydrochloride
  • Step 4 methyl- (2R, 4R) -4- ( (6-bromo-3-fluoropyridin-2-yl) methyl) -1- (-1- (3-chloro-2-fluo-rophenyl) ethyl) -2-methylpiperidine-4-carboxylate
  • Step 5 methyl- (2R, 4R) -4- ( (6- ( (1- (tert-butoxycarbonyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoropyridin-2-yl) methyl) -1- (-1- (3-chloro-2-fluorophenyl) ethyl) -2-methylpiperidine-4-carboxylate
  • Step 6 methyl- (2R, 4R) -1- (1- (3-chloro-2-fluorophenyl) ethyl) -4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 7 (2R, 4R) -1- (1- (3-chloro-2-fluorophenyl) ethyl) -4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 1 2- (3-chloro-2-fluorophenyl) ethan-1-ol
  • Step 3 tert-butyl (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluorophenethyl) -2-methylpiperidine-4-carboxylate
  • Step 4 (2R, 4R) -1- (3-chloro-2-fluorophenethyl) -4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 1 2-bromo-1- (3-chloro-2-fluorophenyl) ethan-1-one
  • Step 2 tert-butyl (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoropyridin-2-yl) methyl) -1- (2- (3-chloro-2-fluorophenyl) -2-oxoethyl) -2-methylpiperidine-4-carboxylate
  • Step 3 (2R, 4R) -1- (2- (3-chloro-2-fluorophenyl) -2-oxoethyl) -4- ( (3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 1 methyl (2R, 4R) -4- ( (6-chloropyrazin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 2 methyl- (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (6-chloropyrazin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 3 methyl- (2R, 4R) -4- ( (6- ( (1- (tert-butoxycarbonyl) -5-methyl-1H-pyrazol-3-yl) amino) pyrazin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidine-4-carboxylate
  • Step 4 methyl- (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -2-methyl-4- ( (6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyrazin-2-yl) methyl) piperidine-4-carboxylate
  • Step 5 (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -2-methyl-4- ( (6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyrazin-2-yl) methyl) piperidine-4-carboxylic acid
  • Step 1 1- (tert-butyl) -4-methyl-4- ( (6-bromo-3-fluoropyridin-2-yl) methyl) piperidine-1, 4-dicarboxylate
  • Step 2 1- (tert-butyl) -4-methyl-4- ( (6-chloro-3-fluoro-4- (3-hydroxyoxetan-3-yl) pyridin-2-yl) methyl) piperidine-1, 4-dicarboxylate
  • Step 3 methyl-1- (3-chloro-2-fluorobenzyl) -4- ( (6-chloro-3-fluoro-4- (3-hydroxyoxetan-3-yl) p-yridin-2-yl) methyl) piperidine-4-carboxylate
  • Step 4 methyl-4- ( (6- ( (1- (tert-butoxycarbonyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoro-4- (3-hydroxyoxetan-3-yl) pyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) piperidine-4-c-arboxylate
  • Step 5 methyl-1- (3-chloro-2-fluorobenzyl) -4- ( (3-fluoro-4- (3-hydroxyoxetan-3-yl) -6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) piperidine-4-carboxylate
  • Step 6 1- (3-chloro-2-fluorobenzyl) -4- ( (3-fluoro-4- (3-hydroxyoxetan-3-yl) -6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) piperidine-4-carboxylic acid
  • Step 1 di-tert-butyl- (2R, 4R) -4- ( (6-bromo-3-fluoro-4- (3-hydroxyoxetan-3-yl) pyridin-2-yl) methyl) -2-methylpiperidine-1, 4-dicarboxylate
  • Step 2 tert-butyl- (2R, 4R) -4- ( (6-bromo-3-fluoro-4- (3-hydroxyoxetan-3-yl) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 3 tert-butyl- (2R, 4R) -4- ( (6-bromo-3-fluoro-4- (3-hydroxyoxetan-3-yl) pyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidine-4-carboxylate
  • Step 4 tert-butyl- (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoro-4- (3-hydroxyoxetan-3-yl) pyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpip eridine-4-carboxylate
  • Step 5 tert-butyl- (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoro-4- (3-fluorooxetan-3-yl) pyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiper idine-4-carboxylate
  • Step 6 (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (3-fluoro-4- (3-fluorooxetan-3-yl) -6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 1 di-tert-butyl- (2R, 4R) -4- ( (6-chloro-3-fluoro-4-methylpyridin-2-yl) methyl) -2-methylpiperidine-1, 4-dicarboxylate
  • Step 2 di-tert-butyl (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoro-4-methylpyridin-2-yl) methyl) -2-methylpiperidine-1, 4-dicarboxylate
  • Step 3 tert-butyl- (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoro-4-methylpyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 4 tert-butyl (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoro-4-methylpyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidine-4-carboxylate
  • Step 5 (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (3-fluoro-4-methyl-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 4 tert-butyl- (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoro-4- (2-hydroxypropan-2-yl) pyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpipe ridine-4-carboxylate
  • Step 5 (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (3-fluoro-4- (2-hydroxypropan-2-yl) -6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 1 tert-butyl- (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (6-chloro-3-fluoro-4- (prop-1-en-2-yl) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 2 tert-butyl- (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoro-4- (prop-1-en-2-yl) pyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidine-4 -carboxylate
  • Step 3 tert-butyl- (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoro-4-isopropylpyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidine-4-carboxylate
  • Step 4 (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (3-fluoro-4-isopropyl-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 4 tert-butyl- (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -4- (difluoromethyl) -3-fluoropyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 5 tert-butyl- (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -4- (difluoromethyl) -3-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidine-4-carboxylate
  • Step 6 (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (4- (difluoromethyl) -3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 3 di-tert-butyl- (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -3-fluoro-4-vinylpyridin-2-yl) methyl) -2-methylpiperidine-1, 4-dicarboxylate
  • Step 5 tert-butyl (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -4-ethyl-3-fluoropyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 6 tert-butyl (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -4-ethyl-3-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidine-4-carboxylate
  • Step 7 (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (4-ethyl-3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 1 tert-butyl (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (6-chloro-3-fluoro-4-formylpyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 3 tert-butyl (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -3-methyl-1H-pyrazol-5-yl) amino) -3 -fluoro-4- ( (E) - (hydroxyimino) methyl) pyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methy lpiperidine-4-carboxylate
  • Step 4 (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (4-cyano-3-fluoro-6- ( (3-methyl-1H-pyrazol-5-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 1 di-tert-butyl- (2R, 4R) -4- ( (6-chloro-3-fluoro-4-iodopyridin-2-yl) methyl) -2-methylpiperidine-1, 4-dicarboxylate
  • Step 2 di-tert-butyl (2R, 4R) -4- ( (6-chloro-4- (1-ethoxyvinyl) -3-fluoropyridin-2-yl) methyl) -2-methylpiperidine-1, 4-dicarboxylate
  • Step 3 di-tert-butyl (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -4- (1-ethoxyvinyl) -3-fluoropyridin-2-yl) methyl) -2-methylpiperidine-1, 4-dicarboxylate
  • Step 4 tert-butyl (2R, 4R) -4- ( (4-acetyl-6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) ami-no) -3-fluoropyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 5 tert-butyl (2R, 4R) -4- ( (4-acetyl-6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) a-mino) -3-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidine-4-carb oxylate
  • Step 6 (2R, 4R) -4- ( (4-acetyl-3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) -pyridin-2-yl) met-hyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidine-4-carboxylic acid
  • Step 1 tert-butyl (2R, 4R) -4- ( (4-acetyl-6-chloro-3-fluoropyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 2 tert-butyl (2R, 4R) -4- ( (4-acetyl-6-chloro-3-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidine-4-carboxylate
  • Step 3 tert-butyl (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (6-chloro-4- (1, 1-difluoroethyl) -3-fluoropyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylate
  • Step 4 tert-butyl (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -4- (1, 1-difluoroethyl) -3-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidi ne-4-carboxylate
  • Step 5 (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (4- (1, 1-difluoroethyl) -3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 4 tert-butyl- (2R, 4R) -4- ( (6- ( (1- (tert-butyl) -5-methyl-1H-pyrazol-3-yl) amino) -4-chloro-3-fluoropyridin-2-yl) methyl) -1- (3-chloro-2-fluorobenzyl) -2-methylpiperidine-4-carboxylate
  • Step 5 (2R, 4R) -1- (3-chloro-2-fluorobenzyl) -4- ( (4-chloro-3-fluoro-6- ( (5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) methyl) -2-methylpiperidine-4-carboxylic acid
  • Step 1 di-tert-butyl (2R, 4R) -4- ( (4- (azetidin-1-yl) -6-chloro-3-fluoropyridin-2-yl) methyl) -2-methylpiperidine-1, 4-dicarboxylate

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CN116354936A (zh) 2023-06-30
IL294247A (en) 2022-08-01
US11384066B1 (en) 2022-07-12
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