WO2018149986A1 - 2-(bicyclo-heteroaryl)-isonicotinic derivatives as histone demethylase inhibitors - Google Patents

2-(bicyclo-heteroaryl)-isonicotinic derivatives as histone demethylase inhibitors Download PDF

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Publication number
WO2018149986A1
WO2018149986A1 PCT/EP2018/053925 EP2018053925W WO2018149986A1 WO 2018149986 A1 WO2018149986 A1 WO 2018149986A1 EP 2018053925 W EP2018053925 W EP 2018053925W WO 2018149986 A1 WO2018149986 A1 WO 2018149986A1
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compound
alkyl
aryl
carbocyclyl
heteroaryl
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PCT/EP2018/053925
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French (fr)
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Jorge Salas Solana
Elena CARCELLER GONZÁLEZ
Alberto ORTEGA MUÑOZ
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Oryzon Genomics, S.A.
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Publication of WO2018149986A1 publication Critical patent/WO2018149986A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to compounds useful as inhibitors of histone demethylases.
  • the invention also relates to pharmaceutical compositions comprising these compounds and to their use in therapy, including e.g., in the treatment of cancer.
  • Histones are highly conserved proteins that play a dynamic role in modulating chromatin structure.
  • the covalent modification of histones is closely associated with regulation of gene transcription.
  • Chromatin modifications have been suggested to represent an epigenetic code that is dynamically 'written' and 'erased' by specialized proteins, and 'read', or interpreted, by proteins that translate the code into gene expression changes.
  • Histone methylation is among the most relevant modifications.
  • Methylation of histone lysines or arginines by histone methyltransferases (HMTs) can be reversed by histone lysine demethylases (KDMs) or arginine demethylases (RDMs).
  • KDMs are divided into two families based on sequence conservation and catalytic mechanism: FAD dependent amine oxidases (KDM1); and Jumonji C (JmjC) domain-containing demethylases (JmjC-KDMs).
  • JmjC-KDMs are iron(l Independent enzymes and catalyze the demethylation of mono-, di- and tri-methylated lysines.
  • the JmjC-KDM family contains over 30 members and includes the KDM2 to KDM8 subfamilies as well as JMJD6.
  • the present invention provides a compound of Formula (I) as described below or a salt thereof:
  • R 1 is selected from -OH, -OR 7 and -NR 8 R 9 ;
  • R 2 is selected from hydrogen, halo and methyl
  • R 3 is selected from hydrogen and halo
  • R 4 and R 5 are each independently selected from hydrogen, C 1-16 alkyl, C 1-16 haloalkyl, -L 1 -carbocyclyl, -L 1 -aryl, -L 1 -heterocyclyl, -L 1 -heteroaryl, - ⁇ C 1-16 alkylene)-OR 10 , -( C 1-16 alkylene)-NR 11 R 12 , -( C 1-16 alkylene)-CONR 13 R 14 , -(C 2-16 alkenylene)-CONR 1 3R 14 , -(C 1-16 alkylene)-NR 15 COR 16 , -(C 1-16 alkylene)-NR 15 CONR 17 R 18 , -(C 1-16 alkylene)- NR 15 S0 2 R 19 , -CONR 13 R 14 and -COR 16 , wherein the carbocyclyl in -L 1 -carbocyclyl, the aryl in -L 1 -ary
  • R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 alkylene)-OR 32 , -(C 1-6 alkyleneJ-NR ⁇ R 34 , -(C 1-6 alkylene)- CONR 35 R 36 , -(C 1-6 alkylene)-OCONR 35 R 38 , -(C 1-6 alkylene)-OCOR 37 , -(C 1-6 alkylene)-OCOOR 37 , -L 3 -carbocyclyl, -L 3 -aryl, -L 3 -heterocyclyl and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -L 3 -aryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R 38 ,
  • R 8 and R 9 are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 10 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -L 4 -carbocyclyl, -L 4 -aryl, -LAheterocyclyl and -L 4 - heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L 4 -aryl, the heterocyclyl in -L 4 -heterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 39 ;
  • R 11 and R 12 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -CN, -L 4 -carbocyclyl, -L 4 - aryl, -L 4 -heterocyclyl and -L 4 -heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L 4 -aryl, the heterocyclyl in -L 4 -heterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 39 ;
  • R 13 and R 14 are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -CR ⁇ R ⁇ -CN, -L 4 -carbocyclyl, -L 4 -aryl, -L 4 -heterocyclyl and -L 4 -heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L 4 -aryl, the heterocyclyl in -L 4 -heterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 39 , or R 13 and R 14 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted
  • each R 19 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -L 4 -carbocyclyl, -L 4 -aryl, -L 4 - heterocyclyl and -L 4 -heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L 4 -aryl, the heterocyclyl in -L 4 -heterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 39 ;
  • each R 20 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, -OH, -NR ⁇ R 46 ,-CN, -COR 47 , -CONR 48 R 49 , -OCOR 47 , -NRSOCOR 47 , -NR ⁇ CONR ⁇ R 49 , -NR 5 °S0 2 R 51 , -S0 2 NR 48 R 49 , -SO2R 51 , -L 5 -carbocyclyl, -L 5 -aryl, -L 5 -heterocyclyl and -L 5 -heteroaryl, wherein the carbocyclyl in -L 5 -carbocyclyl, the aryl in -L 5 -aryl, the heterocyclyl in -L 5 -heterocyclyl and the heteroaryl in -L 5 -heteroaryl
  • each R 21 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • R 22 and R 23 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl and -CN;
  • R 24 and R 26 are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and -CR+oR ⁇ -CN, or R24 an( j R25 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C 1-6 alkyl, -OH, -NH2, -NH(C 1-6 alkyl), and -N(C 1-6 alkyl)2;
  • each R 30 is independently selected from 0-s alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
  • R 31 and R 39 are each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, -OH, -NR ⁇ R 46 , -CN, -COR 47 , -CONR+SR 49 , -OCOR 47 , -NR 5 °COR 47 , -NRSOCONR ⁇ R 49 , -NR 50 SO 2 R 51 , -S0 2 NR 48 R 49 , and -S0 2 R 51 ;
  • each R 32 , R 33 and R 34 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -L 4 -carbocyclyl, -L 4 - aryl, -L 4 -heterocyclyl and -L 4 -heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L 4 -aryl, the heterocyclyl in -L 4 -heterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 38 ;
  • R 35 and R 36 are each independently selected from hydrogen, C 1-6 alkyl, -L 4 -carbocyclyl, -L 4 -aryl, -L 4 -heterocyclyl and -L 4 -heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L 4 -aryl, the heterocyclyl in -L 4 - heterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 38 , or R 35 and R 36 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7- membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C 1-6 alkyl, -OH, -NH 2
  • each R 37 is independently selected from C 1-6 alkyl, -L 4 -carbocyclyl, -L 4 -aryl, -L 4 -heterocyclyl and -L 4 -heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L 4 -aryl, the heterocyclyl in -L 4 -heterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 3B ;
  • each R 38 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, -OH, -NR 52 R 53 ,-CN, -COR 54 , -CONR 55 R 56 , -OCOR 54 , -NR ⁇ COR 54 , -NR ⁇ CONRssR 56 , -NR 57 S0 2 R 54 , -S0 2 NR 55 R 58 and -SO2R 54 ;
  • R 40 and R 41 are each independently selected from hydrogen and methyl, or taken together with the C atom to which they are attached form a cyclopropyl ring;
  • each R 42 is independently selected from C 1-6 alkyl
  • R 43 and R 44 are each independently selected from hydrogen and C 1-6 alkyl, or taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C 1-6 alkyl, -OH, -NH 2 , -NH(C 1-6 alkyl), and -N(C 1-6 alkyl) 2 ;
  • R 45 and R 46 are each independently selected from hydrogen, C 1-6 alkyl and -CN;
  • each R 47 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and -COR 42 ;
  • R 48 and R 49 are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and
  • each R 51 is independently selected from C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • each R 54 is independently selected from C 1-6 alkyl and -(C 1-6 alkylene)-NR 62 R 53 ;
  • R M and R 56 are each independently selected from hydrogen, C 1-6 alkyl and -(C 1-6 alkyleneJ-NR ⁇ R 53 ;
  • each L 1 , L 2 , L 3 and L 4 is independently selected from a bond and C 1-10 alkylene
  • each L 5 is independently selected from a bond and C 1-6 alkylene.
  • the compounds of Formula (I) as described herein are inhibitors of JmjC-KDMs, e.g. KDM5 demethylases. These compounds, and pharmaceutical compositions comprising these compounds, are useful for the treatment of diseases associated with JmjC-KDMs, such as a KDM5-mediated disease.
  • the disease is cancer or a viral infection.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Tthe present invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the present invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier, for use in the treatment of a disease associated with JmjC-KDMs.
  • the present invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier.for use as a JmjC-KDM inhibitor.
  • the present invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier, for use in the treatment of cancer.
  • the present invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier.for use in the treatment of a viral infection.
  • the present invention further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease associated with a JmjC- KDM.
  • the present invention further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.
  • the present invention further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a viral infection.
  • the present invention further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for treating a disease associated with a JmjC-KDM.
  • the present invention further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for treating cancer.
  • the present invention further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for treating a viral infection.
  • the present invention further provides a method for treating a disease associated with JmjC-KDMs, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • the present invention further provides a method of inhibiting JmjC-KDM activity, comprising administering to a patient in need of said treatment an amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, sufficient to inhibit JmjC-KDM activity.
  • the present invention further provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • the present invention further provides a method for treating a viral infection, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • the present invention provides a compound of Formula (I) or a salt thereof:
  • R 1 is selected from -OH, -OR 7 and -NR 8 R 9 ;
  • R 2 is selected from hydrogen, halo and methyl
  • R 3 is selected from hydrogen and halo
  • R 4 and R 5 are each independently selected from hydrogen, C 1-16 alkyl, C 1-16 haloalkyl, -L 1 -carbocyclyl, -L 1 -aryl, -L 1 -heterocyclyl, -L 1 -heteroaryl, -(C 1-16 alkylene)-OR 10 , -(C 1-16 alkylene)-NR 11 R 12 , -(C 1-16 alkylene)-CONR 13 R 14 , -(C 2-16 alkenylene)-CONR 13 R 14 , - ⁇ C 1-16 alkylene)-NR 16 COR 16 , -(C 1-16 alkylene)-NR 1 5CONR 17 R 18 , -( C 1-16 alkylene)- NR 15 S0 2 R 19 , -CONR 13 R 14 and -COR 16 , wherein the carbocyclyl in -L 1 -carbocyclyl, the aryl in -L 1 -ary
  • R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 alkylene)-OR 32 , -(C 1-6 alkyleneJ-NR ⁇ R 34 , -(C 1-6 alkylene)- CONR ⁇ R 36 , -(C 1-6 alkyleneJ-OCONR ⁇ R 36 , -(C 1-6 alkylene)-OCOR 37 , -(C 1-6 alkylene)-OCOOR 37 , -L 3 -carbocyclyl, -L 3 -aryl, -L 3 -heterocyclyl and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -L 3 -aryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -L 3 -heteroaryl are each optionally substituted with one or more R 38 ,
  • R s and R 9 are each independently selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 10 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -L 4 -carbocyclyl, -L 4 -aryl, -L 4 -heterocyclyl and -L 4 - heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L*-aryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 39 ;
  • R 11 and R 12 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -CN, -L 4 -carbocyclyl, -L 4 - aryl, -L 4 -heterocyclyl and -L 4 -heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L 4 -aryl, the heterocyclyl in -L 4 -heterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 39 ;
  • R 13 and R 14 are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -CR 40 R 41 -CN, -L 4 -carbocyclyl, -L 4 -aryl, -L 4 -heterocyclyl and -L 4 -heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L 4 -aryl, the heterocyclyl in -L 4 -heterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 39 , or R 13 and R 14 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substitute
  • each R 19 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C ⁇ alkynyl, -L 4 -carbocyclyl, -L 4 -aryl, -L 4 - heterocyclyl and -L 4 -heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L 4 -aryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 39 ;
  • each R 20 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, -OH, -NR 45 R 46 ,-CN, -COR 47 , -CONR 48 R 49 , -OCOR 47 , -NR ⁇ COR 47 , -NR ⁇ CONR ⁇ R 49 , -NR 50 SO 2 R 51 , -S0 2 NR 48 R 49 , -S02R 51 , -lAcarbocyclyl, -L 5 -aryl, -L 5 -heterocyclyl and -L s -heteroaryl, wherein the carbocyclyl in -L 5 -carbocyclyl, the aryl in -L 5 -aryl, the heterocyclyl in -L 5 -heteracyclyl and the heteroaryl in -L 5 -heteroaryl are each optionally
  • each R 21 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl;
  • R 22 and R 23 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl and -CN;
  • R 24 and R 25 are each independently selected from hydrogen, O-s alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and -CR ⁇ R'U-CN, or R24 an( j R25 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C 1-6 alkyl, -OH, -NH2, -NH(C 1-6 alkyl), and -N(C 1-6 alkyl)2;
  • each R 30 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, and C2.6 alkynyl;
  • R 31 and R 39 are each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, -OH, -NR «R « -CN, -COR 47 , -CONR ⁇ R 49 , -OCOR 47 , -NR 5 °COR 47 , -NRSOCONR ⁇ R 49 , -NR 5 °S0 2 R 51 , -S0 2 NR 48 R 49 , and -SO2R 51 ;
  • each R 32 , R 33 and R 34 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -L 4 -carbocyclyl, -L 4 - aryl, -L 4 -heterocyclyl and -L 4 -heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L 4 -aryl, the heterocyclyl in -L 4 -heterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 38 ;
  • R 35 and R 36 are each independently selected from hydrogen, C 1-6 alkyl, -L 4 -carbocyclyl, -L 4 -aryl, -L 4 -heterocyclyl and -L 4 -heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L 4 -aryl, the heterocyclyl in -L 4 - heterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 38 , or R 35 and R 36 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7- membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C 1-6 alkyl, -OH, -NH 2
  • each R 37 is independently selected from alkyl, -L 4 -carbocyclyl, -L 4 -aryl, -L 4 -heterocyclyl and -L 4 -heteroaryl, wherein the carbocyclyl in -L 4 -carbocyclyl, the aryl in -L 4 -aryl, the heterocyclyl in -L 4 -heterocyclyl and the heteroaryl in -L 4 -heteroaryl are each optionally substituted with one or more R 38 ;
  • each R 38 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, -OH, -NR 5Z R 53 ,-CN, -COR 54 , -CONR 55 R 56 , -OCOR 54 , -NR 57 COR M , -NR 57 CONR 55 R 56 , -NR 57 S0 2 R 54 , -S0 2 NR 55 R 56 and -SO2R 54 ;
  • R 40 and R 41 are each independently selected from hydrogen and methyl, or taken together with the C atom to which they are attached form a cyclopropyl ring;
  • each R 42 is independently selected from C 1-6 alkyl
  • R 43 and R 44 are each independently selected from hydrogen and C 1-6 alkyl, or taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C 1-6 alkyl, -OH, -Nhfe, -NH(C 1-6 alkyl), and -N(C 1-6 alkyl) 2 ;
  • R 45 and R 46 are each independently selected from hydrogen, C 1-6 alkyl and -CN;
  • each R 47 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and -COR 42 ;
  • R 48 and R 49 are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and
  • each R 51 is independently selected from C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • each R 54 is independently selected from C 1-6 alkyl and -(C 1-6 alkylene)-NR 52 R 53 ;
  • R 55 and R 56 are each independently selected from hydrogen, C 1-6 alkyl and -(C 1-6 alkylene)-NR 52 R 53 ;
  • each L 1 , L 2 , L 3 and L 4 is independently selected from a bond and C 1-10 alkylene
  • each L 5 is independently selected from a bond and C 1-6 alkylene.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic administration to a subject).
  • each of the embodiments described herein envisions within its scope the salts (for example pharmaceutically acceptable salts) of the compounds described herein. Accordingly, the phrase “or a salt thereof (including also "or a pharmaceutically acceptable salt thereof) is implicit in the description of all compounds described herein. The invention also specifically relates to all compounds described herein in non-salt form.
  • a compound of formula (I) is a bicyclic ring selected from a group of formula (i) to (x) as defined above. Accordingly, a compound of formula (I) includes compounds of Formula (la), (lb), (lc), (Id), (le),(lf), (Ig), (Ih), (li) and (Ij), as shown below:
  • the compound of Formula (I) is a compound (la), (lb), (Id) or (le), and more preferably, the compound of Formula (I) is a compound (la) or (lb).
  • the compound of Formula (I) is a compound of Formula (II)
  • a compound of Formula (II) corresponds to a compound of Formula (la) and (lb) as previously defined.
  • the present invention relates to a compound of any of Formula (I), (la), (lb), (lc), (Id), (le), (If), (lg), (Ih), (li), (Ij) or (II) as defined herein.
  • the compound of Formula (I) in any of the embodiments described herein can be a compound of any of Formula (I), (la), (lb), (lc), (Id), (le), (If), (Ig), (Ih), (li), (Ij) or (II), or a salt thereof.
  • the compound of Formula (I) is a compound of Formula (la), (lb), (Id) or (le), and more preferably a compound of Formula (II), i.e. (la) or (lb).
  • a compound of Formula (II) i.e. (la) or (lb).
  • the compound specified in each of these embodiments is a compound of Formula (la), (lb), (Id) or (le), and more preferably a compound of Formula (II), (la) or (lb), or a salt thereof.
  • a compound of Formula (I) in a compound of Formula (I), is selected from a group of formula (i),
  • a compound of Formula (I) is selected from a group of formula (i), (ii), (iv) and
  • a compound of Formula (I) is selected from a group of formula (i) and (ii), i.e. a compound of Formula (i) is preferably a compound of Formula (II).
  • the compound of Formula (I) is a compound of Formula (la),
  • the compound of Formula (I) is a compound of Formula (lb).
  • the compound of Formula (I) is a compound of Formula (Id).
  • the compound of Formula (I) is a compound of Formula (le).
  • R 1 is selected from -OH, -OR 7 and -NR 8 R 9 .
  • the compounds of the invention thus include carboxylic acids, when in a compound of Formula (I) R 1 is -OH, and esters thereof, when in a compound of Formula (I), R 1 is -OR 7 .
  • Said esters may be used as prodrugs of the corresponding carboxylic acids (i.e. a compound wherein R 1 is -OH).
  • some of said esters exhibit JmjC-KDM inhibitory activity perse.
  • R 7 is C 1-6 alkyl or C 1-6 haloalkyl.
  • R 8 and R 9 are each hydrogen.
  • R 1 is selected from -OH, -O-C 1-6 alkyl, -O-C 1-6 haloalkyl and -
  • R 1 is -OH.
  • R 2 is selected from hydrogen and fluoro.
  • R 2 is hydrogen
  • R 3 is selected from hydrogen and fluoro.
  • R 3 is hydrogen.
  • R 4 and R 5 are each independently selected from hydrogen, C 1-16 alkyl, C 1-16 haloalkyl, -L 1 -carbocyclyl, -L 1 -aryl, -L 1 -heterocyclyl, -L 1 -heteroaryl, -(C 1-16 alkylene)- OR 10 , -(C 1-16 alkylene)-NR 11 R 12 , -( C 1-16 alkylene)-CONR 13 R 14 , and -CONR 13 R 14 , wherein the carbocyclyl in -L 1 - carbocyclyl, the aryl in -L 1 -aryl, the heterocyclyl in -L 1 -heterocyclyl and the heteroaryl in -L 1 -heteroaryl are each optionally substituted with one or more R 20 .
  • R 4 is selected from hydrogen, C 1-16 alkyl, C 1-16 haloalkyl, -L 1 - carbocyclyl, -L 1 -aryl, -L 1 -heterocyclyl and -(C 1-16 alkylene)-OR 10 , wherein the carbocyclyl in -L 1 -carbocyclyl, the aryl in -L 1 -aryl and the heterocyclyl in -L 1 -heterocyclyl are each optionally substituted with one or more R 20 .
  • R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -L 1 - carbocyclyl and -L 1 -aryl, wherein the carbocyclyl in -L 1 -carbocyclyl and the aryl in -L 1 -aryl are each optionally substituted with one or more R 20 .
  • R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, - C 1-10 alkylene-carbocyclyl and -C 1-10 alkylene-aryl, wherein the carbocyclyl in -C 1-10 alkylene-carbocyclyl and the aryl in -C 1-10 alkylene-aryl are each optionally substituted with one or more R 20 .
  • R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -C 1-10 alkylene-C 3-7 cycloalkyl and -C 1-10 alkylene-phenyl, wherein the C 3-7 cycloalkyl in -C 1-10 alkylene-C 3-7 cycloalkyl and the phenyl in -C 1-10 alkylene-phenyl are each optionally substituted with one or more R 20 .
  • any C 1-10 alkylene in any said -C 1-10 alkylene-C 3-7 cycloalkyl and -C 1-10 alkylene-phenyl groups is independently selected from (CH2)MO, more preferably (CH2K4.
  • R 4 is C 1-16 alkyl. In some embodiments,
  • R 4 is -(CH2)o-i5-CH3. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is n-propyl. In some embodiments, R 4 is n-butyl. In some embodiments, R 4 is n-pentyl. In some embodiments, R 4 is n-hexyl. In some embodiments, R 4 is n-heptyl. In some embodiments, R 4 is n-octyl. In some embodiments, R 4 is n-nonyl. In some embodiments, R 4 is n-decyl.
  • R 4 is C 1-16 haloalkyl. In some embodiments, R 4 is C 1-16 fluoroalkyl. In some embodiments, R 4 is -(CH2)o-i5-CF3. In some embodiments, R 4 is 3,3,3-trifluoropropyl. In some embodiments, R 4 is 4,4,4-trifluorobutyl. In some embodiments, R 4 is 10,10,10- trifluorodecyl. In some embodiments, R 4 is 9-fluorononyl.
  • R 4 is -C 1-10 alkylene-C 3-7 cycloalkyl wherein the C 3-7 cycloalkyl in -C 1-10 alkylene-C 3-7 cycloalkyl is optionally substituted with one or more R 20 .
  • R 4 is -(CH2)MO-C 3-7 cycloalkyl wherein the C 3-7 cycloalkyl in - ⁇ CH 2 )MO-C 3-7 cycloalkyl is optionally substituted with one or more R 20 .
  • R 4 is -(CH2) 1-4 -C 3-7 cycloalkyl wherein the C 3-7 cycloalkyl in -(CH2) 1-4 -C 3-7 cycloalkyl is optionally substituted with one or more R 20 .
  • R 4 is -(CH2) 1-4 -cyclohexyl wherein the cyclohexyl is optionally substituted with one or more R 20 .
  • R 4 is -(CH 2 ) 1-4 -cyclopentyl wherein the cyclopentyl is optionally substituted with one or more R 20 .
  • R 4 is -(CH2) 1-4 -cyclobutyl wherein the cyclobutyl is optionally substituted with one or more R 20 .
  • R 4 is -(CH2) 1-4 -cyclopropyl wherein the cyclopropyl is optionally substituted with one or more R 20 .
  • said optional substituent(s) R 20 in any of said cycloalkyl rings is(are) selected from fluoro and methyl.
  • said cycloalkyl ring has no optional substituent R 20 .
  • R 4 is -(CH2) 1-4 -cyclohexyi.
  • R 4 is -(Chbju- cyclopentyl. In some embodiments, R 4 is -(CH 2 ) 1-4 -cyclobutyl. In some embodiments, R 4 is -(CH 2 ) 1-4 - cyclopropyl.
  • R 4 is C 1-10 alkylene-phenyl, wherein the phenyl in - C 1-10 alkylene-phenyl is optionally substituted with one or more R 20 .
  • R 4 is - (CH2) 1-10 -phenyl wherein the phenyl in - ⁇ CH2) 1-10 -phenyl is optionally substituted with one or more R 20 .
  • R 4 is -(Chbju-phenyl wherein the phenyl in -(CH2) 1-4 -phenyl is optionally substituted with one or more R 20 .
  • R 4 is -(Chbju-phenyl wherein the phenyl in -(Chbju-phenyl is optionally substituted with one or more halo (e.g. fluoro or chloro). In some embodiments, R 4 is - ⁇ Chbju-phenyl, preferably -CHfeCFVphenyl.
  • R 4 is selected from C 1-16 alkyl, -(CH 2 ) 1- 4-C 3-7 cycloalkyl wherein the C 3-7 cycloalkyl in -(CH 2 ) 1-4 -C 3-7 cycloalkyl is optionally substituted with one or more groups selected from halo and methyl, and -(CH2) 1-4 -phenyl wherein the phenyl in -(CH 2 ) 1-4 -phenyl is optionally substituted with one or more R 20 , wherein preferably said optional substituent(s) R 20 in said phenyl ring is (are) independently selected from halo.
  • R 4 is selected from n-butyl, -CH2- cyclohexyl and -CH 2 CH2-phenyl.
  • R 4 is n-butyl
  • R 4 is -CHb-cyclohexyl.
  • R 4 is -ChbChb-phenyl.
  • R 5 is selected from hydrogen, C 1-16 alkyl, C 1-16 haloalkyl, -( C 1-16 alkylene)-NR 11 R 12 , -L 1 -carbocyclyl and -L 1 -aryl, wherein the carbocyclyl in -L 1 -carbocyclyl and the aryl in -L 1 -aryl are each optionally substituted with one or more R 20 .
  • R 5 is selected from hydrogen, C 1-16 alkyl and -( C 1-16 alkylene)-NR 11 R 12 .
  • R 5 is hydrogen
  • L 1 is C 1-10 alkylene.
  • R 6 is selected from hydrogen, C 1-10 alkyl, C 1-10 haloalkyl, -L 2 -aryl, -L ⁇ heterocyclyl, -lAheteroaryl, -(C 1-10 alkylene)-NR 22 R 23 , -(C 1-10 alkylene)-NR 2 6COR 27 , -(C 1-10 alkylene)-NR 26 CONR 2B R 29 , and -( C 1-10 alkylene)-NR 26 SO 2 R 30 1 wherein the aryl in -L ⁇ aryl, the heterocyclyl in -L 2 - heterocyclyl and the heteroaryl in -lAheteroaryl are each optionally substituted with one or more R 31 .
  • R 6 is selected from hydrogen, C 1-10 alkyl, -L 2 - aryl, -lAheterocyclyl, -lAheteroaryl, -(C 1-10 alkylene)-NR 22 R 23 , -(C 1-10 alkyleneJ-NR ⁇ COR ⁇ and -(C 1-10 alkylene)- NR ⁇ CONR ⁇ R 29 , wherein the aryl in the C 1-10 alkylene-aryl, the heterocyclyl in -L 2 -heterocyclyl and the heteroaryl in -L ⁇ heteroaryl are each optionally substituted with one or more R 31 .
  • R 6 is hydrogen
  • R 6 is selected from the group consisting of:
  • each R 20 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, -NR 45 R 46 , -CN, -COR 47 , -NR 5 °COR 47 , -NR 50 SO 2 R 51 , -L 5 - carbocyclyl, -L 5 -aryl, -lAheterocyclyl and -L 5 -heteroaryl, wherein the carbocyclyl in -L 5 -carbocyclyl, the aryl in - lAaryl, the heterocyclyl in -L 5 -heterocyclyl and the heteroaryl in -lAheteroaryl are each optionally substituted with one or more R 39 .
  • each R 31 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, -NR «R « -CN, -COR 47 , -NR ⁇ COR 47 and -NR 60 SO 2 R 61 .
  • each R 39 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, -NR «R* -CN, -COR 47 , -NR 50 COR 47 and -NR 5 °S0 2 R 51 .
  • a preferred embodiment relates to a compound of Formula (I), or a salt thereof, wherein:
  • R 1 is -OH; is selected from a group of formula (i), (ii), (iv) and (v);
  • R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -L 1 -carbocyclyl and -L 1 -aryl, wherein the carbocyclyl in - L 1 -carbocyclyl and the aryl in -L 1 -aryl are each optionally substituted with one or more R 20 .
  • R 5 is hydrogen.
  • R 6 is hydrogen.
  • R 5 and R 6 are hydrogen.
  • Another preferred embodiment relates to a compound of Formula (I), or a salt thereof, wherein:
  • RMs -OH is selected from a group of formula (i), (ii), (iv) and (v); and R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -C 1-10 alkylene-carbocyclyl and -C 1-10 alkylene-aryl, wherein the carbocyclyl in -C 1-10 alkylene-carbocyclyl and the aryl in -C 1-10 alkylene-aryl are each optionally substituted with one or more R 20 .
  • R 5 is hydrogen.
  • R 6 is hydrogen.
  • R 5 and R 6 are hydrogen.
  • Another preferred embodiment relates to a compound of Formula (I), or a salt thereof, wherein:
  • R 1 is -OH; is selected from a group of formula (i), (ii), (iv) and (v);
  • R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -C 1-10 alkylene-C 3-7 cycloalkyl and -C 1-10 alkylene-phenyl, wherein the C 3-7 cycloalkyl in -C 1-10 alkylene-C 3-7 cycloalkyl and the phenyl in -C 1-10 alkylene-phenyl are each optionally substituted with one or more R 20 ; wherein preferably, any C 1-10 alkylene in any said -C 1-10 alkylene- C 3-7 cycloalkyl and -C 1-10 alkylene-phenyl groups is independently selected from (CH2)MO, more preferably (CH2) 1-4 .
  • R 5 is hydrogen.
  • R 6 is hydrogen.
  • R 5 and R 6 are hydrogen.
  • Another preferred embodiment relates to a compound of Formula (II), or a salt thereof, wherein: R 1 is -OH; and
  • R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -L 1 -carbocyclyl and -L 1 -aryl, wherein the carbocyclyl in - L 1 -carbocyclyl and the aryl in -L 1 -aryl are each optionally substituted with one or more R 20 .
  • R 5 is hydrogen.
  • R 6 is hydrogen.
  • R 5 and R 6 are hydrogen.
  • Another preferred embodiment relates to a compound of Formula (II), or a salt thereof, wherein:
  • R 1 is -OH
  • R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -C 1-10 alkylene-carbocyclyl and -C 1-10 alkylene-aryl, wherein the carbocyclyl in -C 1-10 alkylene-carbocyclyl and the aryl in -C 1-10 alkylene-aryl are each optionally substituted with one or more R 20 .
  • R 5 is hydrogen.
  • R 6 is hydrogen.
  • R 5 and R 6 are hydrogen.
  • Another preferred embodiment relates to a compound of Formula (II), or a salt thereof, wherein:
  • R 1 is -OH
  • R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -C 1-10 alkylene-C 3-7 cycloalkyl and -C 1-10 alkylene-phenyl, wherein the C 3-7 cycloalkyl in -C 1-10 alkylene-C 3-7 cycloalkyl and the phenyl in -C 1-10 alkylene-phenyl are each optionally substituted with one or more R 20 ; wherein preferably, any C 1-10 alkylene in any said -C 1-10 alkylene-C3- 7 cycloalkyl and -C 1-10 alkylene-phenyl groups is independently selected from (CH2)MO, more preferably (CH 2 )i- 4.
  • R 5 is hydrogen.
  • R 6 is hydrogen.
  • R 5 and R 6 are hydrogen.
  • R 1 is -OH; and R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -L 1 -carbocyclyl and -L 1 -aryl, wherein the carbocyclyl in - U-carbocyclyl and the aryl in -L 1 -aryl are each optionally substituted with one or more R 20 .
  • R 5 is hydrogen.
  • R 6 is hydrogen.
  • R 5 and R 6 are hydrogen.
  • Another preferred embodiment relates to a compound of Formula (la), or a salt thereof, wherein:
  • R 1 is -OH
  • R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -C 1-10 alkylene-carbocyclyl and -C 1-10 alkylene-aryl, wherein the carbocyclyl in -C 1-10 alkylene-carbocyclyl and the aryl in -C 1-10 alkylene-aryl are each optionally substituted with one or more R 20 .
  • R s is hydrogen.
  • R 6 is hydrogen.
  • R 5 and R 6 are hydrogen.
  • Another preferred embodiment relates to a compound of Formula (la), or a salt thereof, wherein:
  • R 1 is -OH
  • R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -C 1-10 alkylene-C 3-7 cycloalkyl and -C 1-10 alkylene-phenyl, wherein the C 3-7 cycloalkyl in -C 1-10 alkylene-C 3-7 cycloalkyl and the phenyl in -C 1-10 alkylene-phenyl are each optionally substituted with one or more R 20 ; wherein preferably, any C 1-10 alkylene in any said -C 1-10 alkylene-C3- 7 cycloalkyl and -C 1-10 alkylene-phenyl groups is independently selected from (CH2)MO, more preferably (CH2)i- 4.
  • R 5 is hydrogen.
  • R 6 is hydrogen.
  • R 5 and R 6 are hydrogen.
  • Another preferred embodiment relates to a compound of Formula (lb), or a salt thereof, wherein: R 1 is -OH; and
  • R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -L 1 -carbocyclyl and -L 1 -aryl, wherein the carbocyclyl in - L 1 -carbocyclyl and the aryl in -L 1 -aryl are each optionally substituted with one or more R 20 .
  • R 6 is hydrogen.
  • Another preferred embodiment relates to a compound of Formula (lb), or a salt thereof, wherein: R 1 is -OH; and
  • R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -C 1-10 alkylene-carbocyclyl and -C 1-10 alkylene-aryl, wherein the carbocyclyl in -C 1-10 alkylene-carbocyclyl and the aryl in -C 1-10 alkylene-aryl are each optionally substituted with one or more R 20 .
  • R 6 is hydrogen.
  • Another preferred embodiment relates to a compound of Formula (lb), or a salt thereof, wherein: R 1 is -OH; and
  • R 4 is selected from C 1-16 alkyl, C 1-16 haloalkyl, -C 1-10 alkylene-C 3-7 cycloalkyl and -C 1-10 alkylene-phenyl, wherein the C 3-7 cycloalkyl in -C 1-10 alkylene-C 3-7 cycloalkyl and the phenyl in -C 1-10 alkylene-phenyl are each optionally substituted with one or more R 20 ; wherein preferably, any C 1-10 alkylene in any said -C 1-10 alkylene-C3- 7 cycloalkyl and -C 1-10 alkylene-phenyl groups is independently selected from (CH2K10, more preferably (CH2)i- 4. In certain embodiments, R 6 is hydrogen.
  • R 2 and R 3 are hydrogen.
  • the invention provides a compound of Formula (I), or a salt thereof, selected from the compounds listed in Table 1 below, or salts thereof.
  • the compound is selected among the compounds in Table 1 wherein R 1 is -OH, or a salt thereof.
  • the invention provides a compound of Formula (I), or a salt thereof, selected from the compounds listed below, or salts thereof:
  • Methyl 2-(3-butyl-1-(pyrrolidin-3-yl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate Methyl 2-(1-(azetidin-3-yl)-3-butyl-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate, Methyl 2-(1 -propyl-3-(1 H-pyrazol-4-yl)-1 H-pyTOlo[2,3-c]pyridin-5-yl)isonicotinate, Methyl 2-(3-butyl-1 -(pi perid in-4-y I)- 1 H-pyrolo[3,2-c]pyridin-6-yl)i ⁇ ni ⁇ tinate, Methyl 2-(1-(azetidin-3-ylmethyl)-3-butyl-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate
  • Methyl 2-(3-chloro-1 -phenethyl-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate Methyl 2-(1 -butyl-2-(piperidin-1 -ylmethyl)-1 H-pyrolo[2,3-c]pyridin-5-yl)isonicotinate, Methyl 2-(1-butyl-2-(piperidine-1-cart>onyl)-1H-pyrrofo[2,3-c]pyridin-5-yl)isonicotinate, Methyl 2-( 1 -buty l-2-(d iethy lcarbamoyl)- 1 H-pyrTolo[2,3-c]pyridin-5-yl)isonicotinate, Methyl 2-(2-(diethylcarbamoyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
  • the compound is selected among the compounds listed above wherein R 1 is -OH, or a salt thereof.
  • the invention provides a compound of Formula (I), or a salt thereof, selected from the compounds in Table 2 below, or salts thereof:
  • the invention provides a compound of Formula (I), or a salt thereof, selected from:
  • aryl, heteroaryl, carbocyclyl and heterocyclyl groups are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency.
  • pyridyl (or pyridinyl) may refer to a pyridin-2- yl, pyridin-3-yl or pyridin-4-yl ring
  • piperidinyl may refer to a piperidin-1-yl, piperidin-2-yl, piperidin-3-yl or piperidin-4-yl ring.
  • n-membered where n is an integer describes the number of ring-forming atoms in a ring system where the number of ring-forming atoms is n.
  • phenyl is an example of a 6-membered aryl
  • cyclopropyl is an example of a 3-membered carbocyclyl
  • pyrazolyl is an example of a 5-membered heteroaryl
  • quinolinyl is an example of a 10-membered heteroaryl
  • piperidinyl is an example of a 6-membered heterocyclyl
  • decahydroquinolinyl is an example of a 10-membered heterocyclyl.
  • C y-z where y and z are integers, used in combination with a chemical group, designates a range of the number of carbon atoms in the chemical group, with y and z being the endpoints, which are included. Examples include C 1-16 , C 2-16 , C 1-6 , C 3-7 and the like.
  • C y-z alkyl refers to a saturated straight or branched acyclic hydrocarbon group having y to z carbon atoms.
  • a C 1-16 alkyl is an alkyl having from one to sixteen carbon atoms.
  • C 1-16 alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,n- tridecyl, n-tetradecyl, n-pentadecyl, and n-hexadecyl.
  • a C 1-6 alkyl is an alkyl having from one to six carbon atoms.
  • Examples of C 1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, or sec-hexyl.
  • C y-z alkenyl refers to a straight or branched acyclic hydrocarbon group having y to z carbon atoms and containing one or more double bonds.
  • a C 2-6 alkenyl is an alkenyl having from two to six carbon atoms.
  • C y-z alkynyl refers to a straight or branched acyclic hydrocarbon group having y to z carbon atoms and containing one or more triple bonds.
  • a C 2-6 alkynyl is an alkynyl having from two to six carbon atoms.
  • C y-z alkoxy refers to an C y-z alkyl group (as defined above) covalently linked to an oxygen atom, i.e. a group of formula -O-alkyl where the alkyl group has y to z carbon atoms.
  • the term C 1-6 alkoxy thus refers to an alkoxy group wherein the alkyl moiety has from 1 to 6 carbon atoms. Examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert- butoxy, n-pentoxy or n-hexyloxy.
  • C y-z alkylene refers to a saturated straight or branched divalent acyclic hydrocarbon group having from y to z carbon atoms.
  • a C 1-16 alkylene is an alkylene having from one to sixteen carbon atoms
  • a C 1-10 alkylene is an alkylene having from one to ten carbon atoms
  • a C 1-6 alkylene is an alkylene having from one to six carbon atoms.
  • said akylene groups are polymethylene groups, i.e. (CH2)x, where x indicates the number of CH2 units in the respective alkylene group, like from 1 to 16, from 1 to 10 or from 1 to 6. Examples include, but are not limited to, methylene, ethylene, propylene, n-butylene, n- pentylene or n-hexylene.
  • C y-z alkenylene refers to a saturated straight or branched divalent acyclic hydrocarbon group having from y to z carbon atoms and containing one or more double bonds.
  • a C 2-16 alkenylene is an alkenylene having from two to sixteen carbon atoms
  • a C2-10 alkenylene is an alkenylene having from two to ten carbon atoms.
  • aryl refers to a 6- to 18-membered hydrocarbon ring system which contains only hydrogen and carbon atoms and which is monocyclic or multicyclic (e.g. fused, bridged or spiro rings), wherein at least one of the rings in the ring system is aromatic.
  • Aryl as used herein thus covers fully aromatic hydrocarbon ring systems, i.e. where all the ring(s) in the system are aromatic, like phenyl, naphthyl or anthracyl, as well as ring systems in which an aromatic hydrocarbon ring (e.g.
  • phenyl is fused to one or more non-aromatic hydrocarbon rings, like indanyl, indenyl, 1-oxo-2,3-dihydro-1H-indenyl, tetrahydronaphthyl, fluorenyl and the like.
  • the point of attachment is on the aromatic hydrocarbon ring.
  • the aryl group has from 6 to 10 carbon atoms.
  • the aryl group is a fully aromatic hydrocarbon ring system.
  • the aryl group is phenyl.
  • Aryl groups can be optionally substituted, as indicated elsewhere in the specification, and the substituent(s) may be placed at any available position in the ring system.
  • bond refers to a single bond
  • carbocyclyl refers to a 3- to 18-membered non-aromatic hydrocarbon ring system which contains only hydrogen and carbon atoms and which is monocyclic or multicyclic (e.g. fused, bridged or spiro rings). Each of the rings in the ring system is partially or fully saturated, i.e. none of the rings is aromatic. One or more ring-forming carbon atoms of a carbocyclyl group can be oxidized to give an oxo group. In some embodiments, carbocyclyl contains from 3 to 10 carbon atoms. In some embodiments, carbocyclyl is a fully saturated hydrocarbon ring system, i.e.
  • carbocyclyl is also referred herein as "cycloalkyl".
  • carbocyclyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, bicyclo[2.2.1]heptanyl, bicy clo [2.2.2]octany I , decalinyl, and the like.
  • carbocyclyl is C 3-7 cycloalkyl.
  • Carbocyclyl groups can be optionally substituted, as indicated elsewhere in the specification, and the substituent(s) may be placed at any available position in the ring system.
  • C 3-7 cycloalkyl refers to a monocyclic cycloalkyl having from 3 to 7 ring-forming carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups can be optionally substituted, as indicated elsewhere in the specification, and the substituent(s) may be placed at any available position in the ring system.
  • Halo or halogen refers to bromo, chloro, fluoro or iodo. Preferably, halo is fluoro.
  • C y-z haloalkyl refers to an alkyl group having from y to z carbon atoms as defined herein which is substituted one or more times with one or more halo, which can be the same or different. Accordingly, a C 1-16 haloalkyl is a C 1-16 alkyl which is substituted one or more times with one or more halo, and a C 1-6 haloalkyl is a C 1-6 alkyl which is substituted one or more times with one or more halo.
  • Haloalkyl groups include perhaloalkyl groups, i.e. alkyl groups where all hydrogen atoms are replaced by halo.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1-fluoro- 2-fluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 4,4,4-trifluorobutyl chloromethyl, dichloromethyl, trichloromethyl difluorochloromethyl, dichlorofluoromethyl, 1,2-dichloroethyl, 3,3-dichloropropyl and the like.
  • the haloalkyl is a fluoroalkyl, i.e. an alkyl group which is substituted one or more times with one or more fluoro.
  • C y-z haloalkenyl refers to an alkenyl group having from y to z carbon atoms as defined herein which is substituted one or more times with one or more halo, which can be the same or different. Accordingly, a C 2-6 haloalkenyl is a C 2-6 alkenyl which is substituted one or more times with one or more halo.
  • C y-z haloalkoxy refers to an haloalkyl group having y to z carbon atoms as defined herein covalently linked to an oxygen atom, i.e. a group of formula -0-C y-z haloalkyl.
  • a C 1-6 haloalkoxy group thus refers to a haloalkoxy group wherein the haloalkyl moiety has from 1 to 6 C atoms.
  • Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2-fluoroethoxy, pentafluoroethoxy, 3-chloropropoxy, 3- fluoropropoxy, heptafluoropropoxy, and the like.
  • heteroaryl refers to a 5- to 18-membered heterocyclic ring system which is monocyclic or multicyclic (e.g. fused, bridged or spiro rings) and which comprises, in addition to C atoms, from 1 to 6 heteroatoms independently selected from N, 0 and S, wherein at least one of the rings in the ring system is aromatic and contains at least one of the heteroatoms.
  • Heteroaryl as used herein thus covers fully aromatic ring systems, i.e.
  • ring(s) in the system are aromatic, like imidazolyl, pyridyl, quinolyl, pyrido[2,3- d]pyrimidinyl and the like, and groups in which an heteroaromatic ring(s) is fused to one or more non-aromatic carbocyclic or heterocyclic rings, such as 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydro-1,8-naphthyridine and the like.
  • the heteroatom(s) in the heteroaryl is optionally oxidized.
  • the heteroaryl comprises a heteroaromatic ring fused to one or more non-aromatic carbocyclic or heterocyclic rings
  • one or more ring- forming carbon atoms in the non-aromatic carbocyclic or heterocyclic ring can be oxidized to give an oxo group.
  • the heteroaryl group can be attached to the rest of the molecule through any C or N atom that results in a stable structure. In some embodiments, the point of attachment is on the heteroaromatic ring.
  • the heteroaryl group has from 1 to 4 heteroatoms. In some embodiments, the heteroaryl group has from 1 to 3 heteroatoms.
  • the heteroaryl is 5- to 6-membered monocyclic or 9- to 10- membered bicyclic. In some embodiments, the heteroaryl is 5- to 6-membered monocyclic. In some embodiments, the heteroaryl group is fully aromatic.
  • heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazine, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, phthalazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, cinnolinyl, indazolyl, indolizinyl, isoindolyl, pteridinyl, purinyl, fur
  • heterocyclyl refers to a 3- to 18-membered partially or fully saturated heterocyclic ring system which is monocyclic or multicyclic (e.g. fused, bridged or spiro rings) which comprises, in addition to C atoms, from 1 to 6 heteroatoms independently selected from N, 0 and S.
  • Heterocyclyl as used herein also includes groups in which a partially or fully saturated heterocyclic ring is fused to one or more phenyl rings, as in 1 ,2,3,4- tetrahydroquinolinyl, benzodioxolyl, carbazolyl or phthalimidyl.
  • the heterocycyl can be attached to the rest of the molecule through any C or N atom that results in a stable structure.
  • the heterocyclyl is 3- to 7-membered monocyclic.
  • heterocyclyl groups include, but are not limited to, pyrrolidinyl, 2- oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, homopiperidinyl, oxepanyl, thiepanyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,
  • substitution means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a monovalent substitutent. It is to be understood that substitution at a given atom is limited by valency. Unless defined otherwise (or limited by valency), a group that is optionally substituted with "one or more" substituents may be unsubstituted or may, for example, carry one, two or three (particularly one or two) substituents.
  • oxo refers to a carbonyl group
  • partially saturated refers to a ring moiety that includes at least one double bond.
  • partially saturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl groups, as herein defined.
  • a wavy line in chemical drawings indicates the point of attachment to the remainder of the molecule.
  • each variable can be a different moiety independently selected from the group defining the variable.
  • the two R groups can represent different moieties independently selected from the group defined for said R.
  • the compounds of the invention may contain one or more asymmetric centers and may thus give rise to stereoisomers. All stereoisomers, such as enantiomers, diastereoisomers and mixtures thereof, are intended unless otherwise indicated.
  • Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active form or racemic mixtures. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, and include for example by resolution of racemic mixtures or by stereoselective synthesis.
  • the compounds of the invention may, in certain embodiments, exist as geometric or conformational isomers. It should be understood that when compounds have geometric or conformational forms (for example Z and E double bond isomers, Z and E conformational isomers), all geometric or conformational forms thereof are intended to be included in the scope of the present invention.
  • tautomers refers to a molecule wherein a proton shift from one atom to another atom of the same molecule is possible. Examples include ketone-enol pairs and annular forms where a proton can occupy two or more positions of a heterocyclic system as for example in 1H- and 3H-imidazole. Tautomeric forms can be in equilibrium or stericaily locked into one form by appropriate substitution.
  • Compounds of the invention include unlabeled forms as well as isotopically labeled forms thereof.
  • Isotopically labeled forms of the compounds are compounds that differ only in the replacement of one or more atoms by a corresponding isotopically enriched atom.
  • isotopes that can be incorporated into compounds of the invention include for example isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F, 36 CI, and 12 s
  • Such isotopically labelled compounds are useful for example as probes in biological assays, as analytical tools, or as therapeutic agents.
  • Polymorphs or “crystal forms” refers to crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, Raman spectra, melting points, differential scanning calorimetry (DSC) spectra, crystal shape, solubility and/or stability, among others. When compounds of the invention exist in different crystal forms, all forms thereof, including amorphous forms and crystal forms, are intended to be included in the scope of the present invention.
  • compound of the invention is meant to include a compound of Formula (I) (including each and every subgenus of a compound of Formula (I) as described herein and in the claims as well as the compounds described in the Examples), including all stereoisomers, tautomers, isotopically labeled forms and polymorphs thereof.
  • the present invention also includes salts of the compounds of the invention.
  • said salts are pharmaceutically acceptable salts.
  • a "pharmaceutically acceptable salt” is intended to mean a salt that retains the biological effectiveness and properties of the parent compound (i.e. the free acid or free base, as applicable) and that is not biologically or otherwise undesirable.
  • Pharmaceutically acceptable salts include salts formed with inorganic or organic bases, and salts formed with inorganic and organic acids. Pharmaceutically acceptable salts are well known in the art.
  • Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, such as hydrochlorides, hydrobromides, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, nitrates, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4 dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine and the like.
  • the pharmaceutically acceptable salts of the present invention can be prepared from the parent compound which contains a basic or acidic moiety by conventional chemical methods. For example, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in a suitable solvent.
  • compounds of the present invention may exist in hydrated or unhydrated (anhydrous) form or as solvates with other solvent molecules.
  • “Solvate” as used herein means solvent addition forms that contain either stoichometric or non-stoichometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate.
  • Non-limiting examples of solvates include hydrates and solvates with alcohols (also named alcoholates) such as ethanol (ethanolates).
  • solvates thereof are intended to be included in the scope of the present invention, particularly pharmaceutically acceptable solvates.
  • a "pharmaceutically acceptable solvate” is a solvate formed with a pharmaceutically acceptable solvent.
  • Pharmaceutically acceptable solvents are well known in the art and include solvents such as water and ethanol.
  • R 1 , R 2 , R 3 and heterocycle A have the same meaning described for a compound of Formula (I), Z is COORa or CN, R a is Ci-e alkyl or aryl-C 1-4 alkyl, preferably methyl, ethyl or benzyl, and M and X have the meaning defined below.
  • the first step involves a cross-coupling reaction of a heteroaryl organometallic species with a heteroaryl halide.
  • Organometallic intermediates can be generated either on the pyridine bearing the COOR a or CN substituent (i.e. a compound of Formula (Ilia) or (lllb)), or in the heteroaryl A (i.e. a compound of Formula (VI)).
  • the second step involves the transformation of the ester or cyano derivative (Vila) or (VI lb) into compounds of Formula (I).
  • cross-coupling reactions can be used for the first step in Scheme 1, including: a Suzuki cross coupling where M is a boronic acid or boron derivative and X is CI, Br or I; a Stille reaction where M is trialkylstannanyl group and X is CI, Br or I; a Negishi coupling where M is a zinc halide and X is triflate, CI, Br or I; and a Hiyama coupling where M is a trialkylsilyl group and X is CI, Br or I.
  • the reaction can be performed using a suitable Pd/ligand combination such as XPhos and Pd2(dba)3,Pd(dppf)2Cl2.DCM or Pd(PPh3) , 1, in a suitable solvent such as toluene or 1-4 dioxane, using a suitable base such as sodium carbonate.
  • a suitable Pd/ligand combination such as XPhos and Pd2(dba)3,Pd(dppf)2Cl2.DCM or Pd(PPh3)
  • a suitable solvent such as toluene or 1-4 dioxane
  • a suitable base such as sodium carbonate.
  • the temperature of the reaction typically can go from room temperature to 120°C and the time of reaction typically from 1h to 48h.
  • boronic derivatives include among others diethyl, dimethyl, pinacol derivative, N-methyliminodiacetic acid (MIDA) derivative and 2,2'- (phenylazanediyl)bis(ethan-l -ol) derivative.
  • the reaction can be performed using a suitable Pd/ligand combination such as Pd(PPh3k Pd(PPh 3 )CI 2 or Pd(dppb)CI 2 in the presence of a suitable Cu salt such as Cul or CuO, in the presence or absence of CsF, in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • a suitable Cu salt such as Cul or CuO
  • CsF tetrahydrofuran, dioxane or dimethylformamide
  • the temperature of the reaction can typically go from room temperature to 120°C and the time of reaction typically from 1h to 48h.
  • the organotin employed can be for example a trimethylstannyl derivative.
  • An intermolecular Stille Kelly reaction can also be used, in which both reagents are haloheteroaryls and are treated with (Bu 3 Sn) 2 , EUNI, and a Pd/ligand combination.
  • the reaction can be performed using a suitable Pd/ligand combination such as PPfi3 and Pd2(dba)3 , XPhos and Pd2(dba)3 , RuPhos and Pd2(dba)s or Pd(PPh 3 )4, in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • a suitable Pd/ligand combination such as PPfi3 and Pd2(dba)3 , XPhos and Pd2(dba)3 , RuPhos and Pd2(dba)s or Pd(PPh 3 )4, in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • the temperature of the reaction can typically go from room temperature to 120°C and the time of reaction typically from 1h to 48h.
  • the reaction can be performed using a suitable Pd/ligand combination such as PdCl2(PPfi3)2 and PPti3 or Pd(OAc)2 and di(1-adamantyl)-n-butylphosphine in the presence of a suitable Cu salt such as Cul or CuBr, in the presence or absence of tetrabutylammonium fluoride in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • a suitable Pd/ligand combination such as PdCl2(PPfi3)2 and PPti3 or Pd(OAc)2 and di(1-adamantyl)-n-butylphosphine
  • a suitable Cu salt such as Cul or CuBr
  • tetrabutylammonium fluoride in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • the temperature of the reaction can typically go from
  • Compounds of Formula (I) can also be prepared in three steps through a direct arylation of a compound of Formula (Villa) or (Vlllb) with halo derivative of Formula (IV) followed by reduction of the resulting N-oxide of Formula (IXa) or (IXb) and subsequent transformation of the ester or cyano derivative (Vila) or (VI lb) into compounds of Formula (I), as outlined in Scheme 2.
  • R 1 , R 2 , R 3 and heterocycle A have the same meaning described for compound of Formula (I), Z is COORa or CN, R a is Ci-s alkyl or aryl-Cualkyl, preferably methyl, ethyl or benzyl, and X is CI or Br.
  • the reaction of (Villa) or (Vlllb) with (IV) can be performed using a suitable Pd/ligand combination such as P'Bu3 and Pd(OAc)2 or PBU3-HBF4 and Pd(OAc)2, in the presence of a suitable base such as potassium carbonate, in a suitable solvent such as toluene.
  • a suitable base such as potassium carbonate
  • the temperature of the reaction can typically go from room temperature to 120°C and the time of reaction typically from 1h to 48h.
  • the resulting N-oxide (IXa) and (IXb) can easily be reduced to compound (Vila) and (Vllb) with hydrogen or sodium borohydride using palladium on charcoal as a catalyst.
  • compounds (Vila) can be hydrolyzed to compounds of Formula (I) in which R 1 is OH by treatment with a base such as LiOH, NaOH, KOH or MesSiOK in a mixture of water and a solvent miscible with water such as dioxane, THF, MeOH, EtOH, typically between 0°C and room temperature for 1 to 3 days.
  • a base such as LiOH, NaOH, KOH or MesSiOK
  • a solvent miscible with water such as dioxane, THF, MeOH, EtOH, typically between 0°C and room temperature for 1 to 3 days.
  • Compounds (Vila) can be also hydrolyzed by treatment with an acid such as HCI, H2SO4 in water optionally mixed with water miscible solvents such as dioxane, THF, MeOH, EtOH, typically between 0°C and room temperature for 1 to 3 days.
  • Suitable activating agents are among others: dicyclohexyl carbodiimide (DCC), 1- hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 1-ethyl-3-(3'-dimethylamino)carbodiimide (EDC), diisopropyl carbodiimide (DIC), carbonyl diimidazole (CDI), Benzotriazol-l-yl-oxytris-(dimethylamino)- phosphonium hexafluorophosphate (BOP), Benzotriazol-1-yl-oxytris-pyrrolidinophosphonium hexafluorophosphate (PyBop), O-ilHbenzotriazol-l-yO-N.N.N'.N'-tetramethyluronium hexafluorophosphate(HBTU), 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-tria
  • the reaction can be carried out in the presence of a base, such as disopropylethylamine, pyridine, thriethylamine, or N-methylmorpholine , in a suitable solvent, such as dimethoxyethane, N,A/-dimethylformamide, tetrahydrofuran, dichloromethane or dioxane.
  • a base such as disopropylethylamine, pyridine, thriethylamine, or N-methylmorpholine
  • a suitable solvent such as dimethoxyethane, N,A/-dimethylformamide, tetrahydrofuran, dichloromethane or dioxane.
  • carboxylic acids are activated as mixed anhydrides or acid chlorides and then coupled with NHR 8 R 9 or R 7 OH in the presence of a suitable base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine or the like.
  • R 4 , R 5 , R 6 have the same meaning described for compound of Formula I, R 4' , R 5' , R 6' have the same meaning described for R 4 R 5 , R 6 except H and X is CI , Br or I.
  • substituents R 4' , R 5 ', or R 6' on the NH of haloheterocycles of Formula (IV-A-F) to give (IV-G-P) can be performed by reaction of the corresponding heterocyclic NH with a suitable alkylating agent (e.g. halides, triflates or sulphonyl clorides) in the presence of a base such us sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, cesium carbonate or potassium carbonate, in a solvent as for example DMSO, DMF, DMA, dioxane, tetrahydrofurane or pyridine.
  • a suitable alkylating agent e.g. halides, triflates or sulphonyl clorides
  • a base such us sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium
  • Temperature can typically be varied from room temperature to 100°C.
  • the reagent is an aryl halide
  • Cu catalysis can be added (Ullmann reaction conditions).
  • the introduction of substituents R 4' , R 5' , or R 6' on the NH of haloheterocycles of Formula (I -A-F) to give (IV-G-P) can be also performed by reaction of a boronic acid or ester in the presence of copper(ll) diacetate and oxygen under Cham-Lam conditions.
  • triazolopyridine derivative (IV-F) in addition to the conditions previously described, Mitsunobu reaction and addition to unsaturated systems can also be used.
  • substituents R 4' , R 5' , or R 6' on the NH of haloheterocycles of Formula (IV-A-F) to give (IV-G-P) can be performed by reaction of the corresponding hetrocyclic NH with a suitable acylating agent, such us car oxylic acids activated as mixed anhydrides or acid chlorides in the presence of a suitable base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine or the like.
  • a suitable acylating agent such us car oxylic acids activated as mixed anhydrides or acid chlorides in the presence of a suitable base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine or the like.
  • the compounds of Formula IV-A, IV-B, IV-C and -IV-D can be obtained through the introduction of substituents R 4' R 5' and R 5' on the corresponding C atom of an unsubstituted haloheterocycle.
  • substituents R 4' R 5' and R 5' can be built through acylation of the electrophilic 5-ring with acyl halides using AlC as catalysis in DCM, optionally followed by reduction of carbonyl group with sodium boro ydride in IPA.
  • these C-C bonds can be formed by reaction with ketones and powder KOH in MeOH, optionally followed by reduction of double bond with H 2 gas and Pd catalysis.
  • Other versatile methods to introduce substituents R 4 ' R 5' and R 6' on the C atom of 5-ring of the haloheterocycle is through a first step of haiogenation followed by Suzuki coupling of the corresponding boronic derivative.
  • Said transformations include, for example: the substitution of a primary or secondary amine by treatment with an alkylating agent under standard conditions, or by reductive amination, i.e. by treatment with an aldehyde or a ketone in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride; the conversion of an amine into a sulfonamide by reaction with a sulfonyl halide, such as sulfonyl chloride, optionally in the presence of a base such as 4-dimethylaminopyridine, in a suitable solvent such as dioxane, chloroform, dichloromethane or pyridine, optionally in the presence of a base such as triethylamine or pyridine; the conversion of an amine into an amide or urea under standard conditions; the alkylation of an amide by treatment with an alkylating agent under basic conditions; the conversion of an alcohol into an ether under standard conditions;
  • any of the aromatic rings of the compounds of the present invention can undergo electrophilic aromatic substitution reactions or nucleophilic aromatic substitution reactions, widely described in the literature.
  • the salts of a compound of Formula (I) can be obtained during the final isolation and purification of the compounds of the invention or can be prepared by treating a compound of Formula (I) with a sufficient amount of the desired acid (or base) to give the salt in a conventional manner.
  • individual stereoisomers of a compound of Formula (I) can be obtained for example by resolution, starting from a compound of formula (I) obtained as a mixture of stereoisomers, using well known methods such as formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallization and regeneration of the free base, or by chiral preparative chromatography.
  • optically pure or enantiomerically enriched synthetic intermediates which can then be used as such in subsequent steps, at various stages of the synthetic procedures described above, using any known method for chiral resolution.
  • the compounds of the invention inhibit the activity of a histone demethylase comprising a JmjC domain (JmjC-KDM).
  • JmjC-KDM histone demethylase comprising a JmjC domain
  • the compounds of the invention have been found to be potent inhibitors of KDM5.
  • some compounds of the invention have been found to inhibit also KDM4 and/or KDM6.
  • the activity of the compounds of the invention as JmjC-KDM inhibitors can be determined using for example the in vitro assays described in the Examples section.
  • Example 36 describes methods to determine KDM5, KDM4 and KDM6 inhibitory activity.
  • the compounds of the invention have been found to be potent KDM5 inhibitors using the assay described in Example 36.
  • Compounds of the invention have also been shown to inhibit JmjC-KDM activity in cells, as shown by the results described in Example 37.
  • histone demethylase refers to an enzyme that removes at least one methyl group from an amino acid side chain (e.g. a lysine) on histones, like H3 or H4.
  • the first histone lysine demethylase discovered was lysine specific demethylase- 1 (LSD1, also known as KDM1A), which demethylates mono- and di-methylated H3K4, using FAD as a cofactor.
  • KDM1A lysine specific demethylase- 1
  • JmjC-KDMs JmjC-domain containing histone demethylases
  • Fe(l Independent enzymes catalyze the demethylation of mono-, di- and tri-methylated lysines using 2-oxoglutarate and oxygen, converting the methyl group in the methyllysine to a hydroxymethyl group, which is subsequently released as formaldehyde.
  • This family contains over 30 members and includes the KDM2 to KDM8 subfamilies as well as JMJD6.
  • the KDM5 subfamily (also known as JARID1) demethylates H3K4me2/3 at the transcription start site of actively transcribed genes.
  • JARID1 demethylates H3K4me2/3 at the transcription start site of actively transcribed genes.
  • KDM5A cooperates with retinoblastoma protein (RB) and KDM5B to control respectively cellular differentiation (Benevolenskaya E.V. ef a/. 2005, Mol Cell 18(6):623-35) and induction of senescence (Chicas A. et al. 2012, PNAS 109(23):8971-6).
  • the oncogenic role of KDM5A is highlighted by knock out studies showing that KDM5A inactivation reduces tumor formation in Rb+/- and Men-/- mice (Lin W. ef al. 2011, PNAS 108(33): 13379-86) .
  • KDM5A is required for the emergence of chemoresistant clones and its inhibition enhances the sensitivity of prostate cancer cells to cisplatin (Sharma S.V. et al. 2010, Cell 141(1):69-80). Sensitisation to anticancer therapy after KD 5A inhibition has also been described in colon, breast, cancer and Non Small Cell Lung Cancer cell lines (Vinogradova M. et al. 2016, Nature Chem Bio 10.1038/nchembio.2085). KDM5A is amplified in a subset of breast cancer cell lines and shRNA-mediated inhibition moderately reduces viability, colony formation in soft agar and drug resistance (Hou J. et al.
  • KDM5A overexpression is responsible for proliferation in vitro, tumor growth in vivo, migration and invasion of lung cancer cells (Teng Y.C. ef al. 2013, Cancer Res 73(15):4711-21).
  • KDM5A has been also described as amplified in prostate cancer (Vieira F.Q. et al. 2013, Endocr Relat Cancer 21(1):51-61), Head and Neck Squamous Carcinoma cell lines (Li H. et al. 2014, Mol Cancer Res 12(4):571-82), temozolomide-resistant glioblastomas (Bannelli B. ef al.
  • KDM5A was found highly expressed in neuroendocrine tumors and it was described to promote a neoplastic phenotype in this tumor subtype (Maggi E.C. et al. 20 6, Oncogenesis 5(8):e257).Translocations involving the human KDM5A and NUP98 gene have also been described in pediatric acute megakaryoblastic leukemias (de Rooij J.D. ef al. 2013, Leukemia 27(12):2280-8).
  • KDM5B-mediated histone demethylation is required for inhibiting the expression of E2F target genes during induction of senescence in murine and human embryonal fibroblasts (Chicas A. ef al. 2012, PNAS 109(23):8971-6).
  • KDM5B represses CDKN1A expression, effectively promoting oncogenic transformation (Wong P.P. et al. 2012, Mol Cell Biol 32(9): 1633-44).
  • Genetic inhibition of KDM5B is able to reduce proliferation, epithelial-mesenchymal transition (EMT), migration and invasion in models of hepatocellular carcinoma (Wang D. ef al. 2016, J Exp Clin Cancer Res 35:37).
  • KDM5B oncogenic role of KDM5B in gastric cancer is confirmed by knock down of endogenous KDM5B expression in GES-1 cells, which abolishes tumor growth and metastasis formation (Wang Z. ef al. 2014, Am J Cancer Res 5(1):87-100). Effects on invasion, migration and EMT were also described in esophageal cancer after targeting KDM5B (Kano Y. et al. 2013, Mol Clin Oncol 1(4)753-757). Cell cycle arrest and induction of senescence are the consequences of KDM5B depletion in colorectal cancer cells (Ohta K. ef al. 2013, Int J Oncol 42(4): 1212-8).
  • High KDM5B expression is associated to worse prognosis in human patients and resistance to conventional treatment in non-Myc-amplified neuroblastoma cell lines.
  • shRNA-mediated KDM5B inhibition reduces clonogenic potential, migration, invasion, chemoresistance and expression of stem cell markers.
  • KDM5B has been identified as an oncogene driving the luminal subtype of tumors and associated with poor prognosis in these patients (Yamamoto S. et al. 2014, Cancer Cell 25(6)762-77).
  • KDM5B inhibition is also relevant in basal-like (Bamodu OA ef al. 2016, BMC Cancer 16(1):160) and advanced- stage breast cancers (Yamane K.
  • KDM5B KDM5B Depletion of KDM5B was also shown to inhibit cell proliferation of hepatocellular carcinoma (Wang D. et al. 2016, J Exp Clin Cancer Res. 35:37). In addition, high expression of KDM5B is associated to EMT of Non-Small-Cell Lung Cancer cells (Haley J. A. ef al. 2014, Front Oncol 4:344) and reduced response to therapy and/or poorer prognosis in ovarian (Wang L. ef al.
  • High KDM5B expression has been observed within a small subset of melanoma cells, characterized by increased clonogenic potential and resistance to several anticancer drugs. KDM5B inhibition sensitizes melanoma cells to chemotherapy (Roesch A. ef al. 2013, Cancer Cell 23(6):811-25) and reduces tumorigenicity. High KDM5B expression was detected also in uveal melanoma (Radberger P. ef al. 2012, Invest Ophthalmol Vis Sci 53(8):4442-9).
  • KDM5B Upregulation of KDM5B has also been described following infection with Respiratory Syncytial Virus. In this setting, an increase of antiviral function and a reduction of pulmonary disease have been described when KDM5B is inhibited in dendritic cells. These results prompt the use of KDM5B inhibitors as a possible strategy to boost the efficacy of dendritic cells-based vaccines (Ptaschinski C. ef al. 2015, PLoS Pathog 11(6):e1004978). Inhibition of KDM5 was also shown to decrease expression of Hepatitis B Virus (HBV) in human primary hepatocytes, supporting the use of KDM5 inhibitors for the treatment of HBV infection.
  • HBV Hepatitis B Virus
  • KDM5C co-occupy with CoREST the neuron-restrictive silencing elements, to suppress the expression of REST target genes (Aguilar-Valles A. ef al. 2014, Biol Psychiatry 76(1):57-65). Loss-of-function of this gene causes mental retardation (Jensen L.R. ef al. 2005, Am J Hum Genet 76(2):227-36) and affects memory in men and mice (Simensen R.J. ef al. 2012, Genet Couns 23(1):31-40), but can also be beneficial in neurodegenerative disease with aberrant REST activity like Huntington's disease (Vashishtha M. ef al. 2013, PNAS 110:E3027-E3036).
  • KDM5C Inactivating mutations of KDM5C have been described in Renal Carcinoma (Dalgliesh G.L. etal. 2010, Nature 463(7279):360-3), while high KDM5C expression is associated to poor outcome in both breast (Patani N. et al. 2011, Anticancer Res 31 (12):4115-25) and prostate cancer patients (Stein J. ef al. 2014, Am J Pathol 184(9):2430-7). Genetic inactivation of KDM5C reduces invasion and migration of gastric (Xu L. ef al. 2016, Technol Cancer Res Treat Epub ahead of print), breast (Wang Q. ef al. 2015, Biochem Biophys Res Commun 464(2):659-66) and hepatocellular carcinoma cell lines (Ji X. etal. 2015, BMC Cancer 15:801).
  • KDM5D has been found to be implicated in spermatogenesis and downregulated in metastatic poor-prognosis human prostate cancers (Lin N. ef al. 2016, Cancer Res 76(4):831-43).
  • KDM4 subfamily (also known as JMJD2) demethylates mainly H3K9me3/2 and H3K36me3/2.
  • KDM4A, KDM4B and KDM4C are highly conserved in all vertebrates and demethylate both H3K9 and H3K36, while KDM4D only accepts H3K9 substrates (Whetstine J.R. ef al. 2006, Cell 125(3):467-81).
  • KDM4 proteins work as transcriptional coactivators by removing the repressive marks H3K9me3/me2, therefore inducing genomic instability (Peters A.H. ef al. 2001, Cell 107(3):323-37) or activating transcription by derealization of HP1 (Cloos, P.A.
  • KDM4A can also work as a transcriptional repressor: it directly interacts with the N-terminal region of the corepressor N-CoR or histone deacetylases (Zhang D. et al. 2005, Mol Cell Biol 25:6404-14).
  • the KDM4 subfamily has been reported to play a role in oncogenesis and cancer progression.
  • KDM4A is critical for growth of both ER-positive and -negative breast tumors (Berry W.L. et al. 2012, Int J Oncol; 41:1701-6).
  • KDM4B expression is higher in ER-positive than in ER-negative breast tumors, where it forms complexes with estrogen receptor a (ERa) and its downregulation in MCF7 or T47D cells reduces cell proliferation and tumor formation in nude mice (Shi L. ef al. 2011, Proc Natl Acad Sci USA. 108(18)7541-6).
  • KDM4C gene is amplified in ER negative cell lines, particularly in aggressive, basal-like subtypes. Exogenous overexpression of KDM4C in MCF10A cells induces transformed phenotypes, including mammosphere forming ability. Additionally, KDM4C demethylase activity regulates the expression of genes critical for stem cell self-renewal, including NOTCH 1, and may be linked to the stem cell phenotypes (Liu G. etal. 2009, Oncogene. 28(50):4491-500).
  • KDM4 proteins are also involved in colon cancer: KDM4A interacts with p53 in stimulating proliferation and survival in HCT116 and in other colon cancer cell lines (Kim T.D. ef al. 2012, Carcinogenesis 113(4):1368- 76). KDM4B is required for increased transcription of many hypoxia-inducible genes in colorectal cancer cell lines. (Fu L. ef al. 2012, Carcinogenesis 33:1664-73) and also promotes a pro-survival gene expression response in renal cancer cells through the accumulation of HIF1a (Beyer S. ef al. 2008, J Biol Chem. 283:36542-36552). KDM4C mediates colonosphere formation through a mechanism involving cross talk between the Wnt and Notch pathways (Yamamoto S. etal. 2013, Carcinogenesis 34( 0):2380-8).
  • KDM4A is overexpressed in mouse and human lung cancer cell lines, where it could function as an oncogene that represents a target for Ras expressing tumors (Mallette F.A. ef al. 2012, Cell Reports 2:1233- 1243). High level of KDM4A in clinical gastric cancer tissues predicts poor prognosis (Hu C.E. et al. 2014, Biochem Biophys Res Commun. 449(1): 1-7). KDM4B has a role in the growth regulation of bladder and lung cancer cells, through the demethylation of H3K9 at the promoter region of CDK6 (Toyokawa G. ef al. 2011, Cancer Prev Res 4(12):2051-61).
  • KDM4B Knockdown of KDM4B in gastric cancer cell lines inhibits cell proliferation and/or induces apoptosis, increases the expression of p53 and p21(CIP1) proteins and suppresses xenograft tumor growth in vivo (Li W. ef al. 2011, Biochem Biophys Res Commun. 416(3-4):372-8). KDM4B was also shown to promote EMT in pancreatic cancer cells (Li S. ef al. 2015, Acta Biochim Biophys Sin 47(12):997-1004).
  • KDM4A, KDM4B and KDM4C are key in androgen signaling and potential progression factors for prostate cancer (Shin S. ef al. 2007, Biochem Biophys Res Commun 359:742-6).
  • KDM4C is coexpressed with LSD1 and androgen receptor in human prostate tumors, and knockdown of either LSD1 or KDM4C severely inhibits androgen dependent proliferation of prostate tumor cells. (Wissmann M. ef al. 2007, Nat Cell Biol. 9(3):347-53).
  • KD 4A is a determinant for invasiveness and metastasis in squamous cell carcinoma (Ding X. ef al. 2013, Sci Signal. 6(273):ra28.1-15).
  • KDM4C (also known as JMJD2C or GASC1: gene amplified in squamous cell carcinoma 1) was first identified in cell lines derived from esophageal squamous cell carcinomas (Yang Z.Q. ef al. 2001, Jpn J Cancer Res. 92(4):423-8).
  • the KDM4C gene lies in the 9p23-p24 chromosome region, which is found to be amplified in various malignancies including non-small cell lung cancers, carcinomas of liver, ovary, uterine cervix, as well as osteosarcomas, mucosa associated lymphoid tissue lymphoma and desmoplastic medulloblastomas (Knuutila, S. etal. 1998, Am. J. Pathol. 152:1107-1123).
  • KDM4C and the tyrosine kinase JAK2 cooperate to promote proliferation and survival and their combined inhibition exerts synergic toxicity (Rui L. et al. 2010, Cancer Cell. 18(6):590-605).
  • KDM4C is required for leukemic transformation together with the H4R3 methyl transferase PRMT1.
  • Genetic or pharmacological inhibition of KDM4C/PRMT1 suppresses transcription and transformation abilities of the MOZ-TIF2 and MLL fusions (Cheung N. ef al. 2016, Cancer Cell. 29(1):32-48).
  • KDM4C is also involved in regulation of self-renewal in embryonic stem cells (Loh.Y.H. et al. 2007 Genes Dev. 21: 2545-2557) and modulates regulation of adipogenesis by the nuclear receptor PPARy (Lizcano F. etal. 2011, Genet Mol Biol 34(1): 19-24).
  • KDM4 subfamily has also been described to be involved in viral infection.
  • the initial phase of the infection of Herpes Simplex Virus requires KDM4A (Liang et al. 2013, Sci Transl Med. 5(167):167ra5).
  • knockdown of KDM4A attenuates viral titers, whereas its overexpression increases Kaposi's sarcoma-associated herpesvirus (KSHV) reactivation (Chang ef al. 2011 , J Virol. 85(7):3283-93).
  • KSHV Kaposi's sarcoma-associated herpesvirus
  • KDM6B also called Jumonji domain-containing protein D3 (JMJD3)
  • KDM6A also called ubiquitously transcribed X-chromosome tetratricopeptide repeat protein (UTX), specifically demethylate H3K27me2 and H3K27me3 (Xiang etal. 2017, Cell Res 17(10):850-7).
  • KDM6B has been described to play an important role in many cellular processes linked to both solid and hematological cancers.
  • KDM6B was shown to be recruited to estrogen receptor enhancers in breast cancer cells, leading to activation of the anti-apoptotic protein, BCL2 (Svotelis ef al.2011, EMBO J. 30(19):3947-61.).
  • BCL2 the anti-apoptotic protein
  • KDM6B allows for TGF-p-induced epithelial-to-mesenchymal transition (EMT) through expression of SNAI1, leading to breast cancer invasion (Ramadoss ef al. 2012, J Biol Chem. 287(53):44508-17.).
  • KDM6B did not affect proliferation of melanoma cells, it was shown to confer enhanced clonogenicity, self-renewal, and transendothelial migration (Park ef al. 2016, Cancer Res 76(1):161- 70). Upregulation of KDM6B was found in renal cell carcinoma compared to normal tissue (Shen ef al. 2012, BMC Cancer 12:470). Additionally, the pro-metastatic activity of the long noncoding NA HOTAIR in renal cell carcinoma cells was associated to the upregulation of KDM6B (Xia ef a/. 2017, Oncotarget). High levels of H3K27 trimethylation and KDM6B were also found to associate with prostate cancer progression (Xiang ef al. 2007, Cell Res. 17(10):850-7).
  • KDM6B was demonstrated to be a critical driver of hepatocellular carcinoma stem cell-like and metastatic behaviors (Tang et al. 2016, Cancer Res 76(22) :6520-6532) . Similarly, in ovarian cancer stem cells inhibition of KDM6A/B induced cell death and decreased their tumor-initiating capacity (Sakaki ef al. 2015, Anticancer Res35(12):6607-14). Several tumors of the central neuronal system have been shown to depend on the activity of KDM6B activity. Gene expression analysis of glioma patient databases revealed high expression levels of KDM6B in patients with high-grade glioma.
  • KDM6A/B were also found highly expressed in mesotheliomas and their inhibition resulted in apoptosis of malignant mesothelioma cells (Cregan ef al. 2017, Int J Oncol. 50(3): 1044-1052). Finally, the central role of KDM6B in regulating Sonic Hedgehog (Shh)-activated gene expression was demonstrated in vivo in Shh activation-dependent model of medulloblastoma (Shi et al. 2014, Nat Commun 5:5425).
  • KDM6B has also been shown to have a role in myelodysplastic syndromes (MDS).
  • MDS myelodysplastic syndromes
  • Peripheral blood CD34+ stem cells in patients with MDS have increased expression of KDM6B and an increased ability to form erythroid colonies upon inhibition of KDM6B (Wei ef al. 2013, Leukemia 27(11):2177-86).
  • KDM6B is implicated in hematopoietic lineage determination, and inhibiting KDM6B could be an option for MDS patients presenting with anemia.
  • MDS may transform into diseases such as acute lymphoblastic leukemia (ALL).
  • ALL acute lymphoblastic leukemia
  • KDM6B was shown to act as an oncogene in T-ALL, allowing for initiation and maintenance of T-ALL (Ntziachristos ef al. 2014, Nature 514(7523):513-7.). KDM6B has also been shown to be involved in Hodgkin's Lymphoma (Anderton et al. 2011, Oncogene 30(17):2037-43). Moreover, KDM6B promoted survival of diffuse large B-cell lymphoma while inhibition of KDM6B sensitized diffuse large B-cell lymphoma to chemotherapeutic drugs (Marthur ef al. 2017, Haematologica 102(2):373-380).
  • KDM6A and KDM6B A role for KDM6A and KDM6B in viral infection has also been suggested by many recent publications.
  • Kaposi's Sarcoma Human Virus PAN RNA was found associated with both KDM6A and KDM6B. This physical interaction with the virus genome appears important to activate lytic replication (Rossetto et al. 2012, PLoS Pathog. 8(5):e1002680).
  • KDM6B was found to enhance the expression of the transcription efficiency of HBV enhancer ll/core promoter (En II) in a C/EBPa-dependent manner (Chen ef al. 2016, Sci Rep. 6:35974).
  • KDM6A and KDM6B expression were both induced by HPV E7 oncoprotein (McLaughlin-Drubin ef al.
  • the compounds of the invention are thus expected to be useful for treating diseases associated with activity of a JmjC-KDM, e.g. a KDM5 protein.
  • a JmjC-KDM e.g. a KDM5 protein.
  • any of the compounds of the invention, including any of the embodiments thereof, may be used.
  • the invention further provides a compound of Formula (I), or pharmaceutically acceptable salt thereof, for use as a medicament.
  • the present invention further provides a compound of Formula (I), or pharmaceutically acceptable salt thereof, for use in treating a disease associated with a JmjC-KDM.
  • the present invention further provides the use of a compound of Formula (I), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease associated with a JmjC- KDM, particularly a KDM5 and/or KDM6 and/or KDM4.
  • the present invention further provides the use of a compound of Formula (I), or pharmaceutically acceptable salt thereof, for treating a disease associated with a JmjC-KDM, particularly a KDM5 and/or KDM6 and/or KDM4.
  • the present invention further provides a method for treating a disease associated with a JmjC-KDM, particularly a KDM5 and/or KDM6 and/or KDM4, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • the present invention further provides a method of inhibiting a JmjC-KDM, particularly a KDM5 and/or KDM4 and/or KDM6 activity, comprising administering to a patient in need of said treatment an amount of a compound of Formula (I), or pharmaceutically acceptable salt thereof, sufficient to inhibit a KDM5 and/or KDM4 and/or KDM6 activity.
  • the present invention further provides a method of inhibiting a KDM5 and/or KDM4 and/or KDM6 activity in a biological sample, comprising contacting said biological sample with a compound of Formula (I), or pharmaceutically acceptable salt thereof.
  • the present invention further provides the use of a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (la), (lb),(ld) or (le), more preferably of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, as a JmjC-KDM inhibitor in research, particularly as a research tool compound for inhibiting a JmjC-KDM, such as KDM5, KDM4 and/or KDM6 (particularly for inhibiting KDM5) .
  • a JmjC-KDM inhibitor particularly as a research tool compound for inhibiting a JmjC-KDM, such as KDM5, KDM4 and/or KDM6 (particularly for inhibiting KDM5) .
  • the invention relates to the in vitro use of a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (la), (lb),(ld) or (le), more preferably of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, as a JmjC-KDM inhibitor (particularly as a KDM5 inhibitor) and, in particular, to the in vitro use of a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (la), (lb),(ld) or (le), more preferably of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, as a research tool compound acting as a JmjC-KDM inhibitor.
  • the invention likewise relates to a method, particularly an in vitro method, of inhibiting a JmjC-KDM (such as KDM5, KDM4 and/or KDM6; particularly KDM5), the method comprising applying a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (la), (lb),(ld) or (le), more preferably of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, to a sample.
  • a JmjC-KDM such as KDM5, KDM4 and/or KDM6; particularly KDM5
  • in vitro is used in this specific context in the sense of "outside a living human or animal body", which includes, in particular, experiments performed with cells, cellular or subcellular extracts, and/or biological molecules in an artificial environment such as an aqueous solution or a culture medium which may be provided, e.g., in a flask, a test tube, a Petri dish, a microtiter plate, etc.
  • said KDM5 is KDM5B.
  • said KDM4 is KDM4C.
  • said KDM6 is KDM6B.
  • the present invention further provides a compound of Formula (I), or pharmaceutically acceptable salt thereof, for use in treating cancer.
  • the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, renal cancer, pancreatic cancer, neuroendocrine tumors, melanoma, glioblastoma, medulloblastoma, neuroblastoma, mesothelioma, multiple myeloma, osteosarcoma, lymphoma and leukemia.
  • the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, melanoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, lymphoma and leukemia.
  • the present invention further provides the use of a compound of Formula (I), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.
  • the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, renal cancer, pancreatic cancer, neuroendocrine tumors, melanoma, glioblastoma, medulloblastoma, neuroblastoma, mesothelioma, multiple myeloma, osteosarcoma, lymphoma and leukemia.
  • the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, melanoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, lymphoma and leukemia.
  • the present invention further provides the use of a compound of Formula (I), or pharmaceutically acceptable salt thereof, for treating cancer.
  • the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, renal cancer, pancreatic cancer, neuroendocrine tumors, melanoma, glioblastoma, medulloblastoma, neuroblastoma, mesothelioma, multiple myeloma, osteosarcoma, lymphoma and leukemia.
  • the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, melanoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, lymphoma and leukemia.
  • the present invention further provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, renal cancer, pancreatic cancer, neuroendocrine tumors, melanoma, glioblastoma, medulloblastoma, neuroblastoma, mesothelioma, multiple myeloma, osteosarcoma, lymphoma and leukemia
  • the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer
  • the present invention further provides a compound of Formula (I), or pharmaceutically acceptable salt thereof, for use in treating a viral infection.
  • a viral infection is an infection caused by an herpes virus, hepatitis B virus, respiratory synctial virus, Kaposi sarcoma virus or Epstein-Barr virus.
  • the present invention further provides the use of a compound of Formula (I), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a viral infection.
  • a viral infection is an infection caused by an herpes virus, hepatitis B virus, respiratory synctial virus, Kaposi sarcoma virus or Epstein-Barr virus.
  • the present invention further provides the use of a compound of Formula (I), or pharmaceutically acceptable salt thereof, for treating a viral infection.
  • a viral infection is an infection caused by an herpes virus, hepatitis B virus, respiratory synctial virus, Kaposi sarcoma virus or Epstein-Barr virus.
  • the present invention further provides a method for treating a viral infection, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • a viral infection is an infection caused by an herpes virus, hepatitis B virus, respiratory synctial virus, Kaposi sarcoma virus or Epstein-Barr virus.
  • any description of a method of treatment includes use of the compounds to provide such treatment as is described herein, as well as use of the compounds to prepare a medicament to treat such condition.
  • Any reference to a compound of Formula (I) herein includes a reference to any of the compounds of Formula (la), (lb), (lc), (Id), (le), (If), (Ig), (Ih), (li), (Ij) or (II) and any embodiments thereof as described herein.
  • the terms "disease associated with JmjC-KDMs”, “disease associated with a JmjC-KDM”, “disorder associated with JmjC-KDMs”, “JmjC-KDM-associated disease”, “JmjC-KDM-mediated disease” and the like refer to any disease or condition in which a JmjC-KDM, such as a KDM5 and/or a KDM4 and/or KDM6, plays a role, and/or where the disease or condition is associated with expression or activity of a JmjC-KDM, such as a KDM5 and/or a KDM4 and/or a KDM6, and/or diseases or conditions the course of which can be influenced by modulating the methylation status of histones or other proteins, wherein said methylation status is mediated at least in part by the activity of a JmjC-KDM, such as a KDM5 and/or a KDM4 and/or a KDM6. Modulation of the
  • said disease is cancer, such as breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, renal cancer, pancreatic cancer, neuroendocrine tumors, melanoma, glioblastoma, medulloblastoma, neuroblastoma, mesothelioma, multiple myeloma, osteosarcoma, lymphoma and leukemia
  • said cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer,
  • said cancer is drug-resistant cancer.
  • said disease is a viral infection.
  • such viral infection is an infection caused by an herpes virus, hepatitis B virus, respiratory synctial virus, Kaposi sarcoma virus or Epstein-Barr virus.
  • the term "subject” or “patient” or “individual” refers to any animals, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swince, cattle, sheep, horses, or primates, and most preferably humans.
  • biological sample includes, without limitation, a cell, cell cultures or extracts thereof; biopsied material obtained from an animal, e.g. a human, or extracts thereof; and blood, saliva, urine, feces, or any other body fluids or extracts thereof.
  • a therapeutically effective amount refers to the amount of active compound that elicits the biological or medicinal response that is being sought in subject (preferably a human). Accordingly, a therapeutically effective amount of a compound may be an amount which is sufficient to treat a disease or disorder, delay the onset or progression of a disease or disorder, and/or alleviate one or more symptoms of the disease or disorder, when administered to a subject suffering from said disease or disorder.
  • the precise effective amount for a subject will depend upon a variety of factors such as the subject's body weight, size and health, the nature and extent of the condition to be treated, and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgement of the clinician.
  • the therapeutically effective amount can be estimated initially either in in vitro assays, e.g. cell culture assays, or in animal models, e.g. mice, rats or dogs.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • Therapeutic efficacy and toxicity may be determined by standard procedures in cell cultures or experimental animals, e.g. ED50 and LD50 values can be determined and the ratio between toxic and therapeutic effects, also known as therapeutic index, may be calculated and used to determine suitable doses for use in humans.
  • treating in relation to a disease, disorder or condition refers to the management and care of a patient for the purpose of combating a disease, disorder or condition, such as to reverse, alleviate, inhibit the process of, or prevent the disease, disorder or condition to which such term applies, or one or more symptoms of such disease, disorder or condition, and includes the administration of a compound of the invention (or a pharmaceutically acceptable salt thereof) to prevent the onset of the symptoms or the complications, or alleviating the symptoms or complications, or eliminating the disease, condition or disorder.
  • treatment is curative or ameliorating.
  • compositions comprise a compound of the invention (or a pharmaceutically acceptable salt thereof) as active pharmaceutical ingredient together with one or more pharmaceutically acceptable carriers.
  • a carrier is suitable for use in the pharmaceutical compositions described herein if it is compatible with the other ingredients of the composition and not deleterious to the recipient of the composition.
  • a “pharmaceutically acceptable carrier” includes non-API (API refers to Active Pharmaceutical Ingredient) substances, such as disintegrators, binders, fillers, lubricants and the like, used in formulating pharmaceutical products and regarded as safe for administering to subjects (particularly humans) according to established governmental standards, including those promulgated by the United States Food and Drug Administration and the European Medical Agency.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and are selected on the basis of the chosen type of formulation and route of administration, according to standard pharmaceutical practice as described for example in Remington: The Science and Practice of Pharmacy 22nd edition, edited by Loyd V Allen Jr, Pharmaceutical Press, Philadelphia, 2012).
  • a pharmaceutical composition comprising a compound of Formula (I) (including any of its subgenus of Formula (la), (lb), (lc), (Id), (le), (If), (Ig), (Ih), (li), (Ij) or (II) and any embodiments thereof as described herein), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical! acceptable carriers.
  • compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, for example via oral, parenteral, pulmonary or topical route.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pulmonary administration includes e.g. by inhalation or insufflation of powders or aerosols, including by nebulizer.
  • Topical administration includes transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery.
  • compositions can be formulated as to provide quick (immediate), sustained or delayed release of the active ingredient after administration to the patient by using methods known in the art.
  • compositions can additionally include further pharmaceutically acceptable excipients including: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emusifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; flavouring agents; and colouring agents.
  • Suitable oral dosage forms include, for examples, tablets, pills, sachets or capsules of hard or soft gelatin or any other suitable material.
  • the active compound can be incorporated into a formulation that includes pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating agents (e.g., alginate, Primogel, corn starch), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). They can then be compressed into tablets or enclosed in capsules using conventional techniques.
  • pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating
  • the capsules and tablets can also be coated with various coatings known in the art to modify the flavors, tastes, colors, and shapes of the capsules and tablets.
  • liquid carriers such as fatty oil can also be included in capsules.
  • Oral formulations can also be in the form of suspensions, solutions, syrups and the like. If desired, conventional agents for modifying flavors, tastes, color and the like can be added.
  • compositions suitable for parenteral administration include sterile aqueous solutions or suspensions, or can be alternatively prepared in lyophilized form for extemporaneous preparation of a solution or suspension using a sterile aqueous carrier prior to use.
  • diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used.
  • Other conventional solvents, pH buffers, stabilizers, anti-bacterial agents, surfactants, and antioxidants can all be included.
  • useful components include sodium chloride, acetates, citrates or phosphates buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like.
  • the parenteral formulations can be stored in any conventional containers such as vials and ampoules.
  • compositions for administration by inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositons may include suitable pharmaceutically acceptable excipients as described above.
  • Such compositions maye be administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions can be nebulized by use of a suitable gas. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask or the breathing chamber. Solutions, suspensions and powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Topical formulations can contain one or more conventional carriers.
  • ointments can contain water and one or more hydrophobic carriers selected from liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline and the like.
  • Carrier compositions of creams can be based on water in combination with glycerol and one or more other components such as cetylstearyl alcohol, glycerin monostearate and the like.
  • Gels can be formulated using isopropyl alcohol and water, suitably in combination with other excipients such as glycerol, hydroxyethyl cellulose and the like.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for administration to subjects, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with one or more suitable pharmaceutical carriers.
  • compositions are to be administered in a manner appropriate to the disease to be treated, as determined by a person skilled in the medical arts.
  • An appropriate dose and suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the disease, the particular form of the active ingredient, the method of administration, among others.
  • an appropriate dose and administration regimen provides the pharmaceutical composition in an amount sufficient to provide therapeutic benefit, for example an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or lessening of symptoms severity, or any other objectively identifiable improvement as noted by the clinicial.
  • Effective doses may generally be assessed or extrapolated using experimental models like dose- response curves derived from in vitro or animal model test systems.
  • compositions of the invention can be included in a container, pack or dispenser together with instructions for administration.
  • the compounds of the invention can be administered in monotherapy (e.g., without concomitantly administering any further therapeutic agents, or without concomitantly administering any further therapeutic agents against the same disease that is to be treated with the compound of the invention).
  • they can be used in the monotherapeutic treatment of cancer (i.e., without administering any other antineoplastic agent until the treatment with the compound of the invention is terminated).
  • the invention also provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier, for use in the monotherapeutic treatment of cancer.
  • the compounds of the invention can also be administered in combination with another active agent as long as the other active agent does not interfere with or adversely affect the effects of the active compounds of this invention.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each additional active agent in its own separate pharmaceutical dosage formulation. If administered separately, the administration can be simultaneous, sequential or separate, and the compound of the invention and the additional therapeutic agent(s) can be administered via the same administration route or using different administration routes, for example one compound can be administered orally and the other intravenously.
  • any antineoplastic agent that has activity versus a cancer being treated or prevented with a compound of the invention may be used.
  • anti-plastic agent refers broadly to any agent used in the therapy of cancer, including chemotherapy and/or radiotherapy.
  • antineoplastic agents examples include, in general, and as appropriate, alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.
  • alkylating agents include, in general, and as appropriate, alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.
  • alkylating agents examples include, in general, and as appropriate, alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazines,
  • Particularly useful members of those classes include, for example, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5- fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo- phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like.
  • antineoplastic agents include estramustine, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
  • the antineoplastic agent to be administered for combination therapy may be selected, as appropriate, from: a tumor angiogenesis inhibitor (for example, a protease inhibitor, an epidermal growth factor receptor kinase inhibitor, or a vascular endothelial growth factor receptor kinase inhibitor); a cytotoxic drug (for example, an antimetabolite, such as purine and pyrimidine analog antimetabolites); an antimitotic agent (for example, a microtubule stabilizing drug or an antimitotic alkaloid); a platinum coordination complex; an anti-tumor antibiotic; an alkylating agent (for example, a nitrogen mustard or a nitrosourea); an endocrine agent (for example, an adrenocorticosteroid, an androgen, an anti-androgen, an estrogen, an anti- estrogen, an aromatase inhibitor, a gonadotropin-releasing hormone agonist, or a somatostatin analog); or a compound that targets an enzyme or
  • An alkylating agent which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, a nitrogen mustard (such as cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, ortrofosfamide), a nitrosourea (such as carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), an alkyl sulfonate (such as busulfan, mannosulfan, or treosulfan), an aziridine (such as hexamethylmelamine (altretamine), triethylenemelamine, ThioTEPA ( ⁇ , ⁇ ' ⁇ '-triethylenethiophosphoramide), carboquone, or triaziquone), a hydrazine (such as procarbazine
  • a platinum coordination complex which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, or triplatin tetranitrate.
  • a cytotoxic drug which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, an antimetabolite, including folic acid analog antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analog antimetabolites (such as cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6- thioguanine), and pyrimidine analog antimetabolites (such as cytarabine, decitabine, azacytidine, 5-fluorouracil (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, orsapacitabine).
  • folic acid analog antimetabolites such as aminopterin, methotrexate, pemetrexed, or raltitrexed
  • An antimitotic agent which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, a taxane (such as docetaxel, larotaxel, ortataxel, paclitaxel/taxol, or tesetaxel), a Vinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine, vinzolidine, or vinorelbine), an epothilone (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F) or an epothilone B analog (such as ixabepilone/azaepothilone B).
  • a taxane such as docetaxel, larotaxel, ortataxel, paclitaxel/taxol, or tesetaxel
  • a Vinca alkaloid such as
  • An anti-tumor antibiotic which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, an anthracycline (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin), an anthracenedione (such as mitoxantrone, or pixantrone) or an anti-tumor antibiotic isolated from Streptomyces (such as actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin).
  • an anthracycline such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin
  • An inhibitor of MAPK/ERK pathway which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example a B-Raf inhibitor like vemurafenib (PLX4032), encorafenib or dabrafenib, or a MEK inhibitor like cobetinib, binimetinib, selumetinib ortrametinib.
  • a B-Raf inhibitor like vemurafenib (PLX4032), encorafenib or dabrafenib
  • MEK inhibitor like cobetinib, binimetinib, selumetinib ortrametinib.
  • a tyrosine kinase inhibitor which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, orvandetanib.
  • a topoisomerase-inhibitor which can. be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, a topoisomerase I inhibitor (such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D) or a topoisomerase II inhibitor (such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin).
  • a topoisomerase I inhibitor such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D
  • a topoisomerase II inhibitor such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin.
  • antineoplastic agents may be used in combination with a compound of the present invention.
  • the antineoplastic agents may include biological or chemical molecules, such as TNF-related apoptosis- inducing ligand (TRAIL), tamoxifen, toremifene, fluoxymesterol, raloxifene, diethylstibestrol, bicalutamide, nilutamide, flutamide, aminoglutethimide, anastrozole, tetrazole, luteinizing hormone release hormone (LHRH) analogues, ketoconazole, goserelin acetate, leuprolide, megestrol acetate, prednisone, mifepristone, amsacrine, bexarotene, estramustine, irofulven, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab,
  • retinoid agents include all natural, recombinant, and synthetic derivatives or mimetics of vitamin A, for example, retinyl palmitate, retinoyl-beta-glucuronide (vitamin A1 beta-glucuronide), retinyl phosphate (vitamin A1 phosphate), retinyl esters, 4-oxoretinol, 4-oxoretinaldehyde, 3-dehydroretinol (vitamin A2), 11-cis-retinal (11-cis-retinaldehyde, 11-cis or neo b vitamin A1 aldehyde), 5,6-epoxyretinol (5,6-epoxy vitamin A1 alcohol), anhydroretinol (anhydro vitamin A1) and 4-ketoretinol (4-keto-vitamin A1 alcohol), all-trans retinoic acid (ATRA; Tretinoin; vitamin A acid; 3,7-dimethyl-9-(
  • lipid formulations of all-trans retinoic acid e.g., ATRA-IV
  • 9-cis retinoic acid (9-cis-RA; Alitretinoin; PanretinTM; LGD1057)
  • 13-cis retinoic acid Isotretinoin
  • Fenretinide N-(4-hydroxyphenyl)retinamide; 4- HPR
  • Etretinate ((all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-n
  • SR11217 (4-(2-methyl-1-(5,6J,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)propenyl)benzoic acid), SR11234, SR11236 (2-(4-carboxyphenyl)-2-(5,6,7 1 8-tetrahydro-5 ) 5,8,8- tetramethyl-2-naphthalenyl)-1,3-dioxane), SR11246, AGN194204, derivatives of 9-cis-RA such as LGD1069 (3- methyl TTNEB; Bexarotene; Targretin®; 4-[1-(5,6,7 > 8-tetrahydro-3 ) 5,5,8 J 8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid).
  • LGD1069 3- methyl TTNEB; Bexarotene; Targretin®; 4-[1-(5,6,7 > 8
  • histone deacetylase inhibitors include, without limitation, MS-275 (SNDX-275; Entinostat),
  • FK228 (FR901228; depsipeptide; Romidepsin), CI-994 (Acetyldinaline; Tacedinaline), Apicidin (cyclo[(2S)-2- amino-8-oxodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-(2R)-2-piperidinexcarbonyl]), A-161906 (7-[4-(4- cyanophenyl)phenoxy]-heptanohydroxamic acid), Scriptaid (6-(1 ,3-Dioxo-1 H,3H-benzo[de]isoquinolin-2-yl)- hexanoic acid hydroxyamide), PXD-101 (Belinostat), Panobinostat, CHAP (cyclic hydroxamic acid-containing peptide), LAQ-824 (Dacinostat), BML-EI319 (Depudecin), 03139 (Oxamflatin), N
  • biological drugs like antibodies, antibody fragments, antibody constructs (for example, single-chain constructs), and/or modified antibodies (like CDR-grafted antibodies, humanized antibodies, "full humanized” antibodies, etc.) directed against cancer or tumor markers/factors/cytokines involved in cancer can be employed in cotherapeutic approaches with the compounds of the invention.
  • Such biological molecules are alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab,
  • biologic agents include, but are not limited to, immunomodulating proteins such as cytokines
  • interferons such as interleukin-2 (IL-2, Aldesleukin), Epoietin-alpha.; EPO
  • G-CSF granulocyte-CSF
  • Filgrastin granulocyte-macrophage-CSF
  • GM-CSF granulocyte-macrophage-CSF
  • interferons e.g., interferon-alpha, interferon-beta and interferon-gamma
  • bacillus Calmette-Guerin levamisole, and octreotide
  • endostatin e.g., tumor suppressor genes (e.g., DPC4, NF- 1, NF-2, B, p53, WT1, BRCA1, and BRCA2)
  • cancer vaccines e.g., tumor associated antigens such as gangliosides (GM2), prostate specific antigen (PSA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) (
  • the invention relates to methods of treating or preventing drug resistance in a patient using a compound as described herein.
  • a method of treating or preventing drug resistant cancer in a patient comprises administering a therapeutically effective amount of a compound of the invention to the patient alone or in combination with an antineoplastic agent.
  • the patient starts treatment comprising administration of a compound of the invention prior to treatment with the antineoplastic agent.
  • the individual concurrently receives treatment comprising the compound of the invention and the antineoplastic agent, in some embodiments, the compound of the invention increases the period of cancer sensitivity and/or delays development of cancer resistance.
  • the invention provides a method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an antineoplastic agent.
  • the respective amounts of the compound of the invention and the antineoplastic agent are effective to increase the period of cancer sensitivity and/or delay the development of cancer cell resistance to the antineoplastic agent.
  • the respective amounts of the compound of the invention and the antineoplastic agent are effective to increase efficacy of a cancer treatment comprising the antineoplastic agent.
  • the respective amounts of the compound of the invention and the antineoplastic agent are effective to increase response compared to a cancer treatment comprising administering the antineoplastic agent without the compound of the invention.
  • the invention further provides a method for increasing efficacy of a cancer therapy comprising an antineoplastic agent in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the antineoplastic agent.
  • the invention further provides a method for delaying and/or preventing development of cancer resistant to a cancer therapy comprising an antineoplastic agent in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the antineoplastic agent.
  • the invention further provides a method for increasing sensitivity to a cancer therapy comprising an antineoplastic agent in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the antineoplastic agent.
  • the invention further provides a method for extending the period of sensitivity to a cancer therapy comprising an antineoplastic agent in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the antineoplastic agent.
  • the invention further provides a method for extending the duration of response to a cancer therapy comprising an antineoplastic agent in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the antineoplastic agent.
  • any compound of Formula (I) in any of the above methods is meant to include any compound of Formula (I) as described herein, including any compound of Formula (la), (lb), (lc), (Id), (le), (If), (Ig), (Ih), (li), (Ij) or (II) and any embodiments thereof as described herein
  • the antineoplastic agent is selected from the lists of antineoplastic agents disclosed above.
  • the subject has a cancer selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, melanoma, glioblastoma, medullob!astoma, neuroblastoma, osteosarcoma, lymphoma and leukemia.
  • a cancer selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, melanoma, glioblastoma, medullob!astoma, neuroblastoma, osteosarcoma, lymphoma and leukemia.
  • BINAP 2,2'-bis(diphenylphosphine)-1 ,1 '-binaphthyl
  • DAST Diethylaminosulfur trifluoride
  • DCE 1,2-dichloroethane
  • DIPEA N, N-Diisopropylethylamine
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • HATU 1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
  • HOBt 1-Hydroxybenzotriazole
  • Pd(dppb)Cl2 1 ,4-Bis(diphenylphosphino)butane-palladium(ll) chloride
  • Pd(dppf)2Cb 1,1'-Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride
  • Pd(PPh 3 )4 tetrakis(thphenylphosphine) palladium (0)
  • Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium chloride
  • Pet ether petroleum ether
  • T3P Propylphosphonic anhydride
  • TBAF Tetra-W-butylammonium fluoride
  • 3 ⁇ 4uOH ferf-butanol
  • TFA Trifluoroacetic acid
  • XPhos Dicyclohexyl(2',4 , ,6 , -triisopropyl-2-biphenylyl)phosphine.
  • One of the following methods was used for the determination by LC-MS:
  • Method 1 Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile Phase: B: 0.1% Formic Acid in Water A: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B: 0/97, 0.3/97, 3.2/2, 4/2, 4.01/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min;
  • Method 2 Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ ); Mobile Phase: A: 0.1% Formic Acid in Acetonitrile, B: 0.1% Formic Acid in water; Gradient: Time/% B: 0/97, 0.3/97, 2.2/2, 3/2, 3.01/97, Column Temp: 35°C; Flow Rate: 0.6 mL/min;
  • Method 3 Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile Phase: B: 0.1% Formic Acid in Water, A: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B: 0/97, 0.3/97, 3.0/2, 4.5/2, 4.51/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min.
  • Method 4 Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile Phase: A: 0.1% Formic Acid in water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B: 0/97, 0.3/97, 2.7/2, 3.5/2, 3.51/97, Column Temp: 35°C; Flow Rate: 0.6 mL/min;
  • Method 5 Column: Xbridge C18 (50mm x 3.0mm, 2.5 ⁇ m); Mobile Phase: B: Acetonitrile: 5 mM Ammonium Acetate (90:10), A: 5 mM Ammonium Acetate in Aq; Gradient: Time/% B: 0/5, 3/98, 5.5/98, 6/5, 7/5, Column Temp: 40°C; Flow Rate: 0.6 mL/min.
  • Method 6 Column: KINETEX-1.7u XB-C18 100A (50mm x 2.1mm, 1.7 ⁇ m); Mobile Phase: A: 0.05% Formic Acid in Water B: 0.05% Formic Acid in Acetonitrile; Gradient: Time/%A: 0/97, 0.3/97,3.2/2,4.8/2,5/97,5.10/97 Column Temp: 35°C; Flow Rate: 0.6 mL/min
  • Method 7 Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ ); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A: 0/97, 0.4/97, 2.0/2, 5/2, 5.5/97, 6/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min;
  • Method 8 Column: Xbridge C18 (75mm x 4.6mm, 3.5 ⁇ m); Mobile Phase: B: Acetonitrile, A: 0.01 M Ammonium Bicarbonate in Aq; Gradient: Time/% B: 0/5, 1/5, 4.5/90, 5.5/98, 8/98, 8.01/10; Flow Rate: 1.0 mL/min; Diluent: Acetonitrile: Water (1:1); Method 9: Column: Xbridge C18 (75mm x 4.6mm, 3.5 ⁇ m); Mobile Phase: B: Acetonitrile, A: 0.01 M Ammonium Bicarbonate in Aq; Gradient: Time/% B: 0/10, 1/10, 4.5/90, 5.5/98, 8/98, 8.01/10; Flow Rate: 1.0 mL/min; Diluent: Acetonitrile:Water (1:1);
  • Method 10 Column: Xbridge C18 (75mm x 4.6mm, 3.5 ⁇ m); Mobile Phase: A: 10 mM Ammonium Acetate in Aq, B: Acetonitrile; Gradient: Time/% B: 0.0/10, 0.2/10, 2.5/75, 3.0/100, 4.8/100, 5.0/10; Flow Rate: 2.0 mL/min; Method 11: Column: Eclipse XDB-C18 (150mmX4.6mm, 5 ⁇ ); Mobile Phase: A: 10 mM Ammonium Bicarbonate , B: 100% Acetonitrile ; Gradient: Time/ %B: 0/5, 1.5/5, 3/15, 7/55, 10/95, 14/95, 17/5, 20/5 Column Temp: Ambient, Flow Rate: 1.0 ml/min. Diluent: (ACN.WATER: 70:30
  • Method 12 Column: Xbridge C18 (75mm x 4.6mm, 3.5 ⁇ m); Mobile Phase: B: 10 mM Ammonium in water, A: Acetonitrile: Time/% A: 0/2, 2/2, 4/15, 7/55, 10/95, 14/95, 14.1/2. Flow Rate: 1 mL/min; Diluent: DMSO:ACN: 8:2
  • Method 13 Column: Xbridge C18 (75mm x 4.6mm, 3.5 ⁇ m); Mobile Phase: B: 10 mM Ammonium in water, A: Acetonitrile: Time/% A: 0/2, 2/2, 4/15, 7/55, 10/95, 14/95, 14.1/2. Flow Rate: 1 mL/min; Diluent: THF:Water:ACN: 3:1:1
  • Method 14 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ⁇ m); Mobile Phase: B: 0.1 % Formic Acid in Water A: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B: 0/97,2.6/0,3.3/0,3.6/97,4.0/97; Column Temp: 35°C; Flow Rate: 0.55 mL/min;
  • Method 15 Column: KINETEX-C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile Phase: A: 0.05% Formic Acid in Water B: 0.05% Formic Acid in Acetonitrile; Gradient: Time/%A: 0.01/97,0.5/97,3.0/2,4.5/2,4.6/97,6/97 Column Temp: 35°C; Flow Rate: 1 mL/min
  • Method 16 Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile Phase: B: 0.1% Formic Acid in Water A: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B: 0/97,0.3/97,2.2/2, 3.30/2,4.5/2,4.51/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min;
  • Method 17 Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile Phase:-A: 0.1%FA in Water ,B: 0.1% FA in Acetonitrile: T%A of: 0/90, 1/10, 2.20/10, 2.30/90.2.60./90
  • Method 18 Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile phase-A: 0.1%FA in Water ,B: 0.1% FA in Acetonitrile; T%A of: 0/970.3/97,3.0/2,4.0/2,4.2/97,4.50/97
  • Method 19 Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile phase-A: 0.1%FA in Water ,B: 0.1% FA in Acetonitrile; T%A of: 0/980.2/98,1.8/2,2.4/2,2.60/98,3.0/98. Flow-0.8mL/min, Temp:50°
  • Method 20 Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile phase-B: 0.1%FA in Water ,A: 0.1% FA in Acetonitrile T%B of: 0/970.3/97,3.2/2,3.8/2,4.2/97,4.51/97.Flow-0.6mlJmin, Temp:35°C
  • Method 21 Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile phase-A: .1%FA in Water .B: Acetonitrile, T%B of: 0/98, 0.5/98, 3.4/2.0, 4.2/2.0, 4.5/98.0, 5.0/98.0
  • Method 22 Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile phase-A: .1%FA in Water ,B: Acetonitrile, T%B of. 0/98, 0.5/98, 3.4/2.0, 4.2/2.0, 4.5/98.0;
  • Method 23 Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile phase-A: 0.1 %FA in Water ,B: 0.1% FA in Acetonitrile T%A of.0/95,0.3/95,2.0/5,3.5/5,3.6/95,4.2/95
  • Method 24 Column: Xbridge C18 (100mm x 4.6mm, 3.5 ⁇ m); Mobile Phase: B: Acetonitrile: A: 10 mM Ammonium Bicarbonate in Aq; Gradient: Time/% B: 0/0, 8/100, 12/100, 12.50/10, 15/10; Flow Rate: 1 mL/min
  • Method 25 Column: Atlantis T3 (150mm x 4.6mm, 3.5 ⁇ m); Mobile Phase: B: Acetonitrile: A: 0.1% FA in Water; Gradient: Time/% B: 0/10, 8/100, 12/100, 12.50/10, 15/10; Flow Rate: 1 mL/min
  • Method 26 Column: Xbridge C18 (100mm x 4.6mm, 3.5 ⁇ m); Mobile Phase: B: Acetonitrile: A: 5 mM Ammonium Bicarbonate in Aq; Gradient: Time/% B: 0/0, 8/100, 12/100, 12.50/10, 15/10; Flow Rate: 1 mL/min Method 27: Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile phase-A: 0.1 %FA in Water ,B: 0.1% FA in Acetonitrile T%B of: 0/10,1.8/100,3.8/100, 4.0/10,5/10. Flow-0.7mL/min, Temp:50°C
  • Method 28 Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile Phase: B: Acetonitrile: Mobile Phase A: 10 mM Ammonium Bicarbonate in Aq; Gradient: Time/% of B: 0/3,1/3,7/100, 7.5/100, 9/3, 10/3. Flow: 0.50mL/min, Temp:35°C
  • Method 29 Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile phase-B: 0.1%FA in Water ,A: 0.1% FA in Acetonitrile T%B of:0/97,0.3/97,3.2/2,4.5/2,4.51/97. Flow-0.6mL/min, Temp:35°C
  • Method 30 Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile phase-A: 0.1%FA in Water ,B: 0.1% FA in Acetonitrile T%A of:0/95,0.3/95,2.0/5,3.5/5,3.6/95. Flow-0.6mL/min, Temp:40°C
  • Method 31 Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m)); Mobile phase-A: 0.1 %FA in Water ,B: 0.1% FA in Acetonitrile T%B of: 0/5, 0.3/5, 2.0/95, 3.7/95, 4.2/5, 5.7/5; Flow-0.6mL/min, TemprfO'C
  • Method 32 Column: AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile Phase: B: Acetonitrile, A: 10 mM Ammonium Acetate in Aq; Gradient: Time/% B: 0/5, 0.3/5, 2.0/98, 3.5/98, 3.6/5, Column Temp: 40°C; Flow Rate: 0.6 mL/min.
  • Method 33 Column: AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile Phase: B: Acetonitrile, A: 10 mM Ammonium Acetate in Aq; Gradient: Time/% A: 0/98, 0.3/98, 3.5/2, 3.6/2, 4.2/98, Column Temp: 40°C; Flow Rate: 0.5 mL/min.
  • Method 34 Column: Xbridge BEH C18 (50mm x 2.1mm, 2.5 ⁇ m); Mobile Phase: B: Acetonitrile, A: 10 mM Ammonium Formate in Aq; Gradient: Time/% B: 0/5, 3.0/100, 3.5/100, 3.8/5, 4.3/5, Column Temp: 40°C; Flow Rate: 0.7 mL/min.
  • Method 35 Column: Xbridge BEH C18 (50mm x 3.0mm, 2.5 ⁇ m); Mobile Phase: B: 10 mM Ammonium Formate in WaterAcetonitrile (5:95), A: 10 mM Ammonium Formate in WaterAcetonitrile (95:5); Gradient: Time/% B: 0/2, 4.0/98, 4.5/98, 5.0/2, 5.5/2, 6.5/2; Flow Rate: 1.0 mL/min.
  • Method 36 Column: AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ m); Mobile Phase: B: 10 mM Ammonium Acetate in in Water: Acetonitrile (5:95), A: 10 mM Ammonium Acetate in in WaterAcetonitrile (95:5); Gradient: Time/% B: 0/0, 0.3/0, 2.5/100, 3.5/100, 3.6/0; Column Temp: 40°C; Flow Rate: 0.6 mL/min.
  • Step b Tert-butyl 3-((5-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)pyrrolidine-1 -carboxylate
  • 6-Bromo-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[4,3-c]pyridine To a stirred solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (2.5 g, 12.62 mmol) in DMF (40 mL), dihydropyran (1.59 g, 18.93 mmol), and PTSA (0.43 g, 2.50 mmol) were added at RT. The reaction mixture was heated to 90 °C for 16 h. It was allowed to cool to RT, diluted with ice water (100 mL) and extracted EtOAc (2X 60 mL). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The obtained crude compound was purified by flash column chromatography using 35% ethyl acetate in petroleum ether as an eluent to afford the title compound (2.10 g, 60%) as pale yellow solid.
  • step a 600 mg, 2.52 mmol in isopropyl alcohol (20mL), NaBH 4 (478 mg, 12.6 mmol) was added at 0°C.
  • the reaction mixture was refluxed for 24hr.
  • the progress of the reaction was monitored by LCMS.
  • the reaction mixture was cooled to 0°C, diluted with water and extracted with Ethyl Acetate (3x50ml).
  • the organic layer was washed with brine solution and dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford a crude compound that was purified by silica gel column chromatography using 5% MeOH in DCM to afford the title compound (250 mg, 44.26%) as an off white solid.
  • step b To a stirred solution of the compound obtained in the previous section, step b (250 mg, 1.1mmol) in DMF, 60% NaH (223 mg, 5.58mmol) was added at 0°C. After stirring for 15 minutes at 0°C, butyl iodide (410mg, 2.23mmol) was added ant the reaction mixture was stirred at RT for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to 0°C, diluted with water and extracted with Ethyl Acetate (3x50ml).
  • step a (1.5 g, 5.639 mmol) in isopropanol (30 mL), NaBH* (0.853 g, 22.556 mmol) was added and refluxed for 16h.
  • the reaction mixture was concentrated under reduced pressure and the residue was cooled to 0°C.
  • the cruderesidue was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and the volatiles were removed under reduced pressure.
  • the crude compound was purified by silicagel column chromatography and eluted at 30%EtOAc in pet ether to afford the title compound (800 mg, 56%) as an off- white solid
  • step a (1.4 g, 5.24 mmol, 1.0 equiv) in DMF, 60% NaH (1.04 g, 26.21 mmol, 5.0 equiv) was added at 0°C.
  • the reaction mixture was stirred for 15 minutes at the same temperature and then butyl iodide (1.92 g, 10.48 mmol, 2.0 equiv) was added
  • the suspension was stirred at RT for 16h. It was cooled at 0°C, water was added and extracted with EtOAc.
  • Step b 5-Bromo-1 -butyl-3-(1 -methyl-1 ,2,3,6-tetrahydropyridin-4-yl)-1 H-pyrrolo[2,3-c]pyridine
  • step a To a stirred solution of the compound obtained in the previous section, step a (2.0 g) in DMF (20 mL), 60% NaH (0.824 g, 34.326 mmol) was added at 0°C. The reaction mixture was stirred for 15 minutes at the same temperature and then 1-iodobutane (2.528 g, 13.744 mmol) was added. The suspension was stirred at RT for 4h. It was cooled at 0°C, water was added and extracted with EtOAc.
  • step a To a stirred solution of the compound obtained in the previous section, step a (2.5 g, 7.763 mmol) in DMF (30 mL), 60% NaH (0.931 g, 38.815 mmol) was added at 0°C and stirred for 15 minutes, then added 1-iodobutane (2.856 g, 15.526 mmol) was added. The reaction mixture was allowed to stir at RT for 16h. It was cooled at 0°C and water was added to the reaction mixture. The solid compound formed was filtered, washed with water and dried under vacuum to afford the title compound (2.8 g, 95%) as a pale yellow solid;
  • step b 800 mg, 2.116 mmol in 1, 4- dioxane (10 mL), phenylboronic acid (258 mg, 2.116 mmol) and a solution of Na 2 C03(448 mg, 4.232 mmol) in water, were added. The resulting mixture was degassed with argon. To the reaction mixture, Pd(dppf) 2 Cl2-DCM complex (258 mg, 0.317 mmol) was added and heated to 70°C for 16h. The reaction mixture was diluted with EtOAc and filtered through a celite pad; the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography and eluted at 16% EtOAc in pet ether to afford to afford the title compound (200 mg, LCMS ⁇ 56%) as a brown colour solid.
  • Step b N-Benzyl-9-(5-bromo-1 H-pyrrolo[2,3-c]pyridin-1 -yl)nonanamide
  • Step b N-(2-(6-bromo-3-butyl-1 H-pyrrolo[3,2-c]pyridin-1-yl)ethyl)acrylamide
  • step a 150 mg, 0.45 mmol in DCM (10 mL), TEA (0.316, 1.35 mmol) and acryl chloride (0.08 g, 0.9 mmol) were added at 0°C and stirred at RT for 16 h.
  • the crude reaction mixture was diluted with ice cold water (15 mL), and extracted with DCM (15 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and the filtrated concentrated to get a crude residue.
  • the crude compound was purified by Devisil-silica with 20% of EtOAc/pet ether to afford 150 mg of the title compound as a gummy solid;
  • Step a Tert-butyl 4-(2-(methylsulfonyloxy)ethyl)piperidine-1 -carboxylate
  • Step b 5-bromo-1 -(2-(3,5-dimethyl-1 H-pyrazol-1 -yl)ethyl)-1 H-pyrrolo[2,3-c]pyridine
  • Step b tert-butyl 3-((6-bromo-3-butyl-1 H-pyrrolo[3,2-c]pyridin-1 -yl)methyl)azetidine-1 -carboxylate
  • Step b Methyl 2-(1-(3-aminopropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate hydrochloride
  • step a 500 mg, 1.219 mmol
  • 1,4- dioxane 1,4- dioxane (1 mL)
  • 4M HCI in 1, 4-dioxane 3 mL
  • the reaction mixture was allowed to stir at RT for 4 h. Then, it was concentrated; and the residue was triturated with diethyl ether and dried under reduced pressure to afford the title compound (410 mg) as a hydrochloride salt.
  • Step a 2-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinonitrile
  • reference example 8 To a stirred solution of reference example 8 (2.2 g, 6.74 mmol) in 1,4-dioxane (20 mL), reference example 1a (2.17 g, 8.09 mmol), and CsF (2.0 g, 13.49 mmol) were added followed by Cul( 0.25 g, 1.34 mmol). The reaction mixture was degassed using N2 gas and then Pd(PPt3 ⁇ 4)4 (0.8 g, 0.67 mmol) was added. The reaction mixture was again degassed with N 2 gas and heated to 110 °C for 16h.
  • Step b 2-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinamide
  • step a (0.35 g, 1.00 mmol) in MeOH (10 mL), NaOH (0.12 g, 3.00 mmol) and 30% H2O2 (0.36 g, 3.00 mmol) were added at RT.
  • the resulting reaction mixture was stirred at 70 °C for 2h. It was evaporated under reduced pressure and the crude compound was dissolved with EtOAc (70 mL), and washed with 10% NaOH solution (2 x 30 mL). The organic layer was dried over Na 2 SO 4 and concentrated to obtain the title compound (0.25 g, 68%) as an off white solid.
  • Step c 2-(1H)-Pyrrolo[2,3-c]pyridin-5-yl)isonicotinamide
  • THF 5mL
  • 1M TBAF in THF 2 mL
  • the resulting reaction mixture was stirred at 70 °C for 16h.
  • the reaction mixture was evaporated under reduced pressure; the crude compound was dissolved in EtOAc (50mL), and treated with aqueous ammonia to reach pH ⁇ 8. Solids were collected by filtration and dried.
  • the crude compound was purified by preparative HPLC to obtain the title compound (50 mg, 31 %) as a white color solid.
  • reference example 11 To a stirred solution of reference example 11 (1.5 g, 3.80 mmol) in 1,4-dioxane (20 mL), reference example 1 (1.48 g, 4.94 mmol), CsF (1.15 g, 7.61 mmol), and Cul (0.14 g, 0.76 mmol) were added. The resulting solution was degassed using nitrogen gas, then Pd(PPh3)4 (0.44 g, 0.38 mmol) was added. The reaction mixture was again degassed and heated to 110 °C for 16h. It was cooled to RT, diluted with water (70 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 70% EtOAc/ pet ether to afford the title compound (0.6 g, 35%) as a brown color solid.
  • Step b 2-(1-((1-(7ert-butoxycarbonyl)piperidin-3-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonico-tinic acid
  • step a To a stirred solution of the compound obtained in the previous section, step a, (0.3 g, 0.66 mmol) in THF (3 mL), MeOH (3 mL), and LiOH.H 2 0 (84 mg, 1.99 mmol) in 1 mL of water, were added at RT. The reaction mixture was stirred at RT for 3h and then it was evaporated under reduced pressure. The residue was dissolved in water (10 mL) and acidified (pH ⁇ 4) with aqueous saturated citric acid solution. Then, the solid was filtered, separated, and dried to obtain to obtain the title compound (0.15 g, 52%) as a white color solid.
  • Step c 2-(1-(Piperidin-3-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid hemipentahydrochloride
  • step b To a stirred solution of the compound obtained in the previous section, step b, (0.1 g, 0.22 mmol) in DCM (2 mL), 2M HCI in diethylether (3 mL) was added at 0 °C. T the resulting solution was stirred at RT for 3h. The reaction mixture was evaporated under reduced pressure; the solid residue was triturated with acetonitrile (5 mL), diethyl ether (2 x 10 mL) and dried to afford the title compound (70 mg) as a hydrochloride salt, pale yellow solid.
  • Step a Terf-butyl 3-((5-(4-carbamoylpyridin-2-yl)-1 H-pyrrolo[2,3-c]pyridin-1 -yl)methyl)piperidine-1 - carboxylate
  • step a To a stirred solution of the compound obtained in the previous section, step a, (90 mg, 0.20 mmol) in DCM (3 mL). 2M HCI in diethyl ether (5 mL) was added at 0 °C. The resulting solution was stirred at RT for 3h. The reaction mixture was evaporated under reduced pressure. The solid residue was triturated with acetonitrile (5 mL), pentane (5 mL) and dried to obtain the title compound (65 mg, 79%) as a dihydrochloride salt.
  • Step a Terf-butyl N-[(fert-butoxy)carbonyl]-N- ⁇ 3-[5-(4- cyanopyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1- yl]propyl ⁇ carbamate
  • reference example 5 0.8 g, 1.44 mmol
  • reference example 1a 0.46 g, 1.72 mmol
  • CsF 0.43 g, 2.88 mmol
  • Cul 55 mg, 0.28 mmol
  • Pd(PPI3 ⁇ 4)4 0.16 g, 0.14 mmol
  • the reaction mixture was again degassed and heated to 110 °C for 16h.
  • the reaction mixture was cooled to RT, diluted with water (70 mL), and extracted with EtOAc (2 x 70 mL).
  • Step b Tert-butyl 3-(5-(4-carbamoylpyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)propylcarbamate
  • MeOH MeOH
  • NaOH 34 mg, 0.83 mmol
  • 30% H 2 0 2 0.14 g, 1.25 mmol
  • the resulting reaction mixture was heated at 70 °C for 2h.
  • the reaction mixture was evaporated under reduced pressure and the crude compound was dissolved with EtOAc (70 mL) and washed with 10% NaOH solution (2 x 30 mL).
  • the organic layer dried over Na 2 SO 4 and concentrated to obtain the title compound (0.12 g, 75%) as an off white solid.
  • step b To a stirred solution of the compound obtained in the previous section, step b, (0.12 g, 0.30 mmol) in 1,4- dioxane (3 mL), 4M HCI in 1,4-dioxane (5 mL) was added at 0 °C. The reaction mixture was allowed to stir at RT for 3 h. The reaction mixture was evaporated under reduced pressure and the crude compound was triturated with diethyl ether (10 mL) and dried to obtain the title compound (75 mg) as a dihydrochloride salt.
  • reference example 8 (1g, 3.05 mmol) in toluene (20 mL)
  • reference example 1 (1.19 g, 3.97 mmol)
  • CsF 929 mg, 6.11 mmol
  • Cul 116 mg, 0.61mmol
  • Pd (PPt3 ⁇ 4) 4 353 mg, 0.305 mmol
  • the resulting mixture was heated at 100°C for 16h.
  • the reaction mixture was cooled to RT, filtered through the Celite pad and washed with EtOAc (50 mL).
  • the filtrate was concentrated and the crude compound was purified by column chromatography using silica gel.
  • the product was eluted with 50% EtOAc: pet ether.
  • the obtained compound was further purified by prep.HPLC to afford the title compound (300 mg, 25%) as a pale yellow liquid.
  • Preparative HPLC conditions Column: X-Select C18 19 x 150 mm, 5.0 ⁇ ; Buffers: pump (A): 10 mm NH4HCO3 in water, (B): Acetonitrile; Isocratic: % of B: 70%; Flow: 18.0 mL/min; Max: 215 nm.
  • Step b 2-(1H-Pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid
  • THF 5 mL
  • TBAF (1M solution in THF) 1 mL
  • the reaction mixture was refluxed for 18h.
  • the reaction mixture was cooled to RT and concentrated to dryness.
  • the crude compound was purified by prep.HPLC to afford the title compound in quantitative yield.
  • step a In a sealed tube, to a stirred solution of the compound obtained in the previous section, step a, (180 mg, 0.53 mmol) in DCM (5 m L), 4M HCI in 1,4-dioxane (1 mL) was added at RT. The resulting solution was stirred for 24 h The reaction mixture was concentrated under reduced pressure, the obtained residue was diluted with water (10 mL). The pH was adjusted to ⁇ 8 with saturated NaHC0 3 solution and extracted with EtOAc (3X 10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered; and the filtrate was concentrated under reduced pressure. The crude compound was purified by Grace column chromatography (reverse phase) using with 30% of acetonitrile in 0.1% aqueous formic acid as an eluent to afford the title compound (40 mg, 29%) as pale brown solid.
  • step a To a stirred solution of the compound obtained in the previous section, step a, (330 mg, 1.08 mmol) in DCM (5 mL), TFA ( 5 mL) was added at RT. The resulting solution was stirred for 48 h and then it was concentrated under reduced pressure. The resultant residue was diluted with water (5 mL) and the pH adjusted to ⁇ 8 with saturated NaHC0 3 solution, and extracted with EtOAc (3X15 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure and the obtained crude compound was triturated with diethyl ether to afford the title compound (200 mg, 84%) as an off-white solid.
  • step b To a stirred solution of the compound obtained in the previous section, step b, (65 mg, 0.294 mmol) in i-BuOH (5 mL), KOH (41 mg, 0.735 mmol) was added at RT and the resulting suspension was stirred at 100°C for 30 min. The reaction mixture was concentrated under reduced pressure and the obtained crude compound was purified by prep HPLC method to afford the title compound (35 mg, 49%) as an off-white solid.

Abstract

The invention relates to compounds of Formula (I) as described herein, useful as histone demethylase inhibitors. The invention also relates to pharmaceutical compositions comprising these compounds and to their use in therapy, including e.g., in the treatment of cancer.

Description

HISTONE DEMETHYLASE INHIBITORS
TECHNICAL FIELD
The invention relates to compounds useful as inhibitors of histone demethylases. The invention also relates to pharmaceutical compositions comprising these compounds and to their use in therapy, including e.g., in the treatment of cancer.
BACKGROUND
Histones are highly conserved proteins that play a dynamic role in modulating chromatin structure. The covalent modification of histones is closely associated with regulation of gene transcription. Chromatin modifications have been suggested to represent an epigenetic code that is dynamically 'written' and 'erased' by specialized proteins, and 'read', or interpreted, by proteins that translate the code into gene expression changes. Histone methylation is among the most relevant modifications. Methylation of histone lysines or arginines by histone methyltransferases (HMTs) can be reversed by histone lysine demethylases (KDMs) or arginine demethylases (RDMs). KDMs are divided into two families based on sequence conservation and catalytic mechanism: FAD dependent amine oxidases (KDM1); and Jumonji C (JmjC) domain-containing demethylases (JmjC-KDMs). JmjC-KDMs are iron(l Independent enzymes and catalyze the demethylation of mono-, di- and tri-methylated lysines. The JmjC-KDM family contains over 30 members and includes the KDM2 to KDM8 subfamilies as well as JMJD6.
Altered histone demethylase activity has been associated with human disease, including cancer, and thus JmjC-KDMs have emerged as interesting targets for the development of new drugs to treat cancer and other diseases.
In view of the lack of adequate treatments for conditions such as cancer, there is an ongoing need for new agents for treating cancer and neoplastic diseases that work by inhibiting novel targets. There is thus a need for compounds that inhibit JmjC-KDMs.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound of Formula (I) as described below or a salt thereof:
Figure imgf000002_0001
wherein R1 is selected from -OH, -OR7 and -NR8R9;
R2 is selected from hydrogen, halo and methyl;
R3 is selected from hydrogen and halo;
Figure imgf000003_0001
R4 and R5 are each independently selected from hydrogen, C1-16 alkyl, C1-16 haloalkyl, -L1-carbocyclyl, -L1-aryl, -L1-heterocyclyl, -L1-heteroaryl, -{C1-16 alkylene)-OR10, -( C1-16 alkylene)-NR11R12, -( C1-16 alkylene)-CONR13R14, -(C2-16 alkenylene)-CONR13R14, -(C1-16 alkylene)-NR15COR16, -(C1-16 alkylene)-NR15CONR17R18, -(C1-16 alkylene)- NR15S02R19, -CONR13R14 and -COR16, wherein the carbocyclyl in -L1-carbocyclyl, the aryl in -L1-aryl, the heterocyclyl in -L1-heterocyclyl and the heteroaryl in -L1-heteroaryl are each optionally substituted with one or more R20; R6 is selected from hydrogen, C1-10 alkyl, C1-10 haloalkyl, -LAcarbocyclyl, -L2-aryl, -lAheterocyclyl, -L2- heteroaryl, -(C1-10 alkylene)-OR21, -(C1-10 alkyleneJ-NR^R23, -(C1-10 alkylene)-CONR24R25, -(C2-10 alkenylene)- CONR24R25, -(C1-10 alkylene)-NR26COR27, -(Cuo alkylene)-NR26CONR28R29, -(C1-10 alkylene)-NR26S02R3°, -CONR24R25 and -COR27, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyl in -L2- heterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R31;
R7 is selected from C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-OR32, -(C1-6 alkyleneJ-NR^R34, -(C1-6 alkylene)- CONR35R36, -(C1-6 alkylene)-OCONR35R38, -(C1-6 alkylene)-OCOR37, -(C1-6 alkylene)-OCOOR37, -L3-carbocyclyl, -L3-aryl, -L3-heterocyclyl and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -L3-aryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R38,
R8and R9 are each independently selected from hydrogen, C1-6 alkyl and C1-6 haloalkyl;
R10 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -L4-carbocyclyl, -L4-aryl, -LAheterocyclyl and -L4- heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R39;
R11 and R12 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -CN, -L4-carbocyclyl, -L4- aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R39;
R13 and R14 are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -CR^R^-CN, -L4-carbocyclyl, -L4-aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R39, or R13 and R14 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C1-6 alkyl, -OH, -NH2, -NH(C1-6 alkyl), and -N(C1-6 alkyl).;
each R15, R17, R18, R26, R28, R29, R50, R52, R53 and R57 is independently selected from hydrogen and C1-6 alkyl; each R16 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C2-6 haloalkenyl, -COR42, -CH=CH-CH2-NR43R44, -L4-carbocyclyl, -L4-aryl, -LAheterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -L4- heteroaryl are each optionally substituted with one or more R39;
each R19 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -L4-carbocyclyl, -L4-aryl, -L4- heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R39;
each R20 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -OH, -NR^R46 ,-CN, -COR47, -CONR48R49, -OCOR47, -NRSOCOR47, -NR^CONR^R49, -NR5°S02R51, -S02NR48R49, -SO2R51, -L5-carbocyclyl, -L5-aryl, -L5-heterocyclyl and -L5-heteroaryl, wherein the carbocyclyl in -L5-carbocyclyl, the aryl in -L5-aryl, the heterocyclyl in -L5-heterocyclyl and the heteroaryl in -L5-heteroaryl are each optionally substituted with one or more R39;
each R21 is independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl;
R22 and R23 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl and -CN;
R24 and R26 are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and -CR+oR^-CN, or R24 an(j R25 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C1-6 alkyl, -OH, -NH2, -NH(C1-6 alkyl), and -N(C1-6 alkyl)2;
each R27 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C2-6 haloalkenyl, -COR42 and -CH=CH-CH2-NR43R44;
each R30 is independently selected from 0-s alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R31 and R39 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -OH, -NR^R46, -CN, -COR47, -CONR+SR49, -OCOR47, -NR5°COR47, -NRSOCONR^R49, -NR50SO2R51, -S02NR48R49, and -S02R51;
each R32, R33 and R34 is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -L4-carbocyclyl, -L4- aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R38;
R35 and R36 are each independently selected from hydrogen, C1-6 alkyl, -L4-carbocyclyl, -L4-aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4- heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R38, or R35 and R36 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7- membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C1-6 alkyl, -OH, -NH2, -NH(C1-6 alkyl), and -N(C1-6 alkyl)2;
each R37 is independently selected from C1-6 alkyl, -L4-carbocyclyl, -L4-aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R3B;
each R38 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -OH, -NR52R53 ,-CN, -COR54, -CONR55R56, -OCOR54, -NR^COR54, -NR^CONRssR56, -NR57S02R54, -S02NR55R58 and -SO2R54;
R40 and R41 are each independently selected from hydrogen and methyl, or taken together with the C atom to which they are attached form a cyclopropyl ring;
each R42 is independently selected from C1-6 alkyl; R43 and R44 are each independently selected from hydrogen and C1-6 alkyl, or taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C1-6 alkyl, -OH, -NH2, -NH(C1-6 alkyl), and -N(C1-6 alkyl)2;
R45 and R46 are each independently selected from hydrogen, C1-6 alkyl and -CN;
each R47 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and -COR42;
R48 and R49 are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and
-CRURU-CN;
each R51 is independently selected from C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
each R54 is independently selected from C1-6 alkyl and -(C1-6 alkylene)-NR62R53;
RMand R56 are each independently selected from hydrogen, C1-6 alkyl and -(C1-6 alkyleneJ-NR^R53;
each L1, L2, L3 and L4 is independently selected from a bond and C1-10 alkylene; and
each L5 is independently selected from a bond and C1-6 alkylene.
The compounds of Formula (I) as described herein are inhibitors of JmjC-KDMs, e.g. KDM5 demethylases. These compounds, and pharmaceutical compositions comprising these compounds, are useful for the treatment of diseases associated with JmjC-KDMs, such as a KDM5-mediated disease. For example, the disease is cancer or a viral infection.
The present invention further provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Tthe present invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.
The present invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier, for use in the treatment of a disease associated with JmjC-KDMs.
The present invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier.for use as a JmjC-KDM inhibitor.
The present invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier, for use in the treatment of cancer.
The present invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier.for use in the treatment of a viral infection. The present invention further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease associated with a JmjC- KDM.
The present invention further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.
The present invention further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a viral infection.
The present invention further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for treating a disease associated with a JmjC-KDM.
The present invention further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for treating cancer.
The present invention further provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for treating a viral infection.
The present invention further provides a method for treating a disease associated with JmjC-KDMs, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
The present invention further provides a method of inhibiting JmjC-KDM activity, comprising administering to a patient in need of said treatment an amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, sufficient to inhibit JmjC-KDM activity.
The present invention further provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
The present invention further provides a method for treating a viral infection, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a compound of Formula (I) or a salt thereof:
Figure imgf000007_0001
wherein
R1 is selected from -OH, -OR7 and -NR8R9;
R2 is selected from hydrogen, halo and methyl;
R3 is selected from hydrogen and halo;
Figure imgf000008_0001
R4 and R5 are each independently selected from hydrogen, C1-16 alkyl, C1-16 haloalkyl, -L1-carbocyclyl, -L1-aryl, -L1-heterocyclyl, -L1-heteroaryl, -(C1-16 alkylene)-OR10, -(C1-16 alkylene)-NR11R12, -(C1-16 alkylene)-CONR13R14, -(C2-16 alkenylene)-CONR13R14, -{C1-16 alkylene)-NR16COR16, -(C1-16 alkylene)-NR15CONR17R18, -( C1-16 alkylene)- NR15S02R19, -CONR13R14 and -COR16, wherein the carbocyclyl in -L1-carbocyclyl, the aryl in -L1-aryl, the heterocyclyl in -L1-heterocyclyl and the heteroaryl in -L1-heteroaryl are each optionally substituted with one or more R20; R6 is selected from hydrogen, C1-10 alkyl, C1-10 haloalkyl, -LAcarbocyclyl, -L2-aryl, -L2-heterocyclyl, -L2- heteroaryl, -(C1-10 alkylene)-OR21, -(C1-10 alkylene)-NR22R23, -(C1-10 alkylene)-CONR24R25, -(C2-10 alkenylene)- CONR24R25, -(C1-10 alkyleneJ-NR^COR27, -(C1-10 alkylene)-NR28CONR28R29, -( C1-10 alkylene)-NR25SO2R30 1 -C0NR24R25 and -COR27, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyl in -L2- heterocyclyl and the heteroaryl in -L2-heteroaryl are each optionally substituted with one or more R31;
R7 is selected from C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-OR32, -(C1-6 alkyleneJ-NR^R34, -(C1-6 alkylene)- CONR^R36, -(C1-6 alkyleneJ-OCONR^R36, -(C1-6 alkylene)-OCOR37, -(C1-6 alkylene)-OCOOR37, -L3-carbocyclyl, -L3-aryl, -L3-heterocyclyl and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -L3-aryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -L3-heteroaryl are each optionally substituted with one or more R38,
Rsand R9 are each independently selected from hydrogen, C1-6 alkyl and C1-6 haloalkyl;
R10 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -L4-carbocyclyl, -L4-aryl, -L4-heterocyclyl and -L4- heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L*-aryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R39;
R11 and R12 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -CN, -L4-carbocyclyl, -L4- aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R39;
R13and R14 are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -CR40R41-CN, -L4-carbocyclyl, -L4-aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R39, or R13 and R14 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C1-6 alkyl, -OH, -NH2, -NH(C1-6 alkyl), and -N(C1-6 alkyl)2;
each R15, R17, R1B, R26, R28, R29, R50, R52, R53 and R57 Is independently selected from hydrogen and C1-6 alkyl; each R16 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C2-6 haloalkenyl, -COR42, -CH=CH-CH2-NR43R44, -LAcarbocyclyl, -L4-aryl, -LAheterocyclyl and -LMieteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -L4- heteroaryl are each optionally substituted with one or more R39;
each R19 is independently selected from C1-6 alkyl, C2-6 alkenyl, C^ alkynyl, -L4-carbocyclyl, -L4-aryl, -L4- heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R39;
each R20 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -OH, -NR45R46 ,-CN, -COR47, -CONR48R49, -OCOR47, -NR∞COR47, -NR^CONR^R49, -NR50SO2R51, -S02NR48R49, -S02R51, -lAcarbocyclyl, -L5-aryl, -L5-heterocyclyl and -Ls-heteroaryl, wherein the carbocyclyl in -L5-carbocyclyl, the aryl in -L5-aryl, the heterocyclyl in -L5-heteracyclyl and the heteroaryl in -L5-heteroaryl are each optionally substituted with one or more R39;
each R21 is independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl;
R22 and R23 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl and -CN;
R24 and R25 are each independently selected from hydrogen, O-s alkyl, C2-6 alkenyl, C2-6 alkynyl, and -CR^R'U-CN, or R24 an(j R25 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C1-6 alkyl, -OH, -NH2, -NH(C1-6 alkyl), and -N(C1-6 alkyl)2;
each R27 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C2-6 haloalkenyl, -COR42 and -CH=CH-CH2-NR43R44;
each R30 is independently selected from C1-6 alkyl, C2-6 alkenyl, and C2.6 alkynyl;
R31 and R39 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -OH, -NR«R« -CN, -COR47, -CONR^R49, -OCOR47, -NR5°COR47, -NRSOCONR^R49, -NR5°S02R51, -S02NR48R49, and -SO2R51;
each R32, R33 and R34 is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -L4-carbocyclyl, -L4- aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R38;
R35 and R36 are each independently selected from hydrogen, C1-6 alkyl, -L4-carbocyclyl, -L4-aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4- heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R38, or R35 and R36 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7- membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C1-6 alkyl, -OH, -NH2, -NH(C1-6 alkyl), and -N(C1-6 alkyl)2;
each R37 is independently selected from alkyl, -L4-carbocyclyl, -L4-aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R38;
each R38 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -OH, -NR5ZR53 ,-CN, -COR54, -CONR55R56, -OCOR54, -NR57CORM, -NR57CONR55R56, -NR57S02R54, -S02NR55R56 and -SO2R54;
R40 and R41 are each independently selected from hydrogen and methyl, or taken together with the C atom to which they are attached form a cyclopropyl ring;
each R42 is independently selected from C1-6 alkyl; R43 and R44 are each independently selected from hydrogen and C1-6 alkyl, or taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C1-6 alkyl, -OH, -Nhfe, -NH(C1-6 alkyl), and -N(C1-6 alkyl)2;
R45 and R46 are each independently selected from hydrogen, C1-6 alkyl and -CN;
each R47 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and -COR42;
R48 and R49 are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and
-CR40R41-CN;
each R51 is independently selected from C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
each R54 is independently selected from C1-6 alkyl and -(C1-6 alkylene)-NR52R53;
R55and R56 are each independently selected from hydrogen, C1-6 alkyl and -(C1-6 alkylene)-NR52R53;
each L1, L2, L3 and L4 is independently selected from a bond and C1-10 alkylene; and
each L5 is independently selected from a bond and C1-6 alkylene.
Embodiments of the present invention are outlined in the following paragraphs. Each of the embodiments described below can be combined with any other embodiment described herein that is not inconsistent with the embodiment with which it is combined.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic administration to a subject).
Furthermore, each of the embodiments described herein envisions within its scope the salts (for example pharmaceutically acceptable salts) of the compounds described herein. Accordingly, the phrase "or a salt thereof (including also "or a pharmaceutically acceptable salt thereof) is implicit in the description of all compounds described herein. The invention also specifically relates to all compounds described herein in non-salt form.
In a compound of Formula (I)
Figure imgf000011_0001
, is a bicyclic ring selected from a group of formula (i) to (x) as defined above. Accordingly, a compound of formula (I) includes compounds of Formula (la), (lb), (lc), (Id), (le),(lf), (Ig), (Ih), (li) and (Ij), as shown below:
Figure imgf000011_0002
Figure imgf000012_0001
Preferably, the compound of Formula (I) is a compound (la), (lb), (Id) or (le), and more preferably, the compound of Formula (I) is a compound (la) or (lb).
In some preferred embodiments, the compound of Formula (I) is a compound of Formula (II)
Figure imgf000012_0002
wherein W is CR5 or N. A compound of Formula (II) corresponds to a compound of Formula (la) and (lb) as previously defined.
The present invention relates to a compound of any of Formula (I), (la), (lb), (lc), (Id), (le), (If), (lg), (Ih), (li), (Ij) or (II) as defined herein. Unless otherwise specified, the compound of Formula (I) in any of the embodiments described herein can be a compound of any of Formula (I), (la), (lb), (lc), (Id), (le), (If), (Ig), (Ih), (li), (Ij) or (II), or a salt thereof. As indicated above, preferably, the compound of Formula (I) is a compound of Formula (la), (lb), (Id) or (le), and more preferably a compound of Formula (II), i.e. (la) or (lb). Accordingly, while various embodiments described herein below relate to a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If), (Ig), (Ih), (li), (Ij) or (II), it is particularly preferred that the compound specified in each of these embodiments is a compound of Formula (la), (lb), (Id) or (le), and more preferably a compound of Formula (II), (la) or (lb), or a salt thereof.
In some embodiments, in a compound of Formula (I),
Figure imgf000013_0001
is selected from a group of formula (i),
(ii), (Hi), (iv), (v) and (vi).
Preferably, in a compound of Formula (I),
Figure imgf000013_0002
is selected from a group of formula (i), (ii), (iv) and
More preferably, in a compound of Formula (I),
Figure imgf000013_0003
is selected from a group of formula (i) and (ii), i.e. a compound of Formula (i) is preferably a compound of Formula (II).
In some particularly preferred embodiments, the compound of Formula (I) is a compound of Formula (la),
In some particularly preferred embodiments, the compound of Formula (I) is a compound of Formula (lb).
In some other embodiments, the compound of Formula (I) is a compound of Formula (Id).
In some other embodiments, the compound of Formula (I) is a compound of Formula (le).
In the compounds of Formula (I) R1 is selected from -OH, -OR7 and -NR8R9. The compounds of the invention thus include carboxylic acids, when in a compound of Formula (I) R1 is -OH, and esters thereof, when in a compound of Formula (I), R1 is -OR7. Said esters may be used as prodrugs of the corresponding carboxylic acids (i.e. a compound wherein R1 is -OH). In addition, some of said esters exhibit JmjC-KDM inhibitory activity perse.
In some embodiments, in a compound of Formula (I), R7 is C1-6 alkyl or C1-6 haloalkyl.
In some embodiments, in a compound of Formula (I), R8and R9 are each hydrogen.
Preferably, in a compound of Formula (I), R1 is selected from -OH, -O-C1-6 alkyl, -O-C1-6 haloalkyl and -
NH2.
More preferably, in a compound of Formula (I), R1 is -OH.
In some embodiments, in a compound of Formula (I), R2 is selected from hydrogen and fluoro.
Preferably, in a compound of Formula (I), R2 is hydrogen.
In some embodiments, in a compound of Formula (I), R3 is selected from hydrogen and fluoro.
Preferably, in a compound of Formula (I), R3 is hydrogen. In some embodiments, in a compound of Formula (I), R4and R5 are each independently selected from hydrogen, C1-16 alkyl, C1-16 haloalkyl, -L1-carbocyclyl, -L1-aryl, -L1-heterocyclyl, -L1-heteroaryl, -(C1-16 alkylene)- OR10, -(C1-16 alkylene)-NR11R12, -( C1-16 alkylene)-CONR13R14, and -CONR13R14, wherein the carbocyclyl in -L1- carbocyclyl, the aryl in -L1-aryl, the heterocyclyl in -L1-heterocyclyl and the heteroaryl in -L1-heteroaryl are each optionally substituted with one or more R20.
Preferably, in a compound of Formula (I), R4is selected from hydrogen, C1-16 alkyl, C1-16 haloalkyl, -L1- carbocyclyl, -L1-aryl, -L1-heterocyclyl and -(C1-16 alkylene)-OR10, wherein the carbocyclyl in -L1-carbocyclyl, the aryl in -L1-aryl and the heterocyclyl in -L1-heterocyclyl are each optionally substituted with one or more R20.
More preferably, in a compound of Formula (I), R4 is selected from C1-16 alkyl, C1-16 haloalkyl, -L1- carbocyclyl and -L1-aryl, wherein the carbocyclyl in -L1-carbocyclyl and the aryl in -L1-aryl are each optionally substituted with one or more R20.
Even more preferably, in a compound of Formula (I), R4is selected from C1-16 alkyl, C1-16 haloalkyl, - C1-10 alkylene-carbocyclyl and -C1-10 alkylene-aryl, wherein the carbocyclyl in -C1-10 alkylene-carbocyclyl and the aryl in -C1-10 alkylene-aryl are each optionally substituted with one or more R20.
Still more preferably, in a compound of Formula (I), R4 is selected from C1-16 alkyl, C1-16 haloalkyl, -C1-10 alkylene-C3-7 cycloalkyl and -C1-10 alkylene-phenyl, wherein the C3-7 cycloalkyl in -C1-10 alkylene-C3-7 cycloalkyl and the phenyl in -C1-10 alkylene-phenyl are each optionally substituted with one or more R20. Preferably, any C1-10 alkylene in any said -C1-10 alkylene-C3-7 cycloalkyl and -C1-10 alkylene-phenyl groups is independently selected from (CH2)MO, more preferably (CH2K4.
In some preferred embodiments, in a compound of Formula (I), R4 is C1-16 alkyl. In some embodiments,
R4 is -(CH2)o-i5-CH3. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is n-propyl. In some embodiments, R4 is n-butyl. In some embodiments, R4 is n-pentyl. In some embodiments, R4is n-hexyl. In some embodiments, R4is n-heptyl. In some embodiments, R4 is n-octyl. In some embodiments, R4is n-nonyl. In some embodiments, R4 is n-decyl.
In some preferred embodiments, in a compound of Formula (I), R4 is C1-16 haloalkyl. In some embodiments, R4 is C1-16 fluoroalkyl. In some embodiments, R4 is -(CH2)o-i5-CF3. In some embodiments, R4 is 3,3,3-trifluoropropyl. In some embodiments, R4 is 4,4,4-trifluorobutyl. In some embodiments, R4 is 10,10,10- trifluorodecyl. In some embodiments, R4 is 9-fluorononyl.
In some preferred embodiments, in a compound of Formula (I), R4 is -C1-10 alkylene-C3-7 cycloalkyl wherein the C3-7 cycloalkyl in -C1-10 alkylene-C3-7 cycloalkyl is optionally substituted with one or more R20. In some embodiments, R4 is -(CH2)MO-C3-7 cycloalkyl wherein the C3-7 cycloalkyl in -{CH2)MO-C3-7 cycloalkyl is optionally substituted with one or more R20. In some embodiments, R4 is -(CH2)1-4-C3-7 cycloalkyl wherein the C3-7 cycloalkyl in -(CH2)1-4-C3-7 cycloalkyl is optionally substituted with one or more R20. In some embodiments, R4 is -(CH2)1-4-cyclohexyl wherein the cyclohexyl is optionally substituted with one or more R20. In some embodiments, R4 is -(CH2)1-4-cyclopentyl wherein the cyclopentyl is optionally substituted with one or more R20. In some embodiments, R4 is -(CH2)1-4-cyclobutyl wherein the cyclobutyl is optionally substituted with one or more R20. In some embodiments, R4 is -(CH2)1-4-cyclopropyl wherein the cyclopropyl is optionally substituted with one or more R20. In some embodiments, said optional substituent(s) R20 in any of said cycloalkyl rings is(are) selected from fluoro and methyl. In some other embodiments, said cycloalkyl ring has no optional substituent R20. In some embodiments, R4 is -(CH2)1-4-cyclohexyi. In some embodiments, R4 is -(Chbju- cyclopentyl. In some embodiments, R4 is -(CH2)1-4-cyclobutyl. In some embodiments, R4 is -(CH2)1-4- cyclopropyl.
In some preferred embodiments, in a compound of Formula (I), R4is C1-10 alkylene-phenyl, wherein the phenyl in - C1-10 alkylene-phenyl is optionally substituted with one or more R20. In some embodiments, R4 is - (CH2)1-10-phenyl wherein the phenyl in -{CH2)1-10-phenyl is optionally substituted with one or more R20. In some embodiments, R4 is -(Chbju-phenyl wherein the phenyl in -(CH2)1-4-phenyl is optionally substituted with one or more R20. In some embodiments, , R4 is -(Chbju-phenyl wherein the phenyl in -(Chbju-phenyl is optionally substituted with one or more halo (e.g. fluoro or chloro). In some embodiments, R4 is -{Chbju-phenyl, preferably -CHfeCFVphenyl.
In some preferred embodiments, in a compound of Formula (I), R4is selected from C1-16 alkyl, -(CH2)1- 4-C3-7 cycloalkyl wherein the C3-7 cycloalkyl in -(CH2)1-4-C3-7 cycloalkyl is optionally substituted with one or more groups selected from halo and methyl, and -(CH2)1-4-phenyl wherein the phenyl in -(CH2)1-4-phenyl is optionally substituted with one or more R20, wherein preferably said optional substituent(s) R20 in said phenyl ring is (are) independently selected from halo.
In some preferred embodiments, in a compound of Formula (I), R4 is selected from n-butyl, -CH2- cyclohexyl and -CH2CH2-phenyl.
In some preferred embodiments, in a compound of Formula (I), R4is n-butyl.
In some preferred embodiments, in a compound of Formula (I), R4is -CHb-cyclohexyl.
In some preferred embodiments, in a compound of Formula (I), R4is -ChbChb-phenyl.
In some embodiments, in a compound of Formula (I), R5 is selected from hydrogen, C1-16 alkyl, C1-16 haloalkyl, -( C1-16 alkylene)-NR11R12, -L1-carbocyclyl and -L1-aryl, wherein the carbocyclyl in -L1-carbocyclyl and the aryl in -L1-aryl are each optionally substituted with one or more R20.
In some embodiments, in a compound of Formula (I), R5 is selected from hydrogen, C1-16 alkyl and -( C1-16 alkylene)-NR11R12.
In some embodiments, in a compound of Formula (I), R5 is hydrogen.
In some embodiments, in a compound of Formula (I), L1 is C1-10 alkylene.
In some embodiments, in a compound of Formula (I), R6 is selected from hydrogen, C1-10 alkyl, C1-10 haloalkyl, -L2-aryl, -L^heterocyclyl, -lAheteroaryl, -(C1-10 alkylene)-NR22R23, -(C1-10 alkylene)-NR26COR27, -(C1-10 alkylene)-NR26CONR2BR29, and -( C1-10 alkylene)-NR26SO2R30 1 wherein the aryl in -L^aryl, the heterocyclyl in -L2- heterocyclyl and the heteroaryl in -lAheteroaryl are each optionally substituted with one or more R31.
In some embodiments, in a compound of Formula (I), R6 is selected from hydrogen, C1-10 alkyl, -L2- aryl, -lAheterocyclyl, -lAheteroaryl, -(C1-10 alkylene)-NR22R23, -(C1-10 alkyleneJ-NR^COR^and -(C1-10 alkylene)- NR^CONR^R29, wherein the aryl in the C1-10 alkylene-aryl, the heterocyclyl in -L2-heterocyclyl and the heteroaryl in -L^heteroaryl are each optionally substituted with one or more R31.
In some embodiments, in a compound of Formula (I), R6 is hydrogen.
In some other embodiments, in a compound of Formula (I), R6 is selected from the group consisting of:
Figure imgf000016_0001
Figure imgf000017_0001
In some embodiments, in a compound of Formula (I), each R20 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -NR45R46, -CN, -COR47, -NR5°COR47, -NR50SO2R51, -L5- carbocyclyl, -L5-aryl, -lAheterocyclyl and -L5-heteroaryl, wherein the carbocyclyl in -L5-carbocyclyl, the aryl in - lAaryl, the heterocyclyl in -L5-heterocyclyl and the heteroaryl in -lAheteroaryl are each optionally substituted with one or more R39.
In some embodiments, in a compound of Formula (I), each R31 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -NR«R« -CN, -COR47, -NR^COR47 and -NR60SO2R61.
In some embodiments, in a compound of Formula (I), each R39 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -NR«R* -CN, -COR47, -NR50COR47 and -NR5°S02R51.
A preferred embodiment relates to a compound of Formula (I), or a salt thereof, wherein:
R1 is -OH;
Figure imgf000017_0002
is selected from a group of formula (i), (ii), (iv) and (v); and
R4is selected from C1-16 alkyl, C1-16 haloalkyl, -L1-carbocyclyl and -L1-aryl, wherein the carbocyclyl in - L1-carbocyclyl and the aryl in -L1-aryl are each optionally substituted with one or more R20. In certain embodiments, R5 is hydrogen. In certain embodiments, R6 is hydrogen. In certain embodiments, R5and R6 are hydrogen.
Another preferred embodiment relates to a compound of Formula (I), or a salt thereof, wherein:
RMs -OH;
Figure imgf000017_0003
is selected from a group of formula (i), (ii), (iv) and (v); and R4 is selected from C1-16 alkyl, C1-16 haloalkyl, -C1-10 alkylene-carbocyclyl and -C1-10 alkylene-aryl, wherein the carbocyclyl in -C1-10 alkylene-carbocyclyl and the aryl in -C1-10 alkylene-aryl are each optionally substituted with one or more R20. In certain embodiments, R5 is hydrogen. In certain embodiments, R6 is hydrogen. In certain embodiments, R5 and R6 are hydrogen.
Another preferred embodiment relates to a compound of Formula (I), or a salt thereof, wherein:
R1 is -OH;
Figure imgf000018_0001
is selected from a group of formula (i), (ii), (iv) and (v); and
R4is selected from C1-16 alkyl, C1-16 haloalkyl, -C1-10 alkylene-C3-7 cycloalkyl and -C1-10 alkylene-phenyl, wherein the C3-7 cycloalkyl in -C1-10 alkylene-C3-7 cycloalkyl and the phenyl in -C1-10 alkylene-phenyl are each optionally substituted with one or more R20 ; wherein preferably, any C1-10 alkylene in any said -C1-10 alkylene- C3-7 cycloalkyl and -C1-10 alkylene-phenyl groups is independently selected from (CH2)MO, more preferably (CH2)1-4. In certain embodiments, R5 is hydrogen. In certain embodiments, R6 is hydrogen. In certain embodiments, R5and R6 are hydrogen.
Another preferred embodiment relates to a compound of Formula (II), or a salt thereof, wherein: R1 is -OH; and
R4 is selected from C1-16 alkyl, C1-16 haloalkyl, -L1-carbocyclyl and -L1-aryl, wherein the carbocyclyl in - L1-carbocyclyl and the aryl in -L1-aryl are each optionally substituted with one or more R20. In certain embodiments, R5 is hydrogen. In certain embodiments, R6 is hydrogen. In certain embodiments, R5and R6 are hydrogen.
Another preferred embodiment relates to a compound of Formula (II), or a salt thereof, wherein:
R1 is -OH; and
R4 is selected from C1-16 alkyl, C1-16 haloalkyl, -C1-10 alkylene-carbocyclyl and -C1-10 alkylene-aryl, wherein the carbocyclyl in -C1-10 alkylene-carbocyclyl and the aryl in -C1-10 alkylene-aryl are each optionally substituted with one or more R20. In certain embodiments, R5 is hydrogen. In certain embodiments, R6 is hydrogen. In certain embodiments, R5 and R6 are hydrogen.
Another preferred embodiment relates to a compound of Formula (II), or a salt thereof, wherein:
R1 is -OH; and
R4is selected from C1-16 alkyl, C1-16 haloalkyl, -C1-10 alkylene-C3-7 cycloalkyl and -C1-10 alkylene-phenyl, wherein the C3-7 cycloalkyl in -C1-10 alkylene-C3-7 cycloalkyl and the phenyl in -C1-10 alkylene-phenyl are each optionally substituted with one or more R20; wherein preferably, any C1-10 alkylene in any said -C1-10 alkylene-C3- 7 cycloalkyl and -C1-10 alkylene-phenyl groups is independently selected from (CH2)MO, more preferably (CH2)i- 4. In certain embodiments, R5 is hydrogen. In certain embodiments, R6 is hydrogen. In certain embodiments, R5 and R6 are hydrogen.
Another preferred embodiment relates to a compound of Formula (la), or a salt thereof, wherein: R1 is -OH; and R4 is selected from C1-16 alkyl, C1-16 haloalkyl, -L1-carbocyclyl and -L1-aryl, wherein the carbocyclyl in - U-carbocyclyl and the aryl in -L1-aryl are each optionally substituted with one or more R20. In certain embodiments, R5 is hydrogen. In certain embodiments, R6 is hydrogen. In certain embodiments, R5and R6 are hydrogen.
Another preferred embodiment relates to a compound of Formula (la), or a salt thereof, wherein:
R1 is -OH; and
R4 is selected from C1-16 alkyl, C1-16 haloalkyl, -C1-10 alkylene-carbocyclyl and -C1-10 alkylene-aryl, wherein the carbocyclyl in -C1-10 alkylene-carbocyclyl and the aryl in -C1-10 alkylene-aryl are each optionally substituted with one or more R20. In certain embodiments, Rs is hydrogen. In certain embodiments, R6 is hydrogen. In certain embodiments, R5 and R6 are hydrogen.
Another preferred embodiment relates to a compound of Formula (la), or a salt thereof, wherein:
R1 is -OH; and
R4is selected from C1-16 alkyl, C1-16 haloalkyl, -C1-10 alkylene-C3-7 cycloalkyl and -C1-10 alkylene-phenyl, wherein the C3-7 cycloalkyl in -C1-10 alkylene-C3-7 cycloalkyl and the phenyl in -C1-10 alkylene-phenyl are each optionally substituted with one or more R20; wherein preferably, any C1-10 alkylene in any said -C1-10 alkylene-C3- 7 cycloalkyl and -C1-10 alkylene-phenyl groups is independently selected from (CH2)MO, more preferably (CH2)i- 4. In certain embodiments, R5 is hydrogen. In certain embodiments, R6 is hydrogen. In certain embodiments, R5 and R6 are hydrogen.
Another preferred embodiment relates to a compound of Formula (lb), or a salt thereof, wherein: R1 is -OH; and
R4 is selected from C1-16 alkyl, C1-16 haloalkyl, -L1-carbocyclyl and -L1-aryl, wherein the carbocyclyl in - L1-carbocyclyl and the aryl in -L1-aryl are each optionally substituted with one or more R20. In certain embodiments, R6 is hydrogen.
Another preferred embodiment relates to a compound of Formula (lb), or a salt thereof, wherein: R1 is -OH; and
R4 is selected from C1-16 alkyl, C1-16 haloalkyl, -C1-10 alkylene-carbocyclyl and -C1-10 alkylene-aryl, wherein the carbocyclyl in -C1-10 alkylene-carbocyclyl and the aryl in -C1-10 alkylene-aryl are each optionally substituted with one or more R20. In certain embodiments, R6 is hydrogen.
Another preferred embodiment relates to a compound of Formula (lb), or a salt thereof, wherein: R1 is -OH; and
R4is selected from C1-16 alkyl, C1-16 haloalkyl, -C1-10 alkylene-C3-7 cycloalkyl and -C1-10 alkylene-phenyl, wherein the C3-7 cycloalkyl in -C1-10 alkylene-C3-7 cycloalkyl and the phenyl in -C1-10 alkylene-phenyl are each optionally substituted with one or more R20; wherein preferably, any C1-10 alkylene in any said -C1-10 alkylene-C3- 7 cycloalkyl and -C1-10 alkylene-phenyl groups is independently selected from (CH2K10, more preferably (CH2)i- 4. In certain embodiments, R6 is hydrogen.
Preferably, in any of the above preferred embodiments, R2and R3 are hydrogen. In certain embodiments, the invention provides a compound of Formula (I), or a salt thereof, selected from the compounds listed in Table 1 below, or salts thereof.
Table 1 :
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Preferably, the compound is selected among the compounds in Table 1 wherein R1 is -OH, or a salt thereof.
In certain embodiments, the invention provides a compound of Formula (I), or a salt thereof, selected from the compounds listed below, or salts thereof:
Methyl 2-(1 -(5-aminopentyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(3-butyl-1-(pyrrolidin-3-yl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate , Methyl 2-(1-(azetidin-3-yl)-3-butyl-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate, Methyl 2-(1 -propyl-3-(1 H-pyrazol-4-yl)-1 H-pyTOlo[2,3-c]pyridin-5-yl)isonicotinate, Methyl 2-(3-butyl-1 -(pi perid in-4-y I)- 1 H-pyrolo[3,2-c]pyridin-6-yl)i∞ni∞tinate, Methyl 2-(1-(azetidin-3-ylmethyl)-3-butyl-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate, Methyl 2-(3-butyl-1 -(piperidin-3-yl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate, Methyl 2-(1-(9-hydroxynonyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(9-fluorononyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-(9-methoxynonyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(9-hydroxynonyl)-1 H-pynOlo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-(10,10,10-trifluorodecyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate, Methyl 2-(1 -(2-fluorophenethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-(4-fluorophenethyl)-1H-pyiTOlo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-(3-fluorophenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-(4-(trifluoromethyl)phenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate, Methyl 2-(1-(3-methoxyphenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate, Methyl 2-(1-(2-fluorophenethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate, Methyl 2-(1-(4-fluorophenethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate, Methyl 2-( 1 -(3-cyclobutylpropyl)- 1 H-pyirolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(2-cyclohexylethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -{3-cyclohexylpropyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate, Methyl 2-(1-(4-cyclohexylbutyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(non-8-en-1 -yl)-1 H-pyrralo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-(5-phenylpentyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(6 , 6 ,6-trifl uoro hexy I)- 1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate, Methyl 2-(3-chloro-1 -nonyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(3-chloro-1 -phenethyl-1 H-pyrrolop^-clpyridin-S-ylJisonicotinate,
Methyl 2-(3-chloro-1 -phenethyl-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate, Methyl 2-(1 -butyl-2-(piperidin-1 -ylmethyl)-1 H-pyrolo[2,3-c]pyridin-5-yl)isonicotinate, Methyl 2-(1-butyl-2-(piperidine-1-cart>onyl)-1H-pyrrofo[2,3-c]pyridin-5-yl)isonicotinate, Methyl 2-( 1 -buty l-2-(d iethy lcarbamoyl)- 1 H-pyrTolo[2,3-c]pyridin-5-yl)isonicotinate, Methyl 2-(2-(diethylcarbamoyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(2-(ethylcarbamoyl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate, Methyl 2-(2-(phenethylcarbamoyl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl}isonicotinate, Methyl 2-(3-(cyclohexylmethyl)-3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)isonicotinate, Methyl 2-(1-(cyclohexylmethyl)-1 H-[1 ,2,3]triazolo[4,5-c]pyridin-6-yl)isonicotinate, Methyl 2-(2-(cyclohexylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)isonicotinate, Methyl 2-(1 -(9-cyanononyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(9-(1 H-imidazol-1 -yl)nonyl)-1 H-pyrroloP.S-clpyridin-S-yl)isonicotinate,
Methyl 2-(1-(9-ωοφήοΙϊηοηοηγΙ)-1Η-ργπΌΐο[2,3-ο]ρ/π(.ϊη-5-γΙ)isonicotinate,
Methyl 2-(1-(9-(4,4-difluoropiperidin-1-yl)nonyl)-1H-pyrTolo[2,3-c]pyridin-5-yl)isonicotm
Methyl 2-(2-(3,3,3-trifluoropropyl)-2H-pyictzolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(3-(1 -methyl-1 H-pyrazol-4-yl)-1 -propyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(3-(piperidin-1 -ylmethyl)-1 -propyl-1 H-pyiTOlo[2,3-clpyridin-5-yl)isonicotinate,
Methyl 2-(3-(morpholinomethyl)-1 -propyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-(3-(4-fluorophenyl)propyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(5-phenylpentyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(6,6,6-trifluorohexyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-(4-phenylbutyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -hexyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-heptyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -octyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-decyl-1 H-pyrrolop^-clpyridin-S-ylJisonicotinate,
Methyl 2-(3-(cyclohexylmethyl)-3H-irnidazo[4,5-c]pyridin-6-yl)isonicotinate,
Methyl 2-(1 -(cyclohexylmethyl)-l H-imidazo[4,5-c]pyridin-6-yl)isonicotinate,
Methyl 2-(1-(2-(3,5-dimethyl-1 H-pyrazol-1 -yl)ethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-(2,6-dichlorophenethyl)-1H-pyiTolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(2-(trifluoromethyl)phenethyl)-1 H-pyrrOlo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(2-(2-chlorophenethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(4-chlorophenethyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-(2-chlorophenethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(2-nonyl-2H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-(3-phenylpropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1-(4-phenylbutyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(4-methylphenethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(2-fluorophenethyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(4-(trifluoromethyl)phenethyl)-1 H-pyrazolop^-clpyridin-S-yl)isonicotinate,
Methyl 2-(1 -(4-cyanophenethyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(3-(cyclohexylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate,
Methyl 2-(3-(1 -(tert-butoxycarbonyl)-l ,2,3,6-tetrahydropyridin-4-yl)-1 -butyl-1 H-pyrrolo[2,3-c]pyridin-5- yl)isonicotinate, Methyl 2-(1 -((4,4-difluorocyclohexyl)methyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate, Methyl 2-(2-(4-chlorophenethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(3-fluorophenethyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -(8 , 8 , 8-trifl uoroocty I)- 1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinate,
2-(1 -(9-hydroxynonyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1-(9-fluorononyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(9-methoxynonyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1-(9-hydroxynonyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)lsonicotinic acid,
2-(1 -(10, 10, 10-trifluorodecyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1-(2-fluorophenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1-(4-fluorophenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(3-fluorophenethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(4-(trifluoromethyl)phenethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid, 2-(1 -(3-methoxyphenethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(2-fluorophenethyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1-(4-fluorophenethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-( 1 -(3-cyclobutyl propyl)- 1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid ,
2-(1-(2-cyclohexylethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(3-cyclohexylpropyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(4-cyclohexylbutyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(non-8-en-1 -yl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(5-phenylpentyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(6,6 ,6-trifluorohexyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid ,
2-(3-chloro-1 -nonyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(3-chloro-1 -phenethyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(3-chloro-1 -phenethyl-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1 -butyl-2-(piperidin-1 -ylmethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid, 2-(1-butyl-2-(piperidine-1 -carbonyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid, 2-(1-butyl-2-(diethylca*amoyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(2-(diethylcarbamoyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(2-(ethylcarbamoyl)-1 -propyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(2-(phenethylca*amoyl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)isonk;otinic acid, 2-(2-(3,3,3-trifluoroprOpyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(2-(2,2,2-trifluoroethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1-propyl-3-(1H-pyrazol4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid, 2-(3-(1 -methyl-1 H-pyrazol-4-yl)-1 -propyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(3-(piperidin-1 -ylmethyl)-1 -propyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(3-(moφholinomethyl)-1 -propyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1-(2-(3,5-dimethyl-1 H-pyrazol-1 -yl)ethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid, 2-(1 -(2,6-dichlorophenethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(2-(trifluoromethyl)phenethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1-(2-chlorophenethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(2-(2-chlorophenethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1-(4-chlorophenethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1-hexyl-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1-heptyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1-octyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1-decyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(3-(cyclohexylmethyl)-3H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)isonicotinic acid,
2-(1 -(cyclohexylmethyl)-l H-[1 ,2,3]triazolo[4,5-c]pyridin-6-yl)isonicotinic acid,
2-(2-(cyclohexylmethyl)-2H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)isonicotinic acid,
2-(1 -(4-phenyl butyl)- 1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1-(5-phenylpentyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(3-(cyclohexylmethyl)-3H-imidazo[4,5-c]pyridin-6-yl)isonicotinic acid,
2-(1-(cyclohexylmethyl)-1 H-imidazo[4,5-c]pyridin-6-yl)isonicotinic acid,
2-(1-(9-(1H-imidazol-1-yl)nonyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1-(9-moφholinononyl)-1H-pyιτolo[2,3-c]pyridίn-5-yl)isonicotinic acid,
2-(1-(9-(4,4-difluoropiperidin-1-yl)nonyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic aci
2-(1 -(3-(4-fluorophenyl)propyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(6,6,6-trifluorohexyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(2-nonyl-2H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(3-pheny Ipropy I)- 1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1-(4-phenylbutyl)-1H-pyiTolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1-(4-methylphenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1-(8,8,8-trifluorooctyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(4-(trifluoromethyl)phenethyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(3-(cydohexylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid,
2-(1 -((4,4-difluorocyclohexyl)methyl)-1 H-pyrazolo[3,4-c]pyridin-5-yi)isonicotinic acid,
2-(1 -(3-fluorophenethyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
Methyl 2-(3-(1 -(tert-butoxycarbony l)piperidin-4-yl)-1 -butyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate ,
2-(3-butyl-1 -(2-(vinylsulfonamido)ethyl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid, 2-(3-butyl-1-(2-(2-chloroacetamido)ethyl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid, 2-(1 -(5-ureidopentyf)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1-(1-acryloylpyrrolidin-3-yl)-3-butyl-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid ,
2-(3-butyl-1 -(1 -cyanopyrrolidin-3-yl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid,
2-(3-butyl-1-(1-carbamoylazetidin-3-yl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid,
2-(1-(1-acryloylpiperidin-3-yl)-3-butyl-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic aci
2-(3-butyl-1 -(1 -cyanopiperidin-3-yl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid,
2-(3-butyl-1 -(1 -cyanopiperidin-4-yl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid,
2-(3-butyl-1-((1-ca*amoylazetidin-3-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid,
2-(1-butyl-3-(1-cyanopiperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1-((1-aciyloylazetidin-3-yl)methyl)-3-butyl-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid,
E)-2-(3-butyl-1-(2-(4-(dimethylamino)but-2-enamido)ethyl)-1H-pyiTolo[3,2-c]pyrid acid, 2-(3-butyl-1 -(2-(3-oxobutanamido)ethyl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid,
2-(1-(5-acrylamidopentyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid ,
2-(1-(5-(vinylsulfonamido)pentyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(1 -acryloylazetidin-3-yl)-3-butyl-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid,
2-(3-butyl-1 -(1 -(vinylsulfbnyl)pyrrolidin-3-yl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid,
2-(1 -(4-acrylamidophenethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(3-{1 -acryloylpiperidin-4-yl)-1-butyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1 -(9-cyanononyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1-(4-cyanophenethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid,
2-(1 -butyl-3-((cyanomethyl)carbamoyl)-1 H-pyrralo[2,3-c]pyridin-5-yl)isonicotinic acid,
2-(1 -butyl-3-carbamoyl-1 H-pyrolo[2,3-c]pyridin-5-yl)isonicotinic acid,
Methyl 2-(1-(4-aminophenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate,
Methyl 2-(1 -butyl-3-(piperidin-4-yl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate, and
2-(1 -(10, 10, 10-trifluorodecyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinamide,
or a salt thereof,
wherein preferably the compound is selected among the compounds listed above wherein R1 is -OH, or a salt thereof.
In a preferred embodiment, the invention provides a compound of Formula (I), or a salt thereof, selected from the compounds in Table 2 below, or salts thereof:
Table 2:
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
In a particularly preferred embodiment, the invention provides a compound of Formula (I), or a salt thereof, selected from:
2-(1-Butyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid;
2-(1-Phenethyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid;
2-(1-Phenethyl-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid;
2-(1 -(Cyclohexylmethyl)-I H-pyrazolo [3,4-c]pyridin-5-yl)isonicotinic acid;
2-( 1 -(Cyclohexyl methyl)- 1 H-pyrrolo [2,3-c]pyridin-5-yl)isonicotinic acid;
2-(1-(Cyclobutylmethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid;
2-(1-(4-Chlorophenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid;
2-(1 -(2-Chlorophenethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid;
2-(1 -(2-Cyclopropylethyl)- 1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid;
2-(1-(3-fluorophenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid;
2-(1-(3-fluorophenethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid; 2-(1 -(2-fluorophenethyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid;
2-(1-(9-fluorononyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid; and
2-(1 -(10, 10, 10-trifluorodecyl)-1 H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinic acid ;
or a salt thereof.
Definitions of specific terms as used in the specification and claims are provided below. All other technical and scientific terms used herein and not defined below shall have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the case of conflict, the present specification, including definitions, will control.
In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.
At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
At various places in the present specification various aryl, heteroaryl, carbocyclyl and heterocyclyl groups are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term "pyridyl" (or pyridinyl) may refer to a pyridin-2- yl, pyridin-3-yl or pyridin-4-yl ring, and the term "piperidinyl" may refer to a piperidin-1-yl, piperidin-2-yl, piperidin-3-yl or piperidin-4-yl ring.
The term "n-membered" where n is an integer describes the number of ring-forming atoms in a ring system where the number of ring-forming atoms is n. For example, phenyl is an example of a 6-membered aryl, cyclopropyl is an example of a 3-membered carbocyclyl, pyrazolyl is an example of a 5-membered heteroaryl, quinolinyl is an example of a 10-membered heteroaryl, piperidinyl is an example of a 6-membered heterocyclyl, and decahydroquinolinyl is an example of a 10-membered heterocyclyl.
The term "Cy-z", where y and z are integers, used in combination with a chemical group, designates a range of the number of carbon atoms in the chemical group, with y and z being the endpoints, which are included. Examples include C1-16, C2-16, C1-6, C3-7 and the like.
The term "Cy-z alkyl" refers to a saturated straight or branched acyclic hydrocarbon group having y to z carbon atoms. Thus, a C1-16 alkyl is an alkyl having from one to sixteen carbon atoms. Examples of C1-16 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,n- tridecyl, n-tetradecyl, n-pentadecyl, and n-hexadecyl. A C1-6 alkyl is an alkyl having from one to six carbon atoms. Examples of C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, or sec-hexyl.
The term "Cy-z alkenyl" refers to a straight or branched acyclic hydrocarbon group having y to z carbon atoms and containing one or more double bonds. Thus, a C2-6 alkenyl is an alkenyl having from two to six carbon atoms. The term "Cy-z alkynyl" refers to a straight or branched acyclic hydrocarbon group having y to z carbon atoms and containing one or more triple bonds. Thus, a C2-6 alkynyl is an alkynyl having from two to six carbon atoms.
The term " Cy-z alkoxy" refers to an Cy-z alkyl group (as defined above) covalently linked to an oxygen atom, i.e. a group of formula -O-alkyl where the alkyl group has y to z carbon atoms. The term C1-6 alkoxy thus refers to an alkoxy group wherein the alkyl moiety has from 1 to 6 carbon atoms. Examples of C1-6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert- butoxy, n-pentoxy or n-hexyloxy.
The term "Cy-z alkylene" refers to a saturated straight or branched divalent acyclic hydrocarbon group having from y to z carbon atoms. Thus, for example, a C1-16 alkylene is an alkylene having from one to sixteen carbon atoms, a C1-10 alkylene is an alkylene having from one to ten carbon atoms and a C1-6 alkylene is an alkylene having from one to six carbon atoms. Preferably, said akylene groups are polymethylene groups, i.e. (CH2)x, where x indicates the number of CH2 units in the respective alkylene group, like from 1 to 16, from 1 to 10 or from 1 to 6. Examples include, but are not limited to, methylene, ethylene, propylene, n-butylene, n- pentylene or n-hexylene.
The term "Cy-z alkenylene" refers to a saturated straight or branched divalent acyclic hydrocarbon group having from y to z carbon atoms and containing one or more double bonds. Thus, a C2-16 alkenylene is an alkenylene having from two to sixteen carbon atoms, and a C2-10 alkenylene is an alkenylene having from two to ten carbon atoms.
The term "aryl" refers to a 6- to 18-membered hydrocarbon ring system which contains only hydrogen and carbon atoms and which is monocyclic or multicyclic (e.g. fused, bridged or spiro rings), wherein at least one of the rings in the ring system is aromatic. Aryl as used herein thus covers fully aromatic hydrocarbon ring systems, i.e. where all the ring(s) in the system are aromatic, like phenyl, naphthyl or anthracyl, as well as ring systems in which an aromatic hydrocarbon ring (e.g. phenyl) is fused to one or more non-aromatic hydrocarbon rings, like indanyl, indenyl, 1-oxo-2,3-dihydro-1H-indenyl, tetrahydronaphthyl, fluorenyl and the like. In some embodiments, the point of attachment is on the aromatic hydrocarbon ring. In some embodiments, the aryl group has from 6 to 10 carbon atoms. In some embodiments, the aryl group is a fully aromatic hydrocarbon ring system. Preferably, the aryl group is phenyl. Aryl groups can be optionally substituted, as indicated elsewhere in the specification, and the substituent(s) may be placed at any available position in the ring system.
The term "bond" refers to a single bond.
The term "carbocyclyl" refers to a 3- to 18-membered non-aromatic hydrocarbon ring system which contains only hydrogen and carbon atoms and which is monocyclic or multicyclic (e.g. fused, bridged or spiro rings). Each of the rings in the ring system is partially or fully saturated, i.e. none of the rings is aromatic. One or more ring-forming carbon atoms of a carbocyclyl group can be oxidized to give an oxo group. In some embodiments, carbocyclyl contains from 3 to 10 carbon atoms. In some embodiments, carbocyclyl is a fully saturated hydrocarbon ring system, i.e. it does not contain any unsaturation; a fully saturated carbocyclyl is also referred herein as "cycloalkyl". Examples of carbocyclyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, bicyclo[2.2.1]heptanyl, bicy clo [2.2.2]octany I , decalinyl, and the like. Preferably, carbocyclyl is C3-7 cycloalkyl. Carbocyclyl groups can be optionally substituted, as indicated elsewhere in the specification, and the substituent(s) may be placed at any available position in the ring system.
The term "C3-7 cycloalkyl" refers to a monocyclic cycloalkyl having from 3 to 7 ring-forming carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups can be optionally substituted, as indicated elsewhere in the specification, and the substituent(s) may be placed at any available position in the ring system.
"Halo" or "halogen" refers to bromo, chloro, fluoro or iodo. Preferably, halo is fluoro.
The term "Cy-z haloalkyl" refers to an alkyl group having from y to z carbon atoms as defined herein which is substituted one or more times with one or more halo, which can be the same or different. Accordingly, a C1-16 haloalkyl is a C1-16 alkyl which is substituted one or more times with one or more halo, and a C1-6 haloalkyl is a C1-6 alkyl which is substituted one or more times with one or more halo. Haloalkyl groups include perhaloalkyl groups, i.e. alkyl groups where all hydrogen atoms are replaced by halo. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1-fluoro- 2-fluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 4,4,4-trifluorobutyl chloromethyl, dichloromethyl, trichloromethyl difluorochloromethyl, dichlorofluoromethyl, 1,2-dichloroethyl, 3,3-dichloropropyl and the like. In some embodiments, the haloalkyl is a fluoroalkyl, i.e. an alkyl group which is substituted one or more times with one or more fluoro.
The term "Cy-z haloalkenyl" refers to an alkenyl group having from y to z carbon atoms as defined herein which is substituted one or more times with one or more halo, which can be the same or different. Accordingly, a C2-6 haloalkenyl is a C2-6 alkenyl which is substituted one or more times with one or more halo.
The term "Cy-z haloalkoxy" refers to an haloalkyl group having y to z carbon atoms as defined herein covalently linked to an oxygen atom, i.e. a group of formula -0-Cy-z haloalkyl. A C1-6 haloalkoxy group thus refers to a haloalkoxy group wherein the haloalkyl moiety has from 1 to 6 C atoms. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2-fluoroethoxy, pentafluoroethoxy, 3-chloropropoxy, 3- fluoropropoxy, heptafluoropropoxy, and the like.
The term "heteroaryl" refers to a 5- to 18-membered heterocyclic ring system which is monocyclic or multicyclic (e.g. fused, bridged or spiro rings) and which comprises, in addition to C atoms, from 1 to 6 heteroatoms independently selected from N, 0 and S, wherein at least one of the rings in the ring system is aromatic and contains at least one of the heteroatoms. Heteroaryl as used herein thus covers fully aromatic ring systems, i.e. where all the ring(s) in the system are aromatic, like imidazolyl, pyridyl, quinolyl, pyrido[2,3- d]pyrimidinyl and the like, and groups in which an heteroaromatic ring(s) is fused to one or more non-aromatic carbocyclic or heterocyclic rings, such as 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydro-1,8-naphthyridine and the like. The heteroatom(s) in the heteroaryl is optionally oxidized. Likewise, when the heteroaryl comprises a heteroaromatic ring fused to one or more non-aromatic carbocyclic or heterocyclic rings, one or more ring- forming carbon atoms in the non-aromatic carbocyclic or heterocyclic ring can be oxidized to give an oxo group. The heteroaryl group can be attached to the rest of the molecule through any C or N atom that results in a stable structure. In some embodiments, the point of attachment is on the heteroaromatic ring. In some embodiments, the heteroaryl group has from 1 to 4 heteroatoms. In some embodiments, the heteroaryl group has from 1 to 3 heteroatoms. In some embodiments, the heteroaryl is 5- to 6-membered monocyclic or 9- to 10- membered bicyclic. In some embodiments, the heteroaryl is 5- to 6-membered monocyclic. In some embodiments, the heteroaryl group is fully aromatic. Nonlimiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazine, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, phthalazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, cinnolinyl, indazolyl, indolizinyl, isoindolyl, pteridinyl, purinyl, furopyridinyl, acridinyl, phenazinyl, 5,6,7 ,8-tetrahydroquinoline, 1 ,2,3,4-tetrahydro-1 ,8-naphthyridine and the like. Heteroaryl groups can be optionally substituted, as indicated elsewhere in the specification, and the substituent(s) may be placed at any available position in the ring system.
The term "heterocyclyl" refers to a 3- to 18-membered partially or fully saturated heterocyclic ring system which is monocyclic or multicyclic (e.g. fused, bridged or spiro rings) which comprises, in addition to C atoms, from 1 to 6 heteroatoms independently selected from N, 0 and S. Nitrogen or sulfur atoms may be optionally oxidized (e.g., -N=0, -S(=0)-, or -S(=0)2-) and additionally one or more of the carbon atoms of the heterocyclyl may be optionally oxidized to give an oxo group. "Heterocyclyl" as used herein also includes groups in which a partially or fully saturated heterocyclic ring is fused to one or more phenyl rings, as in 1 ,2,3,4- tetrahydroquinolinyl, benzodioxolyl, carbazolyl or phthalimidyl. The heterocycyl can be attached to the rest of the molecule through any C or N atom that results in a stable structure. In some embodiments, the heterocyclyl is 3- to 7-membered monocyclic. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, 2- oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, homopiperidinyl, oxepanyl, thiepanyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, indolinyl, 1-oxoisoindolinyl, decahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 6-azabicyclo[3.3.1]heptanyl, 8- azabicyclo[3.2.1]octanyl, 3-azaspiro[5.5]undecanyl, 7-azaspiro[3.5]nonanyl, carbazolyl, phthalimidyl, tetrahydrothiopyranyl 1,1-dioxide, 2-azaspiro[4.5]decanyl, 2, 3-d ihyd rospiro [indene-1 ,4 '-piperidi nyl], and the like. Heterocyclyl groups can be optionally substituted, as indicated elsewhere in the specification, and the substituent(s) may be placed at any available position in the ring system.
The term "optionally substituted" means unsubstituted or substituted. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a monovalent substitutent. It is to be understood that substitution at a given atom is limited by valency. Unless defined otherwise (or limited by valency), a group that is optionally substituted with "one or more" substituents may be unsubstituted or may, for example, carry one, two or three (particularly one or two) substituents.
The term "oxo" as used herein refers to a carbonyl group.
The term "partially saturated" as used herein refers to a ring moiety that includes at least one double bond. The term "partially saturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl groups, as herein defined.
A wavy line
Figure imgf000039_0001
in chemical drawings indicates the point of attachment to the remainder of the molecule.
For compounds of the invention in which a variable appears more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties independently selected from the group defined for said R.
The compounds of the invention may contain one or more asymmetric centers and may thus give rise to stereoisomers. All stereoisomers, such as enantiomers, diastereoisomers and mixtures thereof, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active form or racemic mixtures. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, and include for example by resolution of racemic mixtures or by stereoselective synthesis.
The compounds of the invention may, in certain embodiments, exist as geometric or conformational isomers. It should be understood that when compounds have geometric or conformational forms (for example Z and E double bond isomers, Z and E conformational isomers), all geometric or conformational forms thereof are intended to be included in the scope of the present invention.
The compounds presented herein may, in certain embodiments, exist as tautomers. It should be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present invention. A "tautomer" refers to a molecule wherein a proton shift from one atom to another atom of the same molecule is possible. Examples include ketone-enol pairs and annular forms where a proton can occupy two or more positions of a heterocyclic system as for example in 1H- and 3H-imidazole. Tautomeric forms can be in equilibrium or stericaily locked into one form by appropriate substitution.
Compounds of the invention include unlabeled forms as well as isotopically labeled forms thereof. Isotopically labeled forms of the compounds are compounds that differ only in the replacement of one or more atoms by a corresponding isotopically enriched atom. Examples of isotopes that can be incorporated into compounds of the invention include for example isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 15N, 180, 170, 35S, 18F, 36CI, and 12s|. Such isotopically labelled compounds are useful for example as probes in biological assays, as analytical tools, or as therapeutic agents.
"Polymorphs" or "crystal forms" refers to crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, Raman spectra, melting points, differential scanning calorimetry (DSC) spectra, crystal shape, solubility and/or stability, among others. When compounds of the invention exist in different crystal forms, all forms thereof, including amorphous forms and crystal forms, are intended to be included in the scope of the present invention.
The terms "compound of the invention", "compound as described herein" and the like are meant to include a compound of Formula (I) (including each and every subgenus of a compound of Formula (I) as described herein and in the claims as well as the compounds described in the Examples), including all stereoisomers, tautomers, isotopically labeled forms and polymorphs thereof.
The present invention also includes salts of the compounds of the invention. Preferably, said salts are pharmaceutically acceptable salts. As used herein, a "pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness and properties of the parent compound (i.e. the free acid or free base, as applicable) and that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include salts formed with inorganic or organic bases, and salts formed with inorganic and organic acids. Pharmaceutically acceptable salts are well known in the art. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, such as hydrochlorides, hydrobromides, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, nitrates, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4 dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, ethane-sulfonates, propanesulfonates, benzenesulfonates, toluenesulfonates, trifluoromethansulfonates, naphthalene-1 -sulfonates, naphthalene-2-sulfonates, mandelates, pyruvates, stearates, ascorbates, or salicylates. When the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine and the like. The pharmaceutically acceptable salts of the present invention can be prepared from the parent compound which contains a basic or acidic moiety by conventional chemical methods. For example, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in a suitable solvent.
Additionally, compounds of the present invention, or salts thereof, may exist in hydrated or unhydrated (anhydrous) form or as solvates with other solvent molecules. "Solvate" as used herein means solvent addition forms that contain either stoichometric or non-stoichometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate. Non-limiting examples of solvates include hydrates and solvates with alcohols (also named alcoholates) such as ethanol (ethanolates). When compounds of the invention (or salts thereof) exist as solvates, all solvates thereof are intended to be included in the scope of the present invention, particularly pharmaceutically acceptable solvates. As used herein a "pharmaceutically acceptable solvate" is a solvate formed with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents are well known in the art and include solvents such as water and ethanol.
Compounds of the invention, including salts thereof, can be prepared using a number of synthetic routes, including the general synthetic routes described below, starting from commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures. Standard synthetic methods and procedures for the preparation of organic compounds and functional group transformations and manipulations are known in the art and can be found in standard textbooks such as Smith M.B., "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure'', 7th Edition, Wiley, 2013; Greene TW and Wuts PGM "Greene's Protective Groups in Organic Synthesis", 4* edition, Wiley, 2006)
The reaction schemes described below are only meant as illustrative of methods to obtain the compounds of the invention. Other routes known by the ordinary skilled artisan, as well as other reactants and intermediates, can also be used to arrive at the compounds of Formula (I).
In some of the processes described below it may be necessary or advisable to protect reactive or labile groups with conventional protecting groups. Both the nature of these protecting groups and the procedures for their introduction and removal are well known in the art (see for example Greene TW and Wuts PGM, cited supra). Whenever a protecting group is present, a subsequent deprotection step will be required, which can be performed under standard conditions well known in the art, such as those described in the above reference.
Unless otherwise stated, in the methods described below the meanings of the different substituents in each synthetic intermediate and in each compound of Formula (I) are the meanings described above.
In general, the compounds of Formula (I) can be obtained following the procedure shown in Scheme 1 below.
Figure imgf000042_0001
wherein R1, R2, R3 and heterocycle A have the same meaning described for a compound of Formula (I), Z is COORa or CN, Ra is Ci-e alkyl or aryl-C1-4 alkyl, preferably methyl, ethyl or benzyl, and M and X have the meaning defined below.
The first step involves a cross-coupling reaction of a heteroaryl organometallic species with a heteroaryl halide. Organometallic intermediates can be generated either on the pyridine bearing the COORa or CN substituent (i.e. a compound of Formula (Ilia) or (lllb)), or in the heteroaryl A (i.e. a compound of Formula (VI)). The second step involves the transformation of the ester or cyano derivative (Vila) or (VI lb) into compounds of Formula (I).
Several cross-coupling reactions can be used for the first step in Scheme 1, including: a Suzuki cross coupling where M is a boronic acid or boron derivative and X is CI, Br or I; a Stille reaction where M is trialkylstannanyl group and X is CI, Br or I; a Negishi coupling where M is a zinc halide and X is triflate, CI, Br or I; and a Hiyama coupling where M is a trialkylsilyl group and X is CI, Br or I.
When compounds of Formula (I) are prepared through a Suzuki cross coupling with the intermediates indicated in Scheme 1, the reaction can be performed using a suitable Pd/ligand combination such as XPhos and Pd2(dba)3,Pd(dppf)2Cl2.DCM or Pd(PPh3) , 1, in a suitable solvent such as toluene or 1-4 dioxane, using a suitable base such as sodium carbonate. The temperature of the reaction typically can go from room temperature to 120°C and the time of reaction typically from 1h to 48h. Examples of boronic derivatives include among others diethyl, dimethyl, pinacol derivative, N-methyliminodiacetic acid (MIDA) derivative and 2,2'- (phenylazanediyl)bis(ethan-l -ol) derivative.
When compounds of Formula (I) are prepared through a Stille cross coupling with the intermediates indicated in Scheme 1, the reaction can be performed using a suitable Pd/ligand combination such as Pd(PPh3k Pd(PPh3)CI2 or Pd(dppb)CI2 in the presence of a suitable Cu salt such as Cul or CuO, in the presence or absence of CsF, in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide. The temperature of the reaction can typically go from room temperature to 120°C and the time of reaction typically from 1h to 48h. The organotin employed can be for example a trimethylstannyl derivative. An intermolecular Stille Kelly reaction can also be used, in which both reagents are haloheteroaryls and are treated with (Bu3Sn)2, EUNI, and a Pd/ligand combination.
When compounds of Formula (I) are prepared through a Negishi cross coupling with the intermediates indicated in Scheme 1, the reaction can be performed using a suitable Pd/ligand combination such as PPfi3 and Pd2(dba)3 , XPhos and Pd2(dba)3 , RuPhos and Pd2(dba)s or Pd(PPh3)4, in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide. The temperature of the reaction can typically go from room temperature to 120°C and the time of reaction typically from 1h to 48h.
When compounds of Formula (I) are prepared through a Hiyama cross coupling with the intermediates indicated in Scheme 1, the reaction can be performed using a suitable Pd/ligand combination such as PdCl2(PPfi3)2 and PPti3 or Pd(OAc)2 and di(1-adamantyl)-n-butylphosphine in the presence of a suitable Cu salt such as Cul or CuBr, in the presence or absence of tetrabutylammonium fluoride in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide. The temperature of the reaction can typically go from room temperature to 120°C and the time of reaction typically from 1 h to 48h.
Compounds of Formula (I) can also be prepared in three steps through a direct arylation of a compound of Formula (Villa) or (Vlllb) with halo derivative of Formula (IV) followed by reduction of the resulting N-oxide of Formula (IXa) or (IXb) and subsequent transformation of the ester or cyano derivative (Vila) or (VI lb) into compounds of Formula (I), as outlined in Scheme 2.
Figure imgf000043_0001
wherein R1, R2, R3 and heterocycle A have the same meaning described for compound of Formula (I), Z is COORa or CN, Ra is Ci-s alkyl or aryl-Cualkyl, preferably methyl, ethyl or benzyl, and X is CI or Br.
The reaction of (Villa) or (Vlllb) with (IV) can be performed using a suitable Pd/ligand combination such as P'Bu3 and Pd(OAc)2 or PBU3-HBF4 and Pd(OAc)2, in the presence of a suitable base such as potassium carbonate, in a suitable solvent such as toluene. The temperature of the reaction can typically go from room temperature to 120°C and the time of reaction typically from 1h to 48h.The resulting N-oxide (IXa) and (IXb) can easily be reduced to compound (Vila) and (Vllb) with hydrogen or sodium borohydride using palladium on charcoal as a catalyst.
Compounds of Formula (Vila) in Scheme 1 or 2 can be reacted directly with an amine NHR8R9 to give a compound of Formula (I) wherein R1 is -NR8R9. The reaction is performed in a suitable solvent such as methanol, ethanol, isopronanol at a temperature typically going from room temperature to 120°C, optionally under pressure in case of volatile amines, during a time reaction typically from 1h to 48h. Alternatively, compounds (Vila) can be hydrolyzed to compounds of Formula (I) in which R1 is OH by treatment with a base such as LiOH, NaOH, KOH or MesSiOK in a mixture of water and a solvent miscible with water such as dioxane, THF, MeOH, EtOH, typically between 0°C and room temperature for 1 to 3 days. Compounds (Vila) can be also hydrolyzed by treatment with an acid such as HCI, H2SO4 in water optionally mixed with water miscible solvents such as dioxane, THF, MeOH, EtOH, typically between 0°C and room temperature for 1 to 3 days. Compounds Formula (I) in which R1 is OH can be coupled with an amine of formula NHR8R9or alcohol of formula R7OH to give compounds of Formula (I) wherein R1 is -NR8R9 or -OR7, respectively, with the aid of a coupling agent. Examples of suitable activating agents are among others: dicyclohexyl carbodiimide (DCC), 1- hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 1-ethyl-3-(3'-dimethylamino)carbodiimide (EDC), diisopropyl carbodiimide (DIC), carbonyl diimidazole (CDI), Benzotriazol-l-yl-oxytris-(dimethylamino)- phosphonium hexafluorophosphate (BOP), Benzotriazol-1-yl-oxytris-pyrrolidinophosphonium hexafluorophosphate (PyBop), O-ilHbenzotriazol-l-yO-N.N.N'.N'-tetramethyluronium hexafluorophosphate(HBTU), 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU). The reaction can be carried out in the presence of a base, such as disopropylethylamine, pyridine, thriethylamine, or N-methylmorpholine , in a suitable solvent, such as dimethoxyethane, N,A/-dimethylformamide, tetrahydrofuran, dichloromethane or dioxane. Alternatively, carboxylic acids are activated as mixed anhydrides or acid chlorides and then coupled with NHR8R9or R7OH in the presence of a suitable base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine or the like.
Compounds of Formula (VI lb) in Scheme 1 or 2 can be reacted with NaOH or KOH optionally in the presence of typically about 30% H2O2 in a suitable solvent such as MeOH, EtOH or tert-butanol, water or a mixture of them at a temperature typically going from room temperature to reflux for a reaction time typically from 1h to 3 days, to give a compound of Formula (I) in which R1 is NR8R9and R8 and R9 are H. In more drastic conditions, with both acid and basic catalysis, compounds of Formula (Vllb) can generate compounds of Formula (I) in which R1 is OH.
Compounds of Formula (IV) are commercially available or can be obtained from commercial compounds following standard procedures well known to those skilled in the art of organic chemistry. For example, they can be prepared following the methods described in Scheme 3 for the preparation of compounds of Formula (IV-G-P), or analogous synthetic procedures.
Figure imgf000045_0001
wherein R4, R5, R6 have the same meaning described for compound of Formula I, R4', R5', R6' have the same meaning described for R4 R5, R6 except H and X is CI , Br or I.
For example, the introduction of substituents R4', R5', or R6' on the NH of haloheterocycles of Formula (IV-A-F) to give (IV-G-P), can be performed by reaction of the corresponding heterocyclic NH with a suitable alkylating agent (e.g. halides, triflates or sulphonyl clorides) in the presence of a base such us sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, cesium carbonate or potassium carbonate, in a solvent as for example DMSO, DMF, DMA, dioxane, tetrahydrofurane or pyridine. Temperature can typically be varied from room temperature to 100°C. In case the reagent is an aryl halide, Cu catalysis can be added (Ullmann reaction conditions). The introduction of substituents R4', R5', or R6' on the NH of haloheterocycles of Formula (I -A-F) to give (IV-G-P), can be also performed by reaction of a boronic acid or ester in the presence of copper(ll) diacetate and oxygen under Cham-Lam conditions. In the case of triazolopyridine derivative (IV-F), in addition to the conditions previously described, Mitsunobu reaction and addition to unsaturated systems can also be used.
For example, the introduction of substituents R4', R5', or R6' on the NH of haloheterocycles of Formula (IV-A-F) to give (IV-G-P), can be performed by reaction of the corresponding hetrocyclic NH with a suitable acylating agent, such us car oxylic acids activated as mixed anhydrides or acid chlorides in the presence of a suitable base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine or the like.
The compounds of Formula IV-A, IV-B, IV-C and -IV-D can be obtained through the introduction of substituents R4' R5' and R5' on the corresponding C atom of an unsubstituted haloheterocycle. These C-C bonds can be built through acylation of the electrophilic 5-ring with acyl halides using AlC as catalysis in DCM, optionally followed by reduction of carbonyl group with sodium boro ydride in IPA. Alternatively, these C-C bonds can be formed by reaction with ketones and powder KOH in MeOH, optionally followed by reduction of double bond with H2 gas and Pd catalysis. Other versatile methods to introduce substituents R4' R5' and R6' on the C atom of 5-ring of the haloheterocycle is through a first step of haiogenation followed by Suzuki coupling of the corresponding boronic derivative.
Compounds of Formula, Ilia, lllb, IV, Va, Vb, VI, Villa, VII lb are commercially available or may be easily obtained from commercial compound using standard procedures. For example, derivatives of B, Zn, Sn and SI of Formula Ilia, lllb and VI can be readily obtained from the corresponding halo derivatives Va, Vb and IV through halogen-metal exchange.
Finally, some compounds of the present invention can also be obtained from other compounds of
Formula (I) by appropriate conversion reactions of functional groups in one or several steps, using well-known reactions in organic chemistry under the standard experimental conditions.
Said transformations include, for example: the substitution of a primary or secondary amine by treatment with an alkylating agent under standard conditions, or by reductive amination, i.e. by treatment with an aldehyde or a ketone in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride; the conversion of an amine into a sulfonamide by reaction with a sulfonyl halide, such as sulfonyl chloride, optionally in the presence of a base such as 4-dimethylaminopyridine, in a suitable solvent such as dioxane, chloroform, dichloromethane or pyridine, optionally in the presence of a base such as triethylamine or pyridine; the conversion of an amine into an amide or urea under standard conditions; the alkylation of an amide by treatment with an alkylating agent under basic conditions; the conversion of an alcohol into an ether under standard conditions; the partial or total oxidation of an alcohol to give a ketone under standard oxidizing conditions; the reduction of a ketone by treatment with a reducing agent such as sodium borohydride; the conversion of an alcohol into a halogen by reaction with SOCI2, PBr3, tetrabutylammonium bromide in the presence of P2O5, or PCb; the conversion of halogen into an amine by reaction with an amine, optionally in the presence of a suitable solvent, and preferably heating; and the conversion of a primary amide into a -CN group under standard conditions.
Likewise, any of the aromatic rings of the compounds of the present invention can undergo electrophilic aromatic substitution reactions or nucleophilic aromatic substitution reactions, widely described in the literature.
Some of these interconversion reactions are explained in greater detail in the examples. As it will be obvious to those skilled in the art, these interconversion reactions can be carried out upon the compounds of Formula (I), thus generating further compounds of Formula (I), as well as upon any suitable synthesis intermediate thereof.
The salts of a compound of Formula (I) can be obtained during the final isolation and purification of the compounds of the invention or can be prepared by treating a compound of Formula (I) with a sufficient amount of the desired acid (or base) to give the salt in a conventional manner.
Where the processes for the preparation of the compounds of the invention give rise to mixtures of stereoisomers, individual stereoisomers of a compound of Formula (I) can be obtained for example by resolution, starting from a compound of formula (I) obtained as a mixture of stereoisomers, using well known methods such as formation of diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallization and regeneration of the free base, or by chiral preparative chromatography. Alternatively, it is possible to obtain optically pure or enantiomerically enriched synthetic intermediates, which can then be used as such in subsequent steps, at various stages of the synthetic procedures described above, using any known method for chiral resolution. Alternatively, it is possible to obtain optically pure or enantiomerically enriched final compounds (or synthetic intermediates) by using chiral chromatography.
The compounds of the invention inhibit the activity of a histone demethylase comprising a JmjC domain (JmjC-KDM). In particular, the compounds of the invention have been found to be potent inhibitors of KDM5. In addition, some compounds of the invention have been found to inhibit also KDM4 and/or KDM6.
The activity of the compounds of the invention as JmjC-KDM inhibitors can be determined using for example the in vitro assays described in the Examples section. In particular, Example 36 describes methods to determine KDM5, KDM4 and KDM6 inhibitory activity. The compounds of the invention have been found to be potent KDM5 inhibitors using the assay described in Example 36. Compounds of the invention have also been shown to inhibit JmjC-KDM activity in cells, as shown by the results described in Example 37.
A "histone demethylase" refers to an enzyme that removes at least one methyl group from an amino acid side chain (e.g. a lysine) on histones, like H3 or H4. The first histone lysine demethylase discovered was lysine specific demethylase- 1 (LSD1, also known as KDM1A), which demethylates mono- and di-methylated H3K4, using FAD as a cofactor. Subsequently a second family of histone lysine demethylases was discovered, which was named JmjC-domain containing histone demethylases (JmjC-KDMs). These Fe(l Independent enzymes catalyze the demethylation of mono-, di- and tri-methylated lysines using 2-oxoglutarate and oxygen, converting the methyl group in the methyllysine to a hydroxymethyl group, which is subsequently released as formaldehyde. This family contains over 30 members and includes the KDM2 to KDM8 subfamilies as well as JMJD6.
The KDM5 subfamily (also known as JARID1) demethylates H3K4me2/3 at the transcription start site of actively transcribed genes. There are 4 members of the KDM5 subfamily in humans: KDM5A, KDM5B, KDM5C and KDM5D.
KDM5A cooperates with retinoblastoma protein (RB) and KDM5B to control respectively cellular differentiation (Benevolenskaya E.V. ef a/. 2005, Mol Cell 18(6):623-35) and induction of senescence (Chicas A. et al. 2012, PNAS 109(23):8971-6). The oncogenic role of KDM5A is highlighted by knock out studies showing that KDM5A inactivation reduces tumor formation in Rb+/- and Men-/- mice (Lin W. ef al. 2011, PNAS 108(33): 13379-86) . In addition, in human cancer cell lines, KDM5A is required for the emergence of chemoresistant clones and its inhibition enhances the sensitivity of prostate cancer cells to cisplatin (Sharma S.V. et al. 2010, Cell 141(1):69-80). Sensitisation to anticancer therapy after KD 5A inhibition has also been described in colon, breast, cancer and Non Small Cell Lung Cancer cell lines (Vinogradova M. et al. 2016, Nature Chem Bio 10.1038/nchembio.2085). KDM5A is amplified in a subset of breast cancer cell lines and shRNA-mediated inhibition moderately reduces viability, colony formation in soft agar and drug resistance (Hou J. et al. 2012, Am J Transl Res 4(3):247-56). Similarly, KDM5A overexpression is responsible for proliferation in vitro, tumor growth in vivo, migration and invasion of lung cancer cells (Teng Y.C. ef al. 2013, Cancer Res 73(15):4711-21). KDM5A has been also described as amplified in prostate cancer (Vieira F.Q. et al. 2013, Endocr Relat Cancer 21(1):51-61), Head and Neck Squamous Carcinoma cell lines (Li H. et al. 2014, Mol Cancer Res 12(4):571-82), temozolomide-resistant glioblastomas (Bannelli B. ef al. 2015, Cell Cycle 14(21):3418-29), gastric carcinomas (Zeng J. ef al. 2010, Gastroenterology 138(3) :981-92) and cervical carcinomas (Hidalgo A. et al. 2005, BMC Cancer 5:77). In addition, KDM5A was found highly expressed in neuroendocrine tumors and it was described to promote a neoplastic phenotype in this tumor subtype (Maggi E.C. et al. 20 6, Oncogenesis 5(8):e257).Translocations involving the human KDM5A and NUP98 gene have also been described in pediatric acute megakaryoblastic leukemias (de Rooij J.D. ef al. 2013, Leukemia 27(12):2280-8).
KDM5B-mediated histone demethylation is required for inhibiting the expression of E2F target genes during induction of senescence in murine and human embryonal fibroblasts (Chicas A. ef al. 2012, PNAS 109(23):8971-6). In cancer cell lines, KDM5B represses CDKN1A expression, effectively promoting oncogenic transformation (Wong P.P. et al. 2012, Mol Cell Biol 32(9): 1633-44). Genetic inhibition of KDM5B is able to reduce proliferation, epithelial-mesenchymal transition (EMT), migration and invasion in models of hepatocellular carcinoma (Wang D. ef al. 2016, J Exp Clin Cancer Res 35:37). Similarly, the oncogenic role of KDM5B in gastric cancer is confirmed by knock down of endogenous KDM5B expression in GES-1 cells, which abolishes tumor growth and metastasis formation (Wang Z. ef al. 2014, Am J Cancer Res 5(1):87-100). Effects on invasion, migration and EMT were also described in esophageal cancer after targeting KDM5B (Kano Y. et al. 2013, Mol Clin Oncol 1(4)753-757). Cell cycle arrest and induction of senescence are the consequences of KDM5B depletion in colorectal cancer cells (Ohta K. ef al. 2013, Int J Oncol 42(4): 1212-8). High KDM5B expression is associated to worse prognosis in human patients and resistance to conventional treatment in non-Myc-amplified neuroblastoma cell lines. In the latter, shRNA-mediated KDM5B inhibition reduces clonogenic potential, migration, invasion, chemoresistance and expression of stem cell markers. In breast cancer, KDM5B has been identified as an oncogene driving the luminal subtype of tumors and associated with poor prognosis in these patients (Yamamoto S. et al. 2014, Cancer Cell 25(6)762-77). At the same time, KDM5B inhibition is also relevant in basal-like (Bamodu OA ef al. 2016, BMC Cancer 16(1):160) and advanced- stage breast cancers (Yamane K. et al. 2007, Mol Cell 25(6):801-12), and in multiple myeloma (Tumber A. ef a/. 2017, Cell Chem Biol. 24(3):371-380). Depletion of KDM5B was also shown to inhibit cell proliferation of hepatocellular carcinoma (Wang D. et al. 2016, J Exp Clin Cancer Res. 35:37). In addition, high expression of KDM5B is associated to EMT of Non-Small-Cell Lung Cancer cells (Haley J. A. ef al. 2014, Front Oncol 4:344) and reduced response to therapy and/or poorer prognosis in ovarian (Wang L. ef al. 2015, Tumour Biol 36(4):2465-72), bladder (Hayami S. ef al. 2010, Mol Cancer 9:59) and prostate cancer (Xiang Y. ef al. 2007, PNAS 104(49) : 19226-31 ) . High KDM5B expression has been observed within a small subset of melanoma cells, characterized by increased clonogenic potential and resistance to several anticancer drugs. KDM5B inhibition sensitizes melanoma cells to chemotherapy (Roesch A. ef al. 2013, Cancer Cell 23(6):811-25) and reduces tumorigenicity. High KDM5B expression was detected also in uveal melanoma (Radberger P. ef al. 2012, Invest Ophthalmol Vis Sci 53(8):4442-9).
Upregulation of KDM5B has also been described following infection with Respiratory Syncytial Virus. In this setting, an increase of antiviral function and a reduction of pulmonary disease have been described when KDM5B is inhibited in dendritic cells. These results prompt the use of KDM5B inhibitors as a possible strategy to boost the efficacy of dendritic cells-based vaccines (Ptaschinski C. ef al. 2015, PLoS Pathog 11(6):e1004978). Inhibition of KDM5 was also shown to decrease expression of Hepatitis B Virus (HBV) in human primary hepatocytes, supporting the use of KDM5 inhibitors for the treatment of HBV infection.
KDM5C co-occupy with CoREST the neuron-restrictive silencing elements, to suppress the expression of REST target genes (Aguilar-Valles A. ef al. 2014, Biol Psychiatry 76(1):57-65). Loss-of-function of this gene causes mental retardation (Jensen L.R. ef al. 2005, Am J Hum Genet 76(2):227-36) and affects memory in men and mice (Simensen R.J. ef al. 2012, Genet Couns 23(1):31-40), but can also be beneficial in neurodegenerative disease with aberrant REST activity like Huntington's disease (Vashishtha M. ef al. 2013, PNAS 110:E3027-E3036).
Inactivating mutations of KDM5C have been described in Renal Carcinoma (Dalgliesh G.L. etal. 2010, Nature 463(7279):360-3), while high KDM5C expression is associated to poor outcome in both breast (Patani N. et al. 2011, Anticancer Res 31 (12):4115-25) and prostate cancer patients (Stein J. ef al. 2014, Am J Pathol 184(9):2430-7). Genetic inactivation of KDM5C reduces invasion and migration of gastric (Xu L. ef al. 2016, Technol Cancer Res Treat Epub ahead of print), breast (Wang Q. ef al. 2015, Biochem Biophys Res Commun 464(2):659-66) and hepatocellular carcinoma cell lines (Ji X. etal. 2015, BMC Cancer 15:801).
In its turn, KDM5D has been found to be implicated in spermatogenesis and downregulated in metastatic poor-prognosis human prostate cancers (Lin N. ef al. 2016, Cancer Res 76(4):831-43).
The KDM4 subfamily (also known as JMJD2) demethylates mainly H3K9me3/2 and H3K36me3/2. KDM4A, KDM4B and KDM4C are highly conserved in all vertebrates and demethylate both H3K9 and H3K36, while KDM4D only accepts H3K9 substrates (Whetstine J.R. ef al. 2006, Cell 125(3):467-81). KDM4 proteins work as transcriptional coactivators by removing the repressive marks H3K9me3/me2, therefore inducing genomic instability (Peters A.H. ef al. 2001, Cell 107(3):323-37) or activating transcription by derealization of HP1 (Cloos, P.A. ef al. 2006, Nature 442: 307-311). KDM4A can also work as a transcriptional repressor: it directly interacts with the N-terminal region of the corepressor N-CoR or histone deacetylases (Zhang D. et al. 2005, Mol Cell Biol 25:6404-14). The KDM4 subfamily has been reported to play a role in oncogenesis and cancer progression.
In breast cancer, mRNA levels of KD 4A, KDM4B and KDM4C are upregulated. KDM4A is critical for growth of both ER-positive and -negative breast tumors (Berry W.L. et al. 2012, Int J Oncol; 41:1701-6). KDM4B expression is higher in ER-positive than in ER-negative breast tumors, where it forms complexes with estrogen receptor a (ERa) and its downregulation in MCF7 or T47D cells reduces cell proliferation and tumor formation in nude mice (Shi L. ef al. 2011, Proc Natl Acad Sci USA. 108(18)7541-6). KDM4C gene is amplified in ER negative cell lines, particularly in aggressive, basal-like subtypes. Exogenous overexpression of KDM4C in MCF10A cells induces transformed phenotypes, including mammosphere forming ability. Additionally, KDM4C demethylase activity regulates the expression of genes critical for stem cell self-renewal, including NOTCH 1, and may be linked to the stem cell phenotypes (Liu G. etal. 2009, Oncogene. 28(50):4491-500).
KDM4 proteins are also involved in colon cancer: KDM4A interacts with p53 in stimulating proliferation and survival in HCT116 and in other colon cancer cell lines (Kim T.D. ef al. 2012, Carcinogenesis 113(4):1368- 76). KDM4B is required for increased transcription of many hypoxia-inducible genes in colorectal cancer cell lines. (Fu L. ef al. 2012, Carcinogenesis 33:1664-73) and also promotes a pro-survival gene expression response in renal cancer cells through the accumulation of HIF1a (Beyer S. ef al. 2008, J Biol Chem. 283:36542-36552). KDM4C mediates colonosphere formation through a mechanism involving cross talk between the Wnt and Notch pathways (Yamamoto S. etal. 2013, Carcinogenesis 34( 0):2380-8).
KDM4A is overexpressed in mouse and human lung cancer cell lines, where it could function as an oncogene that represents a target for Ras expressing tumors (Mallette F.A. ef al. 2012, Cell Reports 2:1233- 1243). High level of KDM4A in clinical gastric cancer tissues predicts poor prognosis (Hu C.E. et al. 2014, Biochem Biophys Res Commun. 449(1): 1-7). KDM4B has a role in the growth regulation of bladder and lung cancer cells, through the demethylation of H3K9 at the promoter region of CDK6 (Toyokawa G. ef al. 2011, Cancer Prev Res 4(12):2051-61).
Knockdown of KDM4B in gastric cancer cell lines inhibits cell proliferation and/or induces apoptosis, increases the expression of p53 and p21(CIP1) proteins and suppresses xenograft tumor growth in vivo (Li W. ef al. 2011, Biochem Biophys Res Commun. 416(3-4):372-8). KDM4B was also shown to promote EMT in pancreatic cancer cells (Li S. ef al. 2015, Acta Biochim Biophys Sin 47(12):997-1004).
KDM4A, KDM4B and KDM4C are key in androgen signaling and potential progression factors for prostate cancer (Shin S. ef al. 2007, Biochem Biophys Res Commun 359:742-6). KDM4C is coexpressed with LSD1 and androgen receptor in human prostate tumors, and knockdown of either LSD1 or KDM4C severely inhibits androgen dependent proliferation of prostate tumor cells. (Wissmann M. ef al. 2007, Nat Cell Biol. 9(3):347-53). KD 4A is a determinant for invasiveness and metastasis in squamous cell carcinoma (Ding X. ef al. 2013, Sci Signal. 6(273):ra28.1-15). KDM4C (also known as JMJD2C or GASC1: gene amplified in squamous cell carcinoma 1) was first identified in cell lines derived from esophageal squamous cell carcinomas (Yang Z.Q. ef al. 2001, Jpn J Cancer Res. 92(4):423-8). The KDM4C gene lies in the 9p23-p24 chromosome region, which is found to be amplified in various malignancies including non-small cell lung cancers, carcinomas of liver, ovary, uterine cervix, as well as osteosarcomas, mucosa associated lymphoid tissue lymphoma and desmoplastic medulloblastomas (Knuutila, S. etal. 1998, Am. J. Pathol. 152:1107-1123).
In mediastinal thymic B-cell lymphomas and Hodgkin lymphomas KDM4C and the tyrosine kinase JAK2, cooperate to promote proliferation and survival and their combined inhibition exerts synergic toxicity (Rui L. et al. 2010, Cancer Cell. 18(6):590-605). In acute leukemia, KDM4C is required for leukemic transformation together with the H4R3 methyl transferase PRMT1. Genetic or pharmacological inhibition of KDM4C/PRMT1 suppresses transcription and transformation abilities of the MOZ-TIF2 and MLL fusions (Cheung N. ef al. 2016, Cancer Cell. 29(1):32-48).
KDM4C is also involved in regulation of self-renewal in embryonic stem cells (Loh.Y.H. et al. 2007 Genes Dev. 21: 2545-2557) and modulates regulation of adipogenesis by the nuclear receptor PPARy (Lizcano F. etal. 2011, Genet Mol Biol 34(1): 19-24).
The KDM4 subfamily has also been described to be involved in viral infection. In particular, the initial phase of the infection of Herpes Simplex Virus requires KDM4A (Liang et al. 2013, Sci Transl Med. 5(167):167ra5). Moreover, knockdown of KDM4A attenuates viral titers, whereas its overexpression increases Kaposi's sarcoma-associated herpesvirus (KSHV) reactivation (Chang ef al. 2011 , J Virol. 85(7):3283-93).
KDM6B, also called Jumonji domain-containing protein D3 (JMJD3), and KDM6A, also called ubiquitously transcribed X-chromosome tetratricopeptide repeat protein (UTX), specifically demethylate H3K27me2 and H3K27me3 (Xiang etal. 2017, Cell Res 17(10):850-7).
KDM6B has been described to play an important role in many cellular processes linked to both solid and hematological cancers. KDM6B was shown to be recruited to estrogen receptor enhancers in breast cancer cells, leading to activation of the anti-apoptotic protein, BCL2 (Svotelis ef al.2011, EMBO J. 30(19):3947-61.). In mammary epithelial cells, KDM6B allows for TGF-p-induced epithelial-to-mesenchymal transition (EMT) through expression of SNAI1, leading to breast cancer invasion (Ramadoss ef al. 2012, J Biol Chem. 287(53):44508-17.). In colon cancer cells, it was shown that vitamin D leads to the expression of EMT genes such as ZEB1, ZEB2, and SNAI1, through upregulation of KDM6B (Pereira et al. 2012, Cell Cycle. 11(6):1081-9). In Human Papilloma Virus (HPV)+ cervical carcinoma cell lines where retinoblastoma tumor suppressor is inactivated, HPV E7 expression causes an acute dependence on KDM6B expression for cell survival through the downstream regulation of the p16INK4A tumor suppressor ( cLaughlin-Drubin ef al. 2013, PNAS 110(40):16175-80). While KDM6B did not affect proliferation of melanoma cells, it was shown to confer enhanced clonogenicity, self-renewal, and transendothelial migration (Park ef al. 2016, Cancer Res 76(1):161- 70). Upregulation of KDM6B was found in renal cell carcinoma compared to normal tissue (Shen ef al. 2012, BMC Cancer 12:470). Additionally, the pro-metastatic activity of the long noncoding NA HOTAIR in renal cell carcinoma cells was associated to the upregulation of KDM6B (Xia ef a/. 2017, Oncotarget). High levels of H3K27 trimethylation and KDM6B were also found to associate with prostate cancer progression (Xiang ef al. 2007, Cell Res. 17(10):850-7). KDM6B was demonstrated to be a critical driver of hepatocellular carcinoma stem cell-like and metastatic behaviors (Tang et al. 2016, Cancer Res 76(22) :6520-6532) . Similarly, in ovarian cancer stem cells inhibition of KDM6A/B induced cell death and decreased their tumor-initiating capacity (Sakaki ef al. 2015, Anticancer Res35(12):6607-14). Several tumors of the central neuronal system have been shown to depend on the activity of KDM6B activity. Gene expression analysis of glioma patient databases revealed high expression levels of KDM6B in patients with high-grade glioma. Furthermore, pharmacologic inhibition of histone demethylation was demonstrated to reduce tumor growth in preclinical model of pediatric brainstem glioma. Importantly, a similar effect was reproduced by inhibiting specifically KDM6B using siRNA (Hashizume ef al. 2014, Nat Med 20( 2): 1394-6.). In addition, growth of glioblastoma stem cells resistant to the treatment with tyrosine kinase inhibitors was dependent on the expression of KDM6A B (Liau ef al. 2017, Cell Stem Cell 20(2):233-246.e7). KDM6A/B were also found highly expressed in mesotheliomas and their inhibition resulted in apoptosis of malignant mesothelioma cells (Cregan ef al. 2017, Int J Oncol. 50(3): 1044-1052). Finally, the central role of KDM6B in regulating Sonic Hedgehog (Shh)-activated gene expression was demonstrated in vivo in Shh activation-dependent model of medulloblastoma (Shi et al. 2014, Nat Commun 5:5425).
KDM6B has also been shown to have a role in myelodysplastic syndromes (MDS). Peripheral blood CD34+ stem cells in patients with MDS have increased expression of KDM6B and an increased ability to form erythroid colonies upon inhibition of KDM6B (Wei ef al. 2013, Leukemia 27(11):2177-86). This suggests that KDM6B is implicated in hematopoietic lineage determination, and inhibiting KDM6B could be an option for MDS patients presenting with anemia. MDS may transform into diseases such as acute lymphoblastic leukemia (ALL). KDM6B was shown to act as an oncogene in T-ALL, allowing for initiation and maintenance of T-ALL (Ntziachristos ef al. 2014, Nature 514(7523):513-7.). KDM6B has also been shown to be involved in Hodgkin's Lymphoma (Anderton et al. 2011, Oncogene 30(17):2037-43). Moreover, KDM6B promoted survival of diffuse large B-cell lymphoma while inhibition of KDM6B sensitized diffuse large B-cell lymphoma to chemotherapeutic drugs (Marthur ef al. 2017, Haematologica 102(2):373-380).
A role for KDM6A and KDM6B in viral infection has also been suggested by many recent publications. Kaposi's Sarcoma Human Virus PAN RNA was found associated with both KDM6A and KDM6B. This physical interaction with the virus genome appears important to activate lytic replication (Rossetto et al. 2012, PLoS Pathog. 8(5):e1002680). KDM6B was found to enhance the expression of the transcription efficiency of HBV enhancer ll/core promoter (En II) in a C/EBPa-dependent manner (Chen ef al. 2016, Sci Rep. 6:35974). Furthermore, KDM6A and KDM6B expression were both induced by HPV E7 oncoprotein (McLaughlin-Drubin ef al. 2011, PNAS 108(5) :2130-5) while KDM6B was found induced by Epstein-Barr Virus (Anderton ef al. 2011, Oncogene 30(17):2037-43). The compounds of the invention are thus expected to be useful for treating diseases associated with activity of a JmjC-KDM, e.g. a KDM5 protein. For the uses and methods of treatment described herein, any of the compounds of the invention, including any of the embodiments thereof, may be used.
Accordingly, the invention further provides a compound of Formula (I), or pharmaceutically acceptable salt thereof, for use as a medicament.
The present invention further provides a compound of Formula (I), or pharmaceutically acceptable salt thereof, for use in treating a disease associated with a JmjC-KDM.
The present invention further provides the use of a compound of Formula (I), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease associated with a JmjC- KDM, particularly a KDM5 and/or KDM6 and/or KDM4.
The present invention further provides the use of a compound of Formula (I), or pharmaceutically acceptable salt thereof, for treating a disease associated with a JmjC-KDM, particularly a KDM5 and/or KDM6 and/or KDM4.
The present invention further provides a method for treating a disease associated with a JmjC-KDM, particularly a KDM5 and/or KDM6 and/or KDM4, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
The present invention further provides a method of inhibiting a JmjC-KDM, particularly a KDM5 and/or KDM4 and/or KDM6 activity, comprising administering to a patient in need of said treatment an amount of a compound of Formula (I), or pharmaceutically acceptable salt thereof, sufficient to inhibit a KDM5 and/or KDM4 and/or KDM6 activity.
The present invention further provides a method of inhibiting a KDM5 and/or KDM4 and/or KDM6 activity in a biological sample, comprising contacting said biological sample with a compound of Formula (I), or pharmaceutically acceptable salt thereof.
The present invention further provides the use of a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (la), (lb),(ld) or (le), more preferably of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, as a JmjC-KDM inhibitor in research, particularly as a research tool compound for inhibiting a JmjC-KDM, such as KDM5, KDM4 and/or KDM6 (particularly for inhibiting KDM5) . Accordingly, the invention relates to the in vitro use of a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (la), (lb),(ld) or (le), more preferably of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, as a JmjC-KDM inhibitor (particularly as a KDM5 inhibitor) and, in particular, to the in vitro use of a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (la), (lb),(ld) or (le), more preferably of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, as a research tool compound acting as a JmjC-KDM inhibitor. The invention likewise relates to a method, particularly an in vitro method, of inhibiting a JmjC-KDM (such as KDM5, KDM4 and/or KDM6; particularly KDM5), the method comprising applying a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (la), (lb),(ld) or (le), more preferably of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, to a sample. It is to be understood that the term "in vitro" is used in this specific context in the sense of "outside a living human or animal body", which includes, in particular, experiments performed with cells, cellular or subcellular extracts, and/or biological molecules in an artificial environment such as an aqueous solution or a culture medium which may be provided, e.g., in a flask, a test tube, a Petri dish, a microtiter plate, etc.
In some embodiments, said KDM5 is KDM5B. In some embodiments, said KDM4 is KDM4C. In some embodiments, said KDM6 is KDM6B.
The present invention further provides a compound of Formula (I), or pharmaceutically acceptable salt thereof, for use in treating cancer. In some embodiments, the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, renal cancer, pancreatic cancer, neuroendocrine tumors, melanoma, glioblastoma, medulloblastoma, neuroblastoma, mesothelioma, multiple myeloma, osteosarcoma, lymphoma and leukemia. In some embodiments, the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, melanoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, lymphoma and leukemia.
The present invention further provides the use of a compound of Formula (I), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer. In some embodiments, the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, renal cancer, pancreatic cancer, neuroendocrine tumors, melanoma, glioblastoma, medulloblastoma, neuroblastoma, mesothelioma, multiple myeloma, osteosarcoma, lymphoma and leukemia. In some embodiments, the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, melanoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, lymphoma and leukemia.
The present invention further provides the use of a compound of Formula (I), or pharmaceutically acceptable salt thereof, for treating cancer. In some embodiments, the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, renal cancer, pancreatic cancer, neuroendocrine tumors, melanoma, glioblastoma, medulloblastoma, neuroblastoma, mesothelioma, multiple myeloma, osteosarcoma, lymphoma and leukemia. In some embodiments, the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, melanoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, lymphoma and leukemia.
The present invention further provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof. In some embodiments, the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, renal cancer, pancreatic cancer, neuroendocrine tumors, melanoma, glioblastoma, medulloblastoma, neuroblastoma, mesothelioma, multiple myeloma, osteosarcoma, lymphoma and leukemia In some embodiments, the cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, melanoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, lymphoma and leukemia.
The present invention further provides a compound of Formula (I), or pharmaceutically acceptable salt thereof, for use in treating a viral infection. In some embodiments, such viral infection is an infection caused by an herpes virus, hepatitis B virus, respiratory synctial virus, Kaposi sarcoma virus or Epstein-Barr virus.
The present invention further provides the use of a compound of Formula (I), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a viral infection. In some embodiments, such viral infection is an infection caused by an herpes virus, hepatitis B virus, respiratory synctial virus, Kaposi sarcoma virus or Epstein-Barr virus.
The present invention further provides the use of a compound of Formula (I), or pharmaceutically acceptable salt thereof, for treating a viral infection. In some embodiments, such viral infection is an infection caused by an herpes virus, hepatitis B virus, respiratory synctial virus, Kaposi sarcoma virus or Epstein-Barr virus.
The present invention further provides a method for treating a viral infection, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof. In some embodiments, such viral Infection is an infection caused by an herpes virus, hepatitis B virus, respiratory synctial virus, Kaposi sarcoma virus or Epstein-Barr virus.
Unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein, as well as use of the compounds to prepare a medicament to treat such condition.
Any reference to a compound of Formula (I) herein includes a reference to any of the compounds of Formula (la), (lb), (lc), (Id), (le), (If), (Ig), (Ih), (li), (Ij) or (II) and any embodiments thereof as described herein.
The terms "disease associated with JmjC-KDMs", "disease associated with a JmjC-KDM", "disorder associated with JmjC-KDMs", "JmjC-KDM-associated disease", "JmjC-KDM-mediated disease" and the like refer to any disease or condition in which a JmjC-KDM, such as a KDM5 and/or a KDM4 and/or KDM6, plays a role, and/or where the disease or condition is associated with expression or activity of a JmjC-KDM, such as a KDM5 and/or a KDM4 and/or a KDM6, and/or diseases or conditions the course of which can be influenced by modulating the methylation status of histones or other proteins, wherein said methylation status is mediated at least in part by the activity of a JmjC-KDM, such as a KDM5 and/or a KDM4 and/or a KDM6. Modulation of the methylation status of histones can in its turn influence the level of expression of target genes activated by methylation and/or target genes suppressed by methylation.
Diseases associated with a KDM5 and/or a KDM4 and/or a KDM6 include, without limitation, the diseases and conditions as described herein. In some embodiments, said disease is cancer, such as breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, renal cancer, pancreatic cancer, neuroendocrine tumors, melanoma, glioblastoma, medulloblastoma, neuroblastoma, mesothelioma, multiple myeloma, osteosarcoma, lymphoma and leukemia In some embodiments, said cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, melanoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, lymphoma and leukemia. In some embodiments, said cancer is drug-resistant cancer. In some embodiments, said disease is a viral infection. In some embodiments, such viral infection is an infection caused by an herpes virus, hepatitis B virus, respiratory synctial virus, Kaposi sarcoma virus or Epstein-Barr virus.
As used herein, the term "subject" or "patient" or "individual" refers to any animals, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swince, cattle, sheep, horses, or primates, and most preferably humans.
As used herein, the term "biological sample" includes, without limitation, a cell, cell cultures or extracts thereof; biopsied material obtained from an animal, e.g. a human, or extracts thereof; and blood, saliva, urine, feces, or any other body fluids or extracts thereof.
As used herein, the term "therapeutically effective amount" refers to the amount of active compound that elicits the biological or medicinal response that is being sought in subject (preferably a human). Accordingly, a therapeutically effective amount of a compound may be an amount which is sufficient to treat a disease or disorder, delay the onset or progression of a disease or disorder, and/or alleviate one or more symptoms of the disease or disorder, when administered to a subject suffering from said disease or disorder. The precise effective amount for a subject will depend upon a variety of factors such as the subject's body weight, size and health, the nature and extent of the condition to be treated, and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgement of the clinician.
For any compound, the therapeutically effective amount can be estimated initially either in in vitro assays, e.g. cell culture assays, or in animal models, e.g. mice, rats or dogs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity may be determined by standard procedures in cell cultures or experimental animals, e.g. ED50 and LD50 values can be determined and the ratio between toxic and therapeutic effects, also known as therapeutic index, may be calculated and used to determine suitable doses for use in humans.
As used herein, unless otherwise stated, the term "treating" and "treatment" in relation to a disease, disorder or condition refers to the management and care of a patient for the purpose of combating a disease, disorder or condition, such as to reverse, alleviate, inhibit the process of, or prevent the disease, disorder or condition to which such term applies, or one or more symptoms of such disease, disorder or condition, and includes the administration of a compound of the invention (or a pharmaceutically acceptable salt thereof) to prevent the onset of the symptoms or the complications, or alleviating the symptoms or complications, or eliminating the disease, condition or disorder. Preferably, treatment is curative or ameliorating.
While it is possible that a compound of the invention may be administered for use in therapy directly as such, it is typically administered in the form of a pharmaceutical composition. These compositions comprise a compound of the invention (or a pharmaceutically acceptable salt thereof) as active pharmaceutical ingredient together with one or more pharmaceutically acceptable carriers. For the purposes of the invention, a carrier is suitable for use in the pharmaceutical compositions described herein if it is compatible with the other ingredients of the composition and not deleterious to the recipient of the composition. A "pharmaceutically acceptable carrier" includes non-API (API refers to Active Pharmaceutical Ingredient) substances, such as disintegrators, binders, fillers, lubricants and the like, used in formulating pharmaceutical products and regarded as safe for administering to subjects (particularly humans) according to established governmental standards, including those promulgated by the United States Food and Drug Administration and the European Medical Agency.. Pharmaceutically acceptable carriers are well known to those skilled in the art and are selected on the basis of the chosen type of formulation and route of administration, according to standard pharmaceutical practice as described for example in Remington: The Science and Practice of Pharmacy 22nd edition, edited by Loyd V Allen Jr, Pharmaceutical Press, Philadelphia, 2012).
Accordinly, provided herein is a pharmaceutical composition comprising a compound of Formula (I) (including any of its subgenus of Formula (la), (lb), (lc), (Id), (le), (If), (Ig), (Ih), (li), (Ij) or (II) and any embodiments thereof as described herein), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical! acceptable carriers.
Pharmaceutical compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, for example via oral, parenteral, pulmonary or topical route. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pulmonary administration includes e.g. by inhalation or insufflation of powders or aerosols, including by nebulizer. Topical administration includes transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery.
The compositions can be formulated as to provide quick (immediate), sustained or delayed release of the active ingredient after administration to the patient by using methods known in the art.
Examples of pharmaceutically acceptable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, staches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, and methyl cellulose. The pharmaceutical compositions can additionally include further pharmaceutically acceptable excipients including: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emusifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; flavouring agents; and colouring agents.
Suitable oral dosage forms include, for examples, tablets, pills, sachets or capsules of hard or soft gelatin or any other suitable material. For example, the active compound can be incorporated into a formulation that includes pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating agents (e.g., alginate, Primogel, corn starch), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint). They can then be compressed into tablets or enclosed in capsules using conventional techniques. The capsules and tablets can also be coated with various coatings known in the art to modify the flavors, tastes, colors, and shapes of the capsules and tablets. In addition, liquid carriers such as fatty oil can also be included in capsules. Oral formulations can also be in the form of suspensions, solutions, syrups and the like. If desired, conventional agents for modifying flavors, tastes, color and the like can be added.
Pharmaceutical compositions suitable for parenteral administration include sterile aqueous solutions or suspensions, or can be alternatively prepared in lyophilized form for extemporaneous preparation of a solution or suspension using a sterile aqueous carrier prior to use. In such formulations, diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used. Other conventional solvents, pH buffers, stabilizers, anti-bacterial agents, surfactants, and antioxidants can all be included. For example, useful components include sodium chloride, acetates, citrates or phosphates buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like. The parenteral formulations can be stored in any conventional containers such as vials and ampoules.
Compositions for administration by inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositons may include suitable pharmaceutically acceptable excipients as described above. Such compositions maye be administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of a suitable gas. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask or the breathing chamber. Solutions, suspensions and powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
Pharmaceutical compositions for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Topical formulations can contain one or more conventional carriers. For example, ointments can contain water and one or more hydrophobic carriers selected from liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components such as cetylstearyl alcohol, glycerin monostearate and the like. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other excipients such as glycerol, hydroxyethyl cellulose and the like.
The pharmaceutical compositions, like oral and parenteral compositions, can be formulated in unit dosage forms for ease of administration and uniformity of dosage. As used herein, "unit dosage forms" refers to physically discrete units suitable as unitary dosages for administration to subjects, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with one or more suitable pharmaceutical carriers.
In therapeutic applications, pharmaceutical compositions are to be administered in a manner appropriate to the disease to be treated, as determined by a person skilled in the medical arts. An appropriate dose and suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the disease, the particular form of the active ingredient, the method of administration, among others. In general, an appropriate dose and administration regimen provides the pharmaceutical composition in an amount sufficient to provide therapeutic benefit, for example an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or lessening of symptoms severity, or any other objetively identifiable improvement as noted by the clinicial. Effective doses may generally be assessed or extrapolated using experimental models like dose- response curves derived from in vitro or animal model test systems.
The pharmaceutical compositions of the invention can be included in a container, pack or dispenser together with instructions for administration.
The compounds of the invention can be administered in monotherapy (e.g., without concomitantly administering any further therapeutic agents, or without concomitantly administering any further therapeutic agents against the same disease that is to be treated with the compound of the invention). In particular, they can be used in the monotherapeutic treatment of cancer (i.e., without administering any other antineoplastic agent until the treatment with the compound of the invention is terminated). Accordingly, the invention also provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier, for use in the monotherapeutic treatment of cancer. The compounds of the invention can also be administered in combination with another active agent as long as the other active agent does not interfere with or adversely affect the effects of the active compounds of this invention. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each additional active agent in its own separate pharmaceutical dosage formulation. If administered separately, the administration can be simultaneous, sequential or separate, and the compound of the invention and the additional therapeutic agent(s) can be administered via the same administration route or using different administration routes, for example one compound can be administered orally and the other intravenously.
Typically, for combination therapy with a compound of the invention in the field of cancer, any antineoplastic agent that has activity versus a cancer being treated or prevented with a compound of the invention may be used. As used herein, "antineoplastic agent" refers broadly to any agent used in the therapy of cancer, including chemotherapy and/or radiotherapy.
Examples of antineoplastic agents that can be used in combination with the compounds and methods of the present invention include, in general, and as appropriate, alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors. Exemplary classes of antineoplastic agents include the anthracyclines, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones, discodermolides, pteridines, diynenes and podophyllotoxins. Particularly useful members of those classes include, for example, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5- fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo- phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like. Other useful antineoplastic agents include estramustine, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
In some embodiments, the antineoplastic agent to be administered for combination therapy may be selected, as appropriate, from: a tumor angiogenesis inhibitor (for example, a protease inhibitor, an epidermal growth factor receptor kinase inhibitor, or a vascular endothelial growth factor receptor kinase inhibitor); a cytotoxic drug (for example, an antimetabolite, such as purine and pyrimidine analog antimetabolites); an antimitotic agent (for example, a microtubule stabilizing drug or an antimitotic alkaloid); a platinum coordination complex; an anti-tumor antibiotic; an alkylating agent (for example, a nitrogen mustard or a nitrosourea); an endocrine agent (for example, an adrenocorticosteroid, an androgen, an anti-androgen, an estrogen, an anti- estrogen, an aromatase inhibitor, a gonadotropin-releasing hormone agonist, or a somatostatin analog); or a compound that targets an enzyme or receptor that is overexpressed and/or otherwise involved in a specific metabolic pathway that is misregulated in the tumor cell (for example, ATP and GTP phosphodiesterase inhibitors, histone deacetylase inhibitors, protein kinase inhibitors (such as serine, threonine and tyrosine kinase inhibitors (for example, Abelson protein tyrosine kinase)) and the various growth factors, their receptors and kinase inhibitors therefor (such as epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin-like growth factor receptor inhibitors and platelet-derived growth factor receptor kinase inhibitors)); aminopeptidase inhibitors; proteasome inhibitors; cyclooxygenase inhibitors (for example, cyclooxygenase-1 or cyclooxygenase-2 inhibitors); topoisomerase inhibitors (for example, topoisomerase I inhibitors or topoisomerase II inhibitors); or retinoid agents.
An alkylating agent which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, a nitrogen mustard (such as cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, ortrofosfamide), a nitrosourea (such as carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), an alkyl sulfonate (such as busulfan, mannosulfan, or treosulfan), an aziridine (such as hexamethylmelamine (altretamine), triethylenemelamine, ThioTEPA (Ν,Ν'Ν'-triethylenethiophosphoramide), carboquone, or triaziquone), a hydrazine (such as procarbazine), a triazene (such as dacarbazine), or an imidazotetrazines (such as temozolomide).
A platinum coordination complex which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, or triplatin tetranitrate.
A cytotoxic drug which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, an antimetabolite, including folic acid analog antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analog antimetabolites (such as cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6- thioguanine), and pyrimidine analog antimetabolites (such as cytarabine, decitabine, azacytidine, 5-fluorouracil (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, orsapacitabine).
An antimitotic agent which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, a taxane (such as docetaxel, larotaxel, ortataxel, paclitaxel/taxol, or tesetaxel), a Vinca alkaloid (such as vinblastine, vincristine, vinflunine, vindesine, vinzolidine, or vinorelbine), an epothilone (such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, or epothilone F) or an epothilone B analog (such as ixabepilone/azaepothilone B).
An anti-tumor antibiotic which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, an anthracycline (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin), an anthracenedione (such as mitoxantrone, or pixantrone) or an anti-tumor antibiotic isolated from Streptomyces (such as actinomycin (including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin).
An inhibitor of MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example a B-Raf inhibitor like vemurafenib (PLX4032), encorafenib or dabrafenib, or a MEK inhibitor like cobetinib, binimetinib, selumetinib ortrametinib.
A tyrosine kinase inhibitor which can be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, orvandetanib.
A topoisomerase-inhibitor which can. be used as an antineoplastic agent in combination with a compound of the present invention may be, for example, a topoisomerase I inhibitor (such as irinotecan, topotecan, camptothecin, belotecan, rubitecan, or lamellarin D) or a topoisomerase II inhibitor (such as amsacrine, etoposide, etoposide phosphate, teniposide, or doxorubicin).
Further antineoplastic agents may be used in combination with a compound of the present invention. The antineoplastic agents may include biological or chemical molecules, such as TNF-related apoptosis- inducing ligand (TRAIL), tamoxifen, toremifene, fluoxymesterol, raloxifene, diethylstibestrol, bicalutamide, nilutamide, flutamide, aminoglutethimide, anastrozole, tetrazole, luteinizing hormone release hormone (LHRH) analogues, ketoconazole, goserelin acetate, leuprolide, megestrol acetate, prednisone, mifepristone, amsacrine, bexarotene, estramustine, irofulven, trabectedin, cetuximab, panitumumab, tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, alvocidib, seliciclib, aminolevulinic acid, methyl aminolevulinate, efaproxiral, porfimer sodium, talaporfin, temoporfin, verteporfin, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur, celecoxib, demecolcine, elesclomol, elsamitrucin, etoglucid, lonidamine, lucanthone, masoprocol, mitobronitol, mitoguazone, mitotane, oblimersen, omacetaxine, sitimagene, ceradenovec, tegafur, testolactone, tiazofurine, tipifarnib, and vorinostat.
Examples of retinoid agents include all natural, recombinant, and synthetic derivatives or mimetics of vitamin A, for example, retinyl palmitate, retinoyl-beta-glucuronide (vitamin A1 beta-glucuronide), retinyl phosphate (vitamin A1 phosphate), retinyl esters, 4-oxoretinol, 4-oxoretinaldehyde, 3-dehydroretinol (vitamin A2), 11-cis-retinal (11-cis-retinaldehyde, 11-cis or neo b vitamin A1 aldehyde), 5,6-epoxyretinol (5,6-epoxy vitamin A1 alcohol), anhydroretinol (anhydro vitamin A1) and 4-ketoretinol (4-keto-vitamin A1 alcohol), all-trans retinoic acid (ATRA; Tretinoin; vitamin A acid; 3,7-dimethyl-9-(2,6,6,-trimethyl-1-cyclohenen-1-yl)-2,4,6,8- nonatetraenoic acid [CAS No. 302-79-4]), lipid formulations of all-trans retinoic acid (e.g., ATRA-IV), 9-cis retinoic acid (9-cis-RA; Alitretinoin; Panretin™; LGD1057), 13-cis retinoic acid (Isotretinoin), (E)-4-[2-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propenyl]-benzoic acid, 3-methyl-(E)-4-[2-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydro-2-naphthalenyl)-l-propenyl]-benzoic acid, Fenretinide (N-(4-hydroxyphenyl)retinamide; 4- HPR), Etretinate ((all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester; Tegison), Acitretin ((all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid; Ro 10-1670; Soriatane; Neotigason), Tazarotene (ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl] nicotinate; Tazorac; Avage; Zorac), Tocoretinate (9-cis-tretinoin; Tocoferil), Adapalene (6-[3-(1-adamantyl)-4- methoxyphenyl]-2-naphthoic acid; Differin), Motretinide (trimethylmethoxyphenyl-N-ethyl retinamide; Trasmaderm), retinaldehyde (Retinal), CD437 (6-[3-(1-adamantyl)-4-hydroxyphenyl)-2-naphthalene carboxylic acid; AHPN), CD2325, ST1926 ([E-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid), ST1878 (methyl 2-[3- [2-[3-(2-methoxy-1 , 1 -dimethyl-2-oxoethoxy)phenoxy]ethoxy]phenoxy]isobutyrate), ST2307, ST1898, ST2306, ST2474, MM11453, MM002 (3-CI-AHPC), MX2870-1, MX3350-1, MX84, and MX90-1, docosahexaenoic acid (DHA), phytanic acid (3,7,11 ,15-tetramethyl hexadecanoic acid), MS6682 (methoprene acid), LG100268 (LG268), LG100324, SR11203
Figure imgf000063_0001
naphthalenyl)-1,3-dithiane), SR11217 (4-(2-methyl-1-(5,6J,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)propenyl)benzoic acid), SR11234, SR11236 (2-(4-carboxyphenyl)-2-(5,6,718-tetrahydro-5)5,8,8- tetramethyl-2-naphthalenyl)-1,3-dioxane), SR11246, AGN194204, derivatives of 9-cis-RA such as LGD1069 (3- methyl TTNEB; Bexarotene; Targretin®; 4-[1-(5,6,7>8-tetrahydro-3)5,5,8J8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid).
Examples of histone deacetylase inhibitors include, without limitation, MS-275 (SNDX-275; Entinostat),
FK228 (FR901228; depsipeptide; Romidepsin), CI-994 (Acetyldinaline; Tacedinaline), Apicidin (cyclo[(2S)-2- amino-8-oxodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-(2R)-2-piperidinexcarbonyl]), A-161906 (7-[4-(4- cyanophenyl)phenoxy]-heptanohydroxamic acid), Scriptaid (6-(1 ,3-Dioxo-1 H,3H-benzo[de]isoquinolin-2-yl)- hexanoic acid hydroxyamide), PXD-101 (Belinostat), Panobinostat, CHAP (cyclic hydroxamic acid-containing peptide), LAQ-824 (Dacinostat), BML-EI319 (Depudecin), 03139 (Oxamflatin), NSC 696085 (Pyroxamide), MW2796; MW2996, T2580 (Trapoxin A), AN-9 (Pivanex), W222305 (Tributyrin) Trichostatin A, Trichostatin C, Butyric acid, Valproic acid (VPA), Suberoylanilide hydroxamic acid (SAHA; Vorinostat), m-Carboxycinnamic acid bishydroxamide (CBHA), Salicylbishydroxamic acid (S607; SHA; SHAM); Suberoyl bishydroxamic acid (SBHA); Azelaic bishydroxamic acid (ABHA); Azelaic-1-hydroxamate-9-anilide (AAHA); 3CI-UCHA (6-(3- chlorophenylureido) caproic hydroxamic acid); and sodium butyrate, 4-phenylbutyrate, phenylacetate, valerate, isovalerate, butyramide, isobutyramide, 3-bromopropionate, and valproate.
Also biological drugs, like antibodies, antibody fragments, antibody constructs (for example, single- chain constructs), and/or modified antibodies (like CDR-grafted antibodies, humanized antibodies, "full humanized" antibodies, etc.) directed against cancer or tumor markers/factors/cytokines involved in cancer can be employed in cotherapeutic approaches with the compounds of the invention. Examples of such biological molecules are alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rituximab, rovelizumab, rolizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.
Other biologic agents include, but are not limited to, immunomodulating proteins such as cytokines
(such as interleukin-2 (IL-2, Aldesleukin), Epoietin-alpha.; EPO), granulocyte-CSF (G-CSF; Filgrastin), and granulocyte-macrophage-CSF (GM-CSF; Sargramostim) and interferons, (e.g., interferon-alpha, interferon-beta and interferon-gamma), bacillus Calmette-Guerin, levamisole, and octreotide, endostatin, tumor suppressor genes (e.g., DPC4, NF- 1, NF-2, B, p53, WT1, BRCA1, and BRCA2), and cancer vaccines (e.g., tumor associated antigens such as gangliosides (GM2), prostate specific antigen (PSA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) (produced by colon cancers and other adenocarcinomas, e.g., breast, lung, gastric, and pancreatic cancers), melanoma-associated antigens ( ART-I, gaplOO, MAGE 1,3 tyrosinase), papillomavirus E6 and E7 fragments, whole cells or portions/lysates of autologous tumor cells and allogeneic tumor cells.
In another aspect, the invention relates to methods of treating or preventing drug resistance in a patient using a compound as described herein. For example, a method of treating or preventing drug resistant cancer in a patient comprises administering a therapeutically effective amount of a compound of the invention to the patient alone or in combination with an antineoplastic agent. In some embodiments, the patient starts treatment comprising administration of a compound of the invention prior to treatment with the antineoplastic agent. In some embodiments, the individual concurrently receives treatment comprising the compound of the invention and the antineoplastic agent, in some embodiments, the compound of the invention increases the period of cancer sensitivity and/or delays development of cancer resistance.
Accordingly, the invention provides a method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an antineoplastic agent. In some embodiments, the respective amounts of the compound of the invention and the antineoplastic agent are effective to increase the period of cancer sensitivity and/or delay the development of cancer cell resistance to the antineoplastic agent. In some embodiments, the respective amounts of the compound of the invention and the antineoplastic agent are effective to increase efficacy of a cancer treatment comprising the antineoplastic agent. In some embodiments, the respective amounts of the compound of the invention and the antineoplastic agent are effective to increase response compared to a cancer treatment comprising administering the antineoplastic agent without the compound of the invention.
The invention further provides a method for increasing efficacy of a cancer therapy comprising an antineoplastic agent in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the antineoplastic agent. The invention further provides a method for delaying and/or preventing development of cancer resistant to a cancer therapy comprising an antineoplastic agent in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the antineoplastic agent.
The invention further provides a method for increasing sensitivity to a cancer therapy comprising an antineoplastic agent in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the antineoplastic agent.
The invention further provides a method for extending the period of sensitivity to a cancer therapy comprising an antineoplastic agent in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the antineoplastic agent.
The invention further provides a method for extending the duration of response to a cancer therapy comprising an antineoplastic agent in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the antineoplastic agent.
Again, reference to a compound of Formula (I) in any of the above methods is meant to include any compound of Formula (I) as described herein, including any compound of Formula (la), (lb), (lc), (Id), (le), (If), (Ig), (Ih), (li), (Ij) or (II) and any embodiments thereof as described herein
In some embodiments of any of the above methods, the antineoplastic agent is selected from the lists of antineoplastic agents disclosed above.
In some embodiments of any of the above methods, the subject has a cancer selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous cell carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, melanoma, glioblastoma, medullob!astoma, neuroblastoma, osteosarcoma, lymphoma and leukemia.
EXAMPLES
The following abbreviations have been used in the examples:
AcN: acetonitrile,
AcOH: acetic acid,
aq: aqueous,
BINAP: 2,2'-bis(diphenylphosphine)-1 ,1 '-binaphthyl,
Boc: ferf-butyloxycarbonyl,
(Boc)20: di-ferf-butyl dicarbonate,
n-BuOH: n-butanol,
DAST: Diethylaminosulfur trifluoride, DCE: 1,2-dichloroethane,
DCM: Dichloromethane,
DIEA: N, N-diisopropylethylamine,
DIPEA: N, N-Diisopropylethylamine,
DMA: Dimethylacetamide,
DMAP: 4-(dimethylamino)pyridine,
DME: 1 ,2-dimethoxyethane,
DMF: N,N-dimethylformamide,
DMSO: dimethylsulfoxide,
EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,
Et20. Diethyl ether,
EtOAc: ethyl acetate,
EtOH: ethanol,
FA: Formic acid,
HATU: 1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate,
HOBt: 1-Hydroxybenzotriazole,
HPLC: high performance liquid chromatography,
LC-MS: liquid chromatography-mass spectroscopy,
Mel: lodomethane,
MeOH: methanol,
Me3SiOK: potassium trimethylsilanolate,
nm: nanometer,
min.: minute,
Pd2(dba)3 : ths(dibenzylidenacetone)dipalladium(0),
Pd(dppb)Cl2: 1 ,4-Bis(diphenylphosphino)butane-palladium(ll) chloride,
Pd(dppf)2Cb: 1,1'-Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride,
Pd(PPh3)4 : tetrakis(thphenylphosphine) palladium (0),
Pd(PPh3)2Cl2 : Bis(triphenylphosphine)palladium chloride,
Pet ether: petroleum ether,
P'Bu3: Tri-ferf-butylphosphine,
RT: room temperature,
Rt: retention time,
sat.: saturated,
T3P: Propylphosphonic anhydride,
TBAB: Tetra-W-butylammonium bromide,
TBAF: Tetra-W-butylammonium fluoride, ¾uOH: ferf-butanol,
TEA: triethylamine,
TFA: Trifluoroacetic acid,
THF: tetrahydrofurane,
TLC: Thin Layer Chromatography,
TPP: Triphenylphosphine
UPLC: Ultra Performance Liquid Chromatography,
XPhos: Dicyclohexyl(2',4,,6,-triisopropyl-2-biphenylyl)phosphine. One of the following methods was used for the determination by LC-MS:
Method 1: Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile Phase: B: 0.1% Formic Acid in Water A: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B: 0/97, 0.3/97, 3.2/2, 4/2, 4.01/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min;
Method 2: Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 μιπ); Mobile Phase: A: 0.1% Formic Acid in Acetonitrile, B: 0.1% Formic Acid in water; Gradient: Time/% B: 0/97, 0.3/97, 2.2/2, 3/2, 3.01/97, Column Temp: 35°C; Flow Rate: 0.6 mL/min;
Method 3: Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile Phase: B: 0.1% Formic Acid in Water, A: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B: 0/97, 0.3/97, 3.0/2, 4.5/2, 4.51/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min.
Method 4: Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile Phase: A: 0.1% Formic Acid in water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B: 0/97, 0.3/97, 2.7/2, 3.5/2, 3.51/97, Column Temp: 35°C; Flow Rate: 0.6 mL/min;
Method 5: Column: Xbridge C18 (50mm x 3.0mm, 2.5 μm); Mobile Phase: B: Acetonitrile: 5 mM Ammonium Acetate (90:10), A: 5 mM Ammonium Acetate in Aq; Gradient: Time/% B: 0/5, 3/98, 5.5/98, 6/5, 7/5, Column Temp: 40°C; Flow Rate: 0.6 mL/min.
Method 6: Column: KINETEX-1.7u XB-C18 100A (50mm x 2.1mm, 1.7 μm); Mobile Phase: A: 0.05% Formic Acid in Water B: 0.05% Formic Acid in Acetonitrile; Gradient: Time/%A: 0/97, 0.3/97,3.2/2,4.8/2,5/97,5.10/97 Column Temp: 35°C; Flow Rate: 0.6 mL/min
Method 7: Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 μπη); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A: 0/97, 0.4/97, 2.0/2, 5/2, 5.5/97, 6/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min;
Method 8: Column: Xbridge C18 (75mm x 4.6mm, 3.5 μm); Mobile Phase: B: Acetonitrile, A: 0.01 M Ammonium Bicarbonate in Aq; Gradient: Time/% B: 0/5, 1/5, 4.5/90, 5.5/98, 8/98, 8.01/10; Flow Rate: 1.0 mL/min; Diluent: Acetonitrile: Water (1:1); Method 9: Column: Xbridge C18 (75mm x 4.6mm, 3.5 μm); Mobile Phase: B: Acetonitrile, A: 0.01 M Ammonium Bicarbonate in Aq; Gradient: Time/% B: 0/10, 1/10, 4.5/90, 5.5/98, 8/98, 8.01/10; Flow Rate: 1.0 mL/min; Diluent: Acetonitrile:Water (1:1);
Method 10: Column: Xbridge C18 (75mm x 4.6mm, 3.5 μm); Mobile Phase: A: 10 mM Ammonium Acetate in Aq, B: Acetonitrile; Gradient: Time/% B: 0.0/10, 0.2/10, 2.5/75, 3.0/100, 4.8/100, 5.0/10; Flow Rate: 2.0 mL/min; Method 11: Column: Eclipse XDB-C18 (150mmX4.6mm, 5μητι); Mobile Phase: A: 10 mM Ammonium Bicarbonate , B: 100% Acetonitrile ; Gradient: Time/ %B: 0/5, 1.5/5, 3/15, 7/55, 10/95, 14/95, 17/5, 20/5 Column Temp: Ambient, Flow Rate: 1.0 ml/min. Diluent: (ACN.WATER: 70:30
Method 12: Column: Xbridge C18 (75mm x 4.6mm, 3.5 μm); Mobile Phase: B: 10 mM Ammonium in water, A: Acetonitrile: Time/% A: 0/2, 2/2, 4/15, 7/55, 10/95, 14/95, 14.1/2. Flow Rate: 1 mL/min; Diluent: DMSO:ACN: 8:2
Method 13: Column: Xbridge C18 (75mm x 4.6mm, 3.5 μm); Mobile Phase: B: 10 mM Ammonium in water, A: Acetonitrile: Time/% A: 0/2, 2/2, 4/15, 7/55, 10/95, 14/95, 14.1/2. Flow Rate: 1 mL/min; Diluent: THF:Water:ACN: 3:1:1
Method 14: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μm); Mobile Phase: B: 0.1 % Formic Acid in Water A: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B: 0/97,2.6/0,3.3/0,3.6/97,4.0/97; Column Temp: 35°C; Flow Rate: 0.55 mL/min;
Method 15: Column: KINETEX-C18 (50mm x 2.1mm, 1.7 μm); Mobile Phase: A: 0.05% Formic Acid in Water B: 0.05% Formic Acid in Acetonitrile; Gradient: Time/%A: 0.01/97,0.5/97,3.0/2,4.5/2,4.6/97,6/97 Column Temp: 35°C; Flow Rate: 1 mL/min
Method 16: Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile Phase: B: 0.1% Formic Acid in Water A: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B: 0/97,0.3/97,2.2/2, 3.30/2,4.5/2,4.51/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min;
Method 17: Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile Phase:-A: 0.1%FA in Water ,B: 0.1% FA in Acetonitrile: T%A of: 0/90, 1/10, 2.20/10, 2.30/90.2.60./90
Flow-0.8mL/min, Temp:50°C.
Method 18: Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile phase-A: 0.1%FA in Water ,B: 0.1% FA in Acetonitrile; T%A of: 0/970.3/97,3.0/2,4.0/2,4.2/97,4.50/97
Flow-0.6ml_/min, Temp:35°C
Method 19: Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile phase-A: 0.1%FA in Water ,B: 0.1% FA in Acetonitrile; T%A of: 0/980.2/98,1.8/2,2.4/2,2.60/98,3.0/98. Flow-0.8mL/min, Temp:50°
Method 20: Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile phase-B: 0.1%FA in Water ,A: 0.1% FA in Acetonitrile T%B of: 0/970.3/97,3.2/2,3.8/2,4.2/97,4.51/97.Flow-0.6mlJmin, Temp:35°C
Method 21: Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile phase-A: .1%FA in Water .B: Acetonitrile, T%B of: 0/98, 0.5/98, 3.4/2.0, 4.2/2.0, 4.5/98.0, 5.0/98.0 Method 22: Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile phase-A: .1%FA in Water ,B: Acetonitrile, T%B of. 0/98, 0.5/98, 3.4/2.0, 4.2/2.0, 4.5/98.0;
Flow-0.6ml/min, Temp: 35°C
Method 23: Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile phase-A: 0.1 %FA in Water ,B: 0.1% FA in Acetonitrile T%A of.0/95,0.3/95,2.0/5,3.5/5,3.6/95,4.2/95
Flow-0.6mL/min, Temp:40°C
Method 24: Column: Xbridge C18 (100mm x 4.6mm, 3.5 μm); Mobile Phase: B: Acetonitrile: A: 10 mM Ammonium Bicarbonate in Aq; Gradient: Time/% B: 0/0, 8/100, 12/100, 12.50/10, 15/10; Flow Rate: 1 mL/min Method 25: Column: Atlantis T3 (150mm x 4.6mm, 3.5 μm); Mobile Phase: B: Acetonitrile: A: 0.1% FA in Water; Gradient: Time/% B: 0/10, 8/100, 12/100, 12.50/10, 15/10; Flow Rate: 1 mL/min
Method 26: Column: Xbridge C18 (100mm x 4.6mm, 3.5 μm); Mobile Phase: B: Acetonitrile: A: 5 mM Ammonium Bicarbonate in Aq; Gradient: Time/% B: 0/0, 8/100, 12/100, 12.50/10, 15/10; Flow Rate: 1 mL/min Method 27: Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile phase-A: 0.1 %FA in Water ,B: 0.1% FA in Acetonitrile T%B of: 0/10,1.8/100,3.8/100, 4.0/10,5/10. Flow-0.7mL/min, Temp:50°C
Method 28: Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile Phase: B: Acetonitrile: Mobile Phase A: 10 mM Ammonium Bicarbonate in Aq; Gradient: Time/% of B: 0/3,1/3,7/100, 7.5/100, 9/3, 10/3. Flow: 0.50mL/min, Temp:35°C
Method 29: Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile phase-B: 0.1%FA in Water ,A: 0.1% FA in Acetonitrile T%B of:0/97,0.3/97,3.2/2,4.5/2,4.51/97. Flow-0.6mL/min, Temp:35°C
Method 30: Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile phase-A: 0.1%FA in Water ,B: 0.1% FA in Acetonitrile T%A of:0/95,0.3/95,2.0/5,3.5/5,3.6/95. Flow-0.6mL/min, Temp:40°C
Method 31 : Column - AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm)); Mobile phase-A: 0.1 %FA in Water ,B: 0.1% FA in Acetonitrile T%B of: 0/5, 0.3/5, 2.0/95, 3.7/95, 4.2/5, 5.7/5; Flow-0.6mL/min, TemprfO'C
Method 32: Column: AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile Phase: B: Acetonitrile, A: 10 mM Ammonium Acetate in Aq; Gradient: Time/% B: 0/5, 0.3/5, 2.0/98, 3.5/98, 3.6/5, Column Temp: 40°C; Flow Rate: 0.6 mL/min.
Method 33: Column: AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile Phase: B: Acetonitrile, A: 10 mM Ammonium Acetate in Aq; Gradient: Time/% A: 0/98, 0.3/98, 3.5/2, 3.6/2, 4.2/98, Column Temp: 40°C; Flow Rate: 0.5 mL/min.
Method 34: Column: Xbridge BEH C18 (50mm x 2.1mm, 2.5 μm); Mobile Phase: B: Acetonitrile, A: 10 mM Ammonium Formate in Aq; Gradient: Time/% B: 0/5, 3.0/100, 3.5/100, 3.8/5, 4.3/5, Column Temp: 40°C; Flow Rate: 0.7 mL/min.
Method 35: Column: Xbridge BEH C18 (50mm x 3.0mm, 2.5 μm); Mobile Phase: B: 10 mM Ammonium Formate in WaterAcetonitrile (5:95), A: 10 mM Ammonium Formate in WaterAcetonitrile (95:5); Gradient: Time/% B: 0/2, 4.0/98, 4.5/98, 5.0/2, 5.5/2, 6.5/2; Flow Rate: 1.0 mL/min. Method 36: Column: AQUITY UPLC BEH C18 (50mm x 2.1mm, 1.7 μm); Mobile Phase: B: 10 mM Ammonium Acetate in in Water: Acetonitrile (5:95), A: 10 mM Ammonium Acetate in in WaterAcetonitrile (95:5); Gradient: Time/% B: 0/0, 0.3/0, 2.5/100, 3.5/100, 3.6/0; Column Temp: 40°C; Flow Rate: 0.6 mL/min.
REFERENCE EXAMPLE 1
Methyl 2-(trimethylstannyl)isonicotinate
To a stirred solution of methyl 2-chloro isonicotinate (2 g, 12 mmol) in toluene (20 mL), hexamethylditin (4.5 g, 14 mmol) was added. The reaction mixture was degassed with argon for 10 minutes, then Pd(PPI¾)4 (1.35 g, 10 mmol) was added, it was degassed again for 5 minutes and the resulting reaction mixture was heated at 110°C for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to RT, filtered through the Celite pad, washed with EtOAc and the filtrate was concentrated to dryness. The crude compound was purified by column chromatography using neutral alumina and eluted with 5%EtOAc/pet ether to afford the title compound (1.5 g, 42%) as a colorless liquid.
LC-MS (method 1): R, = 1.20 min; m/z = 301.99 (M+H+)
Following a similar procedure to that described in reference example 1, but using the corresponding starting material, the following compound was obtained:
Figure imgf000070_0001
Terf-butyl 3-(5-bromo-1 H-pyrrolo[2,3-c]pyridin-1 -yl)propylcarbamate)
To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (500 mg, 2.53 mmol) in DMF (5 mL), K2C03(875 mg, 6.345 mmol) was added. After 10min, ferf-butyl 3-bromopropylcarbamate (724 mg, 3.045 mmol) was added and the reaction mixture was heated at 60°C for 26h. The reaction mixture was cooled to RT, poured into ice water and extracted with EtOAc (2 x100 mL). The organic layer was washed with brine solution (2 x 20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness. The crude compound was triturated with n-pentane to afford the title compound (200 mg, 27%) as a yellow solid.
LC-MS (method 1): Rt = 2.15 min; m/z = 354.18 (M+H+).
Following a similar procedure to that described in reference example 2, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000070_0002
Figure imgf000071_0001
Figure imgf000072_0001
REFERENCE EXAMPLE 3
6-Bromo-1 -methyl-1 H-pyrrolo[3,2-c]pyridine
To a stirred solution of e-bromo-IH-pyrroloP^-clpyridine (800 mg, 4.06 mmol) in DMF (8 mL), NaH (60%), 243.6 mg, 6.09 mmol) was added at 0°C. The reaction mixture was allowed to stir at RT for 45 min, then it was cooled to 0°C and methyl iodide (384 mg, 2.706 mmol) was added to the mixture and stirred at RT for 3 h. The reaction mixture was quenched in ice water and extracted with EtOAc (2 x 50 mL), washed with brine (30 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated. The resultant crude compound was triturated with n-pentane to afford the title compound (500 mg, 58.6%) as a brown solid.
LC-MS (method 1): Rt = 1.26 min; m/z = 210.95 (M+H+). Following a similar procedure to that described in reference example 3, but using the corresponding starting materials, the following compound was obtained:
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
REFERENCE EXAMPLE 4
1-(5-Bromopentyl)-1 H-pyrazole
To a stirred solution of 1 H-pyrazole. (3.0 g, 44.11 mmol) in DMF (30 mL), 60% NaH (5.293 g, 220.5 mmol) was added at 0°C and it was stirred for 15 minutes at the same temperature. Then, 1,5-dibromopentane (20.11 g, 88.22 mmol) was at 0°C and it was allowed to stir at RT for 16 h. The reaction mixture was cooled to 0°C, diluted with water and extracted with EtOAc. The organic layer was washed with water and brine solution and the combined organic layers were dried over anhydrous NazSO^ filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography and eluted at 20% EtOAc in pet ether to afford the title compound (4.0 g, 42%) as a color less liquid.
LC-MS (method 16): R, = 2.08 min; m/z = 219.16 (M+H++2). REFERENCE EXAMPLE 5
Tert-butyl N-(3-(5-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)propyl)-N-[(ferf-butoxy)carbonyl]carbamate
To a stirred solution of reference example 2 (1.5 g, 5.88 mmol) in ACN (10 mL), B0C2O 3 (1.9 g, 8.82 mmol), TEA (1.19 g, 11.76 mmol) and DMAP (71 mg, 0.58 mmol) were added at RT. The reaction mixture was stirred at RT for 16h. The reaction mixture was diluted with water (70 mL) and extracted with EtOAc (2 X 90 mL). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using Hexane/EtOAc mixtures of increasing polarity as eluent, to afford the title compound (0.8 g, 23%) as a gummy liquid.
LC-MS (method 1): Rt = 2.73 min; m/z = 454.31 (M+H+)
REFERENCE EXAMPLE 6 & 7
5-Bromo-1 -(cyclobutylmethyl)-l H-pyrazolo[3,4-c]pyridine and 5-bromo-2-(cyclobutylmethyl)-2H-pyrazolo[3,4-c]pyridine
To a stirred solution of 5-bromo-1W-pyrazolo[3,4-c]pyridine (1 g, 5.07 mmol) in DMF (10mL), 60% NaH (0.405 g, 10.14 mmol) was added at 0°C and it was stirred at RT for 30 min. Then, (bromomethyl)cyclobutane (1.12 g, 7.56 mmol) was added to the mixture at 0 °C and it was stirred at RT for 16 h. The reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (20 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography using 10% EtOAc/pet ether as eluent to afford fraction-1 5-bromo-1-(cyclobutylmethyl)-1H-pyrazolo[3,4-c]pyridine (reference example 6) (500 mg) as an off-white solid, and 20% EtOAc/pet ether as eluent to afford fraction-2 5- bromo-2-(cyclobutylmethyl)-2W-pyrazolo[3,4-c]pyridine (reference example 7) (450 mg) as an off-white solid Reference example 6: LC-MS (method 1): Rt = 2.30 min; m/z = 265.86 (M+H+).
Reference example 7: LC-MS (method 1): Rt = 2.06 min; m/z = 265.61 (M+H+).
Following a similar procedure to that described in reference example 6&7, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000076_0001
Figure imgf000077_0001
REFERENCE EXAMPLE 8
5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine
To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyiidine (2.5 g, 12.75 mmol) in DMF (20 mL), 60% NaH (0.57 g, 15.30 mmol) was slowly added portionwise at 0 °C. The resulting suspension was stirred at RT for 1h. The reaction mixture was cooled to 0 °C and 2-(chloromethoxy)ethyl)trimethylsilane (2.55 g, 15.30 mmol) was added. The reaction mixture was allowed to stir at RT for 2h. The reaction mixture was quenched with water (70 mL), extracted with EtOAc (2 x 100 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 15% EtOAc/pet ether to afford the title compound (2.7 g, 66%) as a liquid compound.
LC-MS (method 1): R, = 2.73 min; m/z = 329.41 (M+H*+2).
Following a similar procedure to that described in reference example 8, but using the corresponding starting material, the following compound was obtained:
Figure imgf000078_0001
2-(5-Bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)-N,N-diethylethanamine
To a stirred suspension of 60% NaH (0.21 g, 8.88 mmol) in DMF (5 mL), 5-bromo-1H-pyrrolo[2,3-c]pyridine (0.7 g, 3.55 mmol) was added at °0 C and stirred for 15 min. Then, 2-bromo-N,N-diethylethylamine hydrobromide (1.1 g, 4.26 mmol) was added at °0 C. The reaction mixture was stirred at RT for 16 h and poured into ice cold water (50 mL), and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 60% ethyl acetate in pet ether as an eluent to afford the title compound (0.7 g, 66%) as brown liquid.
LC-MS (method 1): Rt =1.22 min; m/z = 296.24 (M+H+)
REFERENCE EXAMPLE 10
5-Bromo-1 -butyl-1 H-pyrrolo[2,3-c]pyridine
To a stirred suspension of 60% NaH (0.146 g, 6.091 mmol) in DMF (20 mL), 5-bromo-1H-pyrrolo[2,3-c]pyridine (0.8 g, 4.06 mmol) was added at °0 C and stirred for 15 min. Then, 1-bromo butane (0.66 g, 4.873 mmol) was added to the reaction mixture at °0 C. The reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction mixture was quenched with water and extracted EtOAc and the organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 10% EtOAc in pet ether as an eluent to afford the title compound (0.78 g, 67%).
LC-MS (method 1): Rt =2.27 min; m/z = 253.17 (M+H+).
Following a similar procedure to that described in reference example 10, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000078_0002
Figure imgf000079_0001
Figure imgf000080_0001
REFERENCE EXAMPLE 11
7ert-butyl 3-((5-bromo-1H-pyrrolo[2,3<]pyridin-1-yl)methyl)piperidine-1-carboxylate
To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (1.5 g, 7.61 mmol) in DMF (15 mL), KOH (1.27 g, 11.42 mmol) was added at RT. The resulting solution was stirred for 30 min. Then, fert-butyl 3- (bΓomomethyl)piperidine-1-caώoxylate (3.17 g, 22.84 mmol) was added at 0 °C, and stirred at RT for 16h. The reaction mixture was diluted with water (70 mL) and extracted with EtOAc (2 x 70 mL), the combined organic layers were dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 30% EtOAc/ pet ether to obtain the title compound (1.6 g, 54%) as an off white solid.
LC-MS (method 1): Rt =2.47 min; m/z = 394.24 (M+H+) Following a similar procedure to that described in reference example 11, but using in the corresponding starting material, the following compounds was obtained:
Figure imgf000081_0001
REFERENCE EXAMPLE 12
Tert-butyl 3-((5-bromo-1 H-pyrrolo[2,3-c]pyridin-1 -yl)methyl)pyrrolidine-1 -carboxylate Step a. Tert-butyl 3-((methylsulfonyloxy)methyl)pyrrolidine-1 -carboxylate
To a stirred solution of ferf-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (6g, 29.8 mmol) in CH2CI2 (50mL), Et3N (10.5 mL, 74.62mmol) and mesyl chloride (3.5ml, 44.77 mmol) were added at 0 °C. The reaction mixture was stirred at RT for 2h, then diluted with 5% NaHC03 solution (50mL) and extracted with CH2CI2 (2 x 100 mL). The organic layer was washed with brine solution (50mL), dried over Na2SO4 and concentrated to obtain the title compound (8 g, 96%) as a brown color liquid.
LC-MS (method 5): R, =2.43 min; m/z = 280.32 (M+H+).
Step b. Tert-butyl 3-((5-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl)pyrrolidine-1 -carboxylate
To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine, (1.1g, 5.61) in DMF (10 mL), NaH (1.12 g, 28.06 mmol) and Kl (1.86 g, 11.22 mmol) were added at 0 °C. The reaction mixture was stirred at RT for 30 min and then cooled to 0 °C. The compound obtained in the previous section, step a (7.82g, 28.56 mmol) was added and the resulting mixture was stirred at RT for 16h. The reaction mixture was diluted with ice-water and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine solution, dried over Na2SO4 and concentrated. The crude compound was purified by column chromatography using silica gel and eluted with 40% EtOAc/pet-ether to obtain the title compound (800 mg, 37%) as a gummy liquid.
LC-MS (method 1 ): Rt =2.34 min; m/z = 380.13 (M+H+). Following a similar procedure to that described in reference example 12, but using in the corresponding starting material, the following compounds was obtained:
Figure imgf000082_0001
REFERENCE EXAMPLE 13
6-Bromo-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[4,3-c]pyridine To a stirred solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (2.5 g, 12.62 mmol) in DMF (40 mL), dihydropyran (1.59 g, 18.93 mmol), and PTSA (0.43 g, 2.50 mmol) were added at RT. The reaction mixture was heated to 90 °C for 16 h. It was allowed to cool to RT, diluted with ice water (100 mL) and extracted EtOAc (2X 60 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude compound was purified by flash column chromatography using 35% ethyl acetate in petroleum ether as an eluent to afford the title compound (2.10 g, 60%) as pale yellow solid.
LC-MS (method 6): Rt =2.47 min; m/z = 282.08 (M+H+)
REFERENCE EXAMPLE 14
5-(5-Bromo-1H-pyrazolo[3,4-c]pyridin-1-yl)-N,N-diethylpentan-1 -amine To a stirred solution of reference example 7g (220 mg, 0.637 mmol) in acetonitrile (5 mL), diethyl amine (232 mg, 3.185 mmol) was added at 0°C and allowed to stir at RT for 16h. The reaction mixture was concentrated under reduced pressure and the crude compound was purified by column chromatography using 8% MeOH/DCM as eluent to afford the title compound (190 mg, 88%) as an off-white gummy.
LC-MS (method 4): R, =1.24 min; m/z = 339.19 (M+H+)
Following a similar procedure to that described in reference example 14, but using in the corresponding starting material, the following compounds was obtained:
Figure imgf000082_0002
Figure imgf000083_0001
REFERENCE EXAMPLE 15
1-Butyl-5-(trimethylstannyl)-1H-pyrrolo [2, 3-c] pyridine
Following a similar procedure to that described in reference example 1 , but using reference example 10 instead of methyl 2-chloro isonicotinate, the desired compound was obtained (54% yield).
LC-MS (method 4): R, = 1.50 min; m/z = 339.16 (M+H+).
Following a similar procedure to that described in reference example 15, but using the corresponding starting material, the following compound was obtained:
Figure imgf000083_0002
REFERENCE EXAMPLE 16
5-Bromo-1 -butyl-3-ethyl-1 H-pyrrolo[2,3-c]pyridine
Step a. 1-(5-Bromo-1H-pyrrolo[2,3-c]pyridin-3-yl)ethanone
To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (500 mg, 2.53 mmol) in DCM (40mL), anhydrous AlCb (675 mg, 5.07 mmol) was added at 0°C. The reaction mixture was stirred at RT for 15 minutes and then, acetyl chloride (396 mg, 5.07 mmol) was added. The reaction mixture was allowed to stirred at RT for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure and poured into crushed ice and neutralized with 2N NaOH: The solid precipitated was filtered and dried under vacuum to afford the title compound (600mg, 98.90%).
LC-MS (method 20): Rt = 1.61 min; m/z = 239.06 (M+H+).
Step b. 5-Bromo-3-ethyl-1H-pyrrolo[2,3-c]pyridine
To a stirred solution of the compound obtained in the previous section, step a (600 mg, 2.52 mmol) in isopropyl alcohol (20mL), NaBH4 (478 mg, 12.6 mmol) was added at 0°C. The reaction mixture was refluxed for 24hr. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to 0°C, diluted with water and extracted with Ethyl Acetate (3x50ml). The organic layer was washed with brine solution and dried over Na2SO4, filtered and concentrated under reduced pressure to afford a crude compound that was purified by silica gel column chromatography using 5% MeOH in DCM to afford the title compound (250 mg, 44.26%) as an off white solid.
Step c. 5-Bromo-1-butyl-3-ethyl-1H-pyrrolo[2,3-c]pyridine
To a stirred solution of the compound obtained in the previous section, step b (250 mg, 1.1mmol) in DMF, 60% NaH (223 mg, 5.58mmol) was added at 0°C. After stirring for 15 minutes at 0°C, butyl iodide (410mg, 2.23mmol) was added ant the reaction mixture was stirred at RT for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to 0°C, diluted with water and extracted with Ethyl Acetate (3x50ml). The organic layer was washed with brine solution and dried over Na2SO4, filtered and concentrated under reduced pressure to afford a crude compound that was purified by silica gel column chromatography using 20% Ethyl Acetate in Pet. Ether to afford the title compound (190mg, 60%) as a pale yellow liquid.
LC-MS (method 17): Rt = 1.39 min; m/z = 282.67 (M+H++2).
Following a similar procedure to that described in reference example 16, but using the corresponding starting material, the following compound was obtained:
Figure imgf000084_0001
REFERENCE EXAMPLE 17
6-Bromo-3-butyl-1 H-pyrrolo [3,2-c]pyridine
Step a. 1-(6-Bromo-1 H-pyrrolo [3, 2-c] pyridin-3-yl) butan-1-one
To a stirred solution of 6-bromo-1H-pyrrolo[3,2-c]pyridine (2.0 g, 10.2 mmol) in DCM (40 mL), anhydrous AICI3 (2.713 g, 20.4 mmmol) was added at 0°C. The resulting mixture was stirred for 15 minutes at RT and then butyryl chloride (2.162 g, 20.4 mmol) was added. The reaction mixture it was allowed to stir at RT for 16h. The mixture was diluted with MeOH and the solution was concentrated under reduced presure. The crude compound was basified to pH~8 using aq. saturated NaHC03 solution and extracted with EtOA. The combined organic phases were dried over anhydrous NaSOt, filtered and concentrated under reduced pressure. The crude compound was triturated with diethyl ether, filtered and dried under vacuum to afford the title compound (1.5 g, 55%) as an off-white solid.
LC-MS (method 16): Rt = 1.92 min; m/z = 267.14 (M+H+).
Step b. 6-Bromo-3-butyl-1 H-pyrrolo [3,2-c]pyridine
To a stirred solution of the compound obtained in the previous section, step a (1.5 g, 5.639 mmol) in isopropanol (30 mL), NaBH* (0.853 g, 22.556 mmol) was added and refluxed for 16h. The reaction mixture was concentrated under reduced pressure and the residue was cooled to 0°C. The cruderesidue was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and the volatiles were removed under reduced pressure. The crude compound was purified by silicagel column chromatography and eluted at 30%EtOAc in pet ether to afford the title compound (800 mg, 56%) as an off- white solid
LC-MS (method 16): R, = 2.01 min; m/z = 253.15 (M+H+).
Following a similar procedure to that described in reference example 17, but using the corresponding starting material, the following compound was obtained:
Figure imgf000085_0001
REFERENCE EXAMPLE 18
6-Bromo-3-butyl-1-methyl-1H-pyrrolo [3, 2-c] pyridine
To a stirred solution of reference example 17 (700 mg, 2.777 mmol) in DMF (10 mL), 60% NaH (333 mg, 13.885 mmol) was added at 0°C. The reaction mixture was stirred for 15 minutes at the same temperature and then methyl iodide (788 mg, 5.554 mmol) was added. The suspension was stirred at RT for 16h. It was cooled at 0°C, water was added and extracted with EtOAc. The organic layer was washed with water and brine solution. The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography and eiuted at 10% EtOAc in pet ether to afford the title compound (400 mg, 54%) as an off-white solid.
LC-MS (method 16): Rt = 2.26 min; m/z = 267.14 (M+H+).
REFERENCE EXAMPLE 19
5-Bromo-1-butyl-N,N-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide Step a. 5-Bromo-N,N-dimethyl-1 H-pyrrolo[2,3-c]pyridine-2-carboxamide
To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (500 mg, 2.07 mmol, 1.0 equiv) in DMF, dimethyl amine hydrochloride (168 mg, 2.07 mmol, 1.0 equiv), TEA (1.49 g, 10.37 mmol, 5.0 equiv) and T3P (1.97 g, 6.21 mmol, 3.0 equiv) were added at 0°C. The reaction mixture was allowed to stir at RT for 16h. The progress of the reaction was monitored by LCMS.. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eiuted at 5% MeOH in DCM in to afford (450 mg, 78%) the title compound.
LC-MS (method 16): Rt = 1.75 min; m/z = 270.15 (M+H++2).
Step b. 5-Bromo-1-butyl-N,N-dimethyl-1 H-pyrrolo[2,3-c]pyridine-2-carboxamide
To a stirred solution of the compound obtained in the previous section, step a (1.4 g, 5.24 mmol, 1.0 equiv) in DMF, 60% NaH (1.04 g, 26.21 mmol, 5.0 equiv) was added at 0°C. The reaction mixture was stirred for 15 minutes at the same temperature and then butyl iodide (1.92 g, 10.48 mmol, 2.0 equiv) was added The suspension was stirred at RT for 16h. It was cooled at 0°C, water was added and extracted with EtOAc. The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure The crude compound was purified by silica gel column chromatography and eiuted at 5% MeOH in DCM in to afford the title compound (1.0 g, 59.8 %)
LC-MS (method 17): R, = 1.10 min; m/z = 325.36 (M+H+). Following a similar procedure to that described in reference example 19, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000086_0001
REFERENCE EXAMPLE 20
1-(5-Bromo-1-butyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-N,N-dimethylmethanamine To a stirred solution of reference example 19 (700 mg, 21.67 mmol, 1.0 equiv) in THF, BH3-DMS (2N) (32.50 mL, 65.01 mmol, 3.0 equiv) was added at RT and stirred at 100°C for 12h. The reaction mixture was cooled to RT and quenched with MeOH. The volatiles were evaporated under reduced pressure, and the resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried and concentrated. The crude compound was purified by silica gel column chromatography using 10-30% EtAcO in hexane to get the title compound (315 mg, 47%) as pale yellow liquid.
LC-MS (method 17): Rt = 1.23 min; m/z = 310.13 (M+H+).
Following a similar procedure to that described in reference example 20, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000086_0002
REFERENCE EXAMPLE 21
5-Bromo-1 -butyl-3-(1 -methyl-1 ,2,3,6-tetrahydropyridin-4-yl)-1 H-pyrrolo[2,3-c]pyridine
Step a. 5-Bromo-3-(1 -methyl-1, 2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo [2,3-c]pyridine
To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (1.5 g, 7.614 mmol) in MeOH (20 mL), powder KOH (1.7 g, 30.456 mmol) was added and the suspension was stirred for 10 minutes at RT. Then, 1-methylpiperidin- 4-one (1.72 g, 15.228 mmol) was added, and the mixture was refluxed for 16h. The reaction mixture was concentrated and the residue was dissolved in water and extracted with EtOAc. The separated organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a brown solid. The crude compound was taken forward to next step without further purification. LC-MS (method 17): Rt = 0.30 min; m/z = 292.02 (M+H+).
Step b. 5-Bromo-1 -butyl-3-(1 -methyl-1 ,2,3,6-tetrahydropyridin-4-yl)-1 H-pyrrolo[2,3-c]pyridine
To a stirred solution of the compound obtained in the previous section, step a (2.0 g) in DMF (20 mL), 60% NaH (0.824 g, 34.326 mmol) was added at 0°C. The reaction mixture was stirred for 15 minutes at the same temperature and then 1-iodobutane (2.528 g, 13.744 mmol) was added. The suspension was stirred at RT for 4h. It was cooled at 0°C, water was added and extracted with EtOAc. The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure The crude compound was purified by silica gel column chromatography and eluted at 80% EtOAc in pet ether to afford the title compound (1.1 g) as an off-white solid.
LC-MS (method 17): Rt = 0.82 min; m/z = 348.18 (M+H+).
Following a similar procedure to that described in reference example 21, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000087_0001
REFERENCE EXAMPLE 22
5-Bromo-1 -butyl-3-phenyl-1 H-pyrrolo[2,3-c]pyridine
Step a. 5-Bromo-3-iodo-1 H-pyrrolo [2,3-c]pyridine
To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (2.0 g, 10.20 mmol) in DMF (30 mL) KOH (2.284 g, 40.8 mmol) and iodine (2.838 g, 1 .222 mmol) were added at 0°C. The reaction mixture was stirred at RT for 2h. It was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine solution. The organic layers were dried over anhydrous IStaSC , filtered and concentrated under reduced pressure. The crude compound was triturated with water, filtered and dried under vacuum to afford the title compound (2.5 g, 76%) as a pale yellow solid.
LC-MS (method 18): Rt = 2.39 min; m/z = 320.84 (M-H+).
Step b. 5-Bromo-1-butyl-3-iodo-1 H-pyrrolo [2,3-c]pyridine
To a stirred solution of the compound obtained in the previous section, step a (2.5 g, 7.763 mmol) in DMF (30 mL), 60% NaH (0.931 g, 38.815 mmol) was added at 0°C and stirred for 15 minutes, then added 1-iodobutane (2.856 g, 15.526 mmol) was added. The reaction mixture was allowed to stir at RT for 16h. It was cooled at 0°C and water was added to the reaction mixture. The solid compound formed was filtered, washed with water and dried under vacuum to afford the title compound (2.8 g, 95%) as a pale yellow solid;
LC-MS (method 18): R, = 3.07 min; m/z = 381.02 (M+H++2).
Step c. 5-Bromo-1 -butyl-3-phenyl-1 H-pyrrolo[2,3-c]pyridine
To a stirred solution of the compound obtained in the previous section, step b (800 mg, 2.116 mmol) in 1, 4- dioxane (10 mL), phenylboronic acid (258 mg, 2.116 mmol) and a solution of Na2C03(448 mg, 4.232 mmol) in water, were added. The resulting mixture was degassed with argon. To the reaction mixture, Pd(dppf)2Cl2-DCM complex (258 mg, 0.317 mmol) was added and heated to 70°C for 16h. The reaction mixture was diluted with EtOAc and filtered through a celite pad; the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography and eluted at 16% EtOAc in pet ether to afford to afford the title compound (200 mg, LCMS~56%) as a brown colour solid.
LC-MS (method 17): R, = 1.45 min; m/z = 330.47 (M+H+).
Following a similar procedure to that described in reference example 22, but using the corresponding starting material, the following compound was obtained:
Figure imgf000088_0001
REFERENCE EXAMPLE 23
6-Bromo-3-butyl-1 -phenyl-1 H-pyrrolo[3,2-c]pyridine
To a stirred solution reference example 17 (1 g, 3.95 mmol) in DCE (20 mL), benzene boronic acid (0.964 g, 7.9 mmol), Na2C03 (0.837 g, 7.9 mmol)), Cu(OAc)2 (1.43g, 7.9 mmol) were added, followed by addition of pyridine (0.93g, 0.95 mL, 11.85 mmol), at RT. The reaction mixture was heated to 75eC for 16 h. The reaction was filtered through a pad of celite, washed with EtOAc (20 mL), and the filtrate was evaporated to dryness.
The crude residue was purified by column chromatography on 230-400 silica with 25 % EtOAc/pet-ether to afford 230 mg (17.6%) of the title compound.
LC-MS (method 17): R, = 1.49 min; m/z = 331.06 (M+H++2).
REFERENCE EXAMPLE 24
6-Bromo-1-phenethyl-1H-pyrazolo [4, 3-c] pyridine
Following a similar procedure to that described in reference example 3, but using 6-bromo-1H-pyrazolo[4,3- cjpyridine and (2-bromoethyl)benzene instead of 6-bromo-1H-pyrrolo[3,2-c]pyridine and methyl iodide, the desired compound was obtained (28% yield).
LC-MS (method 21): Rt = 2.89 min; m/z = 302.08 (M+H+).
Following a similar procedure to that described in reference example 24, but using the corresponding starting material, the following compound was obtained:
Figure imgf000088_0002
Figure imgf000089_0001
REFERENCE EXAMPLE 25
N-Benzyl-9-(5-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)nonanamide
Step a. N-Benzyl-9-bromononanamide
To a stirred solution of 9-bromononanoic acid (300 mg, 1.26 mmol) in DMF, T3P (1.61 g, 2.53 mmol) was added at 0°C. It was stirred for 15 minutes at same temperature. Then, benzyl amine (203 mg, 1.89 mmol) and DIPEA (653 mg, 5.06mmol) were added. The resulting mixture was stirred at RT for 3h. The reaction mixture was diluted with water and extracted with Ethyl Acetate (3x50ml). The combined organic layers were washed with brine solution and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 30% Ethyl Acetate in Pet. Ether to afford the title compound (200mg, 48%) as an off white solid.
LC-MS (method 17): R, = 1.28 min; m/z = 328.19 (M+H++2).
Step b. N-Benzyl-9-(5-bromo-1 H-pyrrolo[2,3-c]pyridin-1 -yl)nonanamide
To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (200 mg, 1.01 mmol) in DMF, 60% NaH (81 mg, 2.03 mmol) was added at 0°C and stirred for 15 minutes at same temperature. Then, the compound obtained in the previous section, step a (397 mg, 1.21 mmol) was added and stirred at RT for 16h. The reaction mixture was cooled to 0°C. It was diluted with water and extracted with Ethyl Acetate (3x50ml). The combined organic layers were washed with brine solution and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 40% Ethyl Acetate in Pet. Ether to afford the title compound (250mg, 90%) as a pale yellow solid.
LC-MS (method 17): Rt = 1.28 min; m/z = 444.39 (M+H++2).
REFERENCE EXAMPLE 26
1 -(5-Bromo-1 -butyl-1 H-pyrrolo[2,3-c]pyridin-3-yl)-N,N-dimethylmethan amine
To a stirred solution of reference example 10 (500 mg, 1.97 mmol) in n-BuOH (20 mL), formaldehyde solution (37%) (0.78 mL, 9.88 mmol), and dimethyl amine hydrochloride (805 mg, 9.88 mmol) were added, and stirred at 120°C for 16 h. The reaction mixture was cooled to RT, and it was evaporated in vacuum to get residue that was diluted with 1N NaOH and extracted with 10 % MeOH/DCM (2 X 50 mL). The crude residue was evaporated to get a crude compound that was purified by column chromatography on 230-400 silica with 85% EtOAc/ pet ether along with 0.5 mL of TEA to afford 400 mg (65%) of the title compound as a gummy solid. LC-MS (method 17): R, = 0.77 min; m/z = 312.12 (M+H++2).
REFERENCE EXAMPLE 27
Tert-butyl 2-(6-bromo-3-butyl-1 H-pyrrolo[3,2-c]pyridin-1 -yl)ethylcarbamate To a stirred solution of reference example 17 (2 g, 7.9 mmol) in DMF, 60% NaH (0.63 g, 26.3 mmol) was added at 0°C. The reaction mixture was stirred for 15 minutes at the same temperature and then tert-butyl 2- bromoethylcarbamate (3.5 g, 15.8 mmol) was added. The reaction mixture was stirred at RT for 16 h. Then, the resulting mixture was poured in crushed ice and diluted with EtOAc (2 x 150 ml.). The organic layer was washed with brine (3 X 80 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to get 3.0 g of crude. The crude compound was purified by Prep HPLC to afford 600 mg of the title compound;
LC-MS (method 23): Rt = 2.20 min; m/z = 397.76 (M+H++2).
REFERENCE EXAMPLE 28
N-(2-(6-bromo-3-butyl-1 H-pyrrolo[3,2-c]pyridin-1 -yl)ethyl)acrylamide
Step a. 2-(6-Bromo-3-butyl-1H-pyrrolo[3,2-c]pyridin-1-yl)ethanamine hydrochloride
To a stirred solution of reference example 27 (0.3 g, 0.756 mmol) in MeOH 1mL, 5 ml of 4N HCI in 1,4 dioxane at 0°C was added and stirred for 16 h at RT. The reaction mixture was concentrated under reduced pressure to get a crude residue. The crude solid was triturated in diethyl ether and dried to afford 250 mg (99 %) of the title compound as an off white solid.
LC-MS (method 23): Rt = 1.51 min; m/z = 298.07 (M+H++2).
Step b. N-(2-(6-bromo-3-butyl-1 H-pyrrolo[3,2-c]pyridin-1-yl)ethyl)acrylamide
To a stirred solution of the compound obtained in the previous section, step a (150 mg, 0.45 mmol) in DCM (10 mL), TEA (0.316, 1.35 mmol) and acryl chloride (0.08 g, 0.9 mmol) were added at 0°C and stirred at RT for 16 h. The crude reaction mixture was diluted with ice cold water (15 mL), and extracted with DCM (15 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrated concentrated to get a crude residue. The crude compound was purified by Devisil-silica with 20% of EtOAc/pet ether to afford 150 mg of the title compound as a gummy solid;
LC-MS (method 23): Rt = 1.82 min; m/z = 350.14 (M+H+).
REFERENCE EXAMPLE 29
Tert-butyl 4-(2-(5-bromo-1 H-pyrrolo[2,3-c]pyridin-1 -yl)ethyl)piperidine-1 -carboxylate
Step a. Tert-butyl 4-(2-(methylsulfonyloxy)ethyl)piperidine-1 -carboxylate
To a stirred solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (2.0 g, 8.73 mmol) in DCM (40 mL), TEA (2.64 g, 13.20 mmol) and methane sulfonyl chloride (1.50 g, 13.2 mmol) were added at 0°C. The resulting mixture was allowed to stir at room temperature for 2h. The reaction mixture was diluted with DCM, washed with water and brine solution, dried over anhydrous Na2SO4, and filtered. The filtrated solution was concentrated under reduced pressure to obtain the title compound (2.50 g, 93%) as brown liquid. The crude compound was taken forward to next step without further purification.
Step b.Tert-butyl 4-(2-(5-bromo-1 H-pyrrolo[2,3-c]pyridin-1 -yl)ethyl)piperidine-1 -carboxylate
To a stirred solution of 5-bromo-1 H-pyrrolo[2,3-c]pyridine (1.0 g, 5.07 mmol) in DMF (20 mL), 60% NaH (0.36 g,15 mmol) was added at 0°C and stirred for 15 minutes at the same temperature. Then, the compound obtained in the previous section, step a, (2.34 g, 7.6 mmol) was adde. The resulting reaction mixture was allowed to stir at room temperature for 16h. The reaction mixture was poured into ice cold water, extracted with ethyl acetate, and the combined organics were dried over Na2SO4 and filtered. The filtrated solution was concentrated under reduced pressure to obtain crude compound that was purified by flash column chromatography using 20% ethyl acetate in pet ether as an eluent to afford the title compound (1.50 g, 73% ) as an off white solid.
LC-MS (method 30): Rt = 2.41 min; m/z = 408.23 (M+H+).
Following a similar procedure to that described in reference example 28, but using the corresponding starting materials, the following compound was obtained:
Figure imgf000091_0001
REFERENCE EXAMPLE 30
5-Bromo-1 -(9-fluorononyl)-1 H-pyrazolo[3,4-c]pyridine (3): (BB-15681 -132)
To a stirred solution of 9-(5-bromo-1H-pyrazolo[3,4-c]pyridin-1-yl)nonan-1-ol (500 mg 1.47 mmol) in DCM was cooled to 0°C and added DAST (948 mg 5.88 mmol) at same temperature and reaction mixture was stirred at RT for 3 h. Progression of reaction was monitored by LCMS. Reaction was quenched with NaHCOsand diluted with water and extracted with ethyl acetate. Organic layer was washed with brine and dried over sodium sulphate, concentrated under reduced pressure to afford crude compound was purified using column chromatography using 30% ethyl acetate in pet.ether to afford 5-bromo-1-(9-fluorononyl)-1H-pyrazolo[3,4- c]pyridine (285 mg, 55 %) a slight yellowish solid.
LC-MS (method 23): Rt = 2.41 min; m/z = 342.17 (M+H+).
REFERENCE EXAMPLE 31
5-Bromo-1 -(9-methoxynonyl)-1 H-pyrazolo[3,4-c]pyridine (6): (BB-15681-126)
To a stirred solution of 9-(5-bromo-1H-pyrazolo[3,4-c]pyridin-1-yl)nonan-1-ol (450 mg, 1.32 mmol) in DMF was added 60% NaH (132 mg, 3.30 mmol) at 0°C and stirred for 15 minutes at same temperature and added Methyl iodide (373 mg, 2.64 mmol) and stirred at RT for 3 h. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to 0°C and added water and extracted with Ethyl Acetate (3x150ml). The organic layer was washed with brine solution and dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude compound which was purified by silica gel column chromatography using 20 % Ethyl Acetate in Pet. Ether to 5-bromo-1-(9-methoxynonyl)-1H-pyrazolo[3,4-c]pyridine (300 mg, 58 %) as a pale yellow solid.
LC-MS (method 23): R, = 2.41 min; m/z = 354.22 (M+H+).
REFERENCE EXAMPLE 32 5-bromo-3-chloro-1-nonyl-1H-pyrrolo[2,3-c]pyridine
To a stirred solution of Reference Example 10r (920 mg 2.85 mmol) in DMF was cooled to 0 °C and added N- Chlorosuccinimide (646 mg 4.85 mmol) at same temperature and reaction mixture was stirred at RT for 16 h. Progression of reaction was monitored by LCMS. Reaction was diluted with water and extracted with ethyl acetate (150 ml x3). Organic layer was washed with brine and dried over sodium sulphate, concentrated under reduced pressure to afford crude compound was purified using column chromatography using 10% ethyl acetate in petether to afford 5-bromo-3-chloro-1-nonyl-1H-pyrrolo[2,3-c]pyridine (550 mg, 54 %) a slight yellowish solid.
LC-MS (method 23): Rt = 2.84 min; m/z = 357.22 (M+H+).
Following a similar procedure to that described in reference example 32, but using the corresponding starting materials, the following compound was obtained:
Figure imgf000092_0001
REFERENCE EXAMPLE 33
6"bromo-3H-imidazo[4,5-c]pyridine
To a stirred solution of 6-bromopyridine-3,4-diamine (1.5 g, 8 mmol) in triethylorthoformate (7.11 g, 48 mmol) was added acetic anhydride (7.35 g, 72 mmol)) and stirred at 90°C for 6h. The reaction mixture was cooled and evaporated to dryness, then 10 mL 10N NaOH solution was added and heated the contents at 60° C for 50 min. After reaction mixture was cooled acidified with AcOH to a pH 6, then added crushed ice stirred for 15 minutes precipitated solid was filtered. The precipitated solid was washed with n-pentane to get 6-bromo-3H- imidazo[4,5-c]pyridine (1.5 g, 94%) as pale brown solid.
LC-MS (method 32): Rt = 0.26 min; m/z = 198.0 (M+H+).
REFERENCE EXAMPLE 34
6-bromo-3H-[1,2,3]triazolo[4,5-c]pyridine
To a stirred solution of 6-bromopyridine-3,4-diamine 7 (2 g, 10.6 mmol) in NaNO. (2M, 25 mL) was added Acetic acid (20 mL) and stirred at 0°C for 15 min and heated the contents of the reaction at 70°C for 1.5 h. The reaction was cooled, poured in crushed ice the precipitated solid was filtered, dried and washed with diethyl ether to get e-bromo-SH-n^.Sltriazolo^S-clpyridine (1.0 g, 47%) as off-white solid.
LC-MS (method 23): Rt = 1.26 min; m/z = 201.00 (M+H++2).
REFERENCE EXAMPLE 35
5-bromo-1-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-1H-pyrrolo[2,3-c]pyridine Step a. 1-(2-bromoethyl)-3,5-dimethyl-1H-pyrazole
To a stirred solution of aqueous 40% NaOH (1.5 mL) was added 3 , 5-d imethyl- 1 H-pyrazole (500 mg, 5.2 mmol, 1.0 eq), TBAB (167 mg, 0.52 mmol, 0.1 eq) and 1,2-dibromopropane (11 mL) and reaction was heated at 80°C for 12. Reaction was monitored by LCMS and TLC. Water was added to the reaction and extracted with EtOAc. Organic layer was dried and concentrated to get crude, purified by silica gel column chromatography using 5- 15% EtOAc in pet ether, to get 1-(2-bromoethyl)-3,5-dimethyl-1 H-pyrazole (600 mg, 57%).
LC-MS (method 23): R, = 1.65 min; m/z = 202.98 (M+H+).
Step b. 5-bromo-1 -(2-(3,5-dimethyl-1 H-pyrazol-1 -yl)ethyl)-1 H-pyrrolo[2,3-c]pyridine
To a stirred solution of 5-bromo-1 H-pyrrolo[2,3-c]pyridine (200 mg, 1.0 mmol, 1.0 eq) in DMF at RT was added 1-(2-bromoethyl)-3,5-dimethyl-1 H-pyrazole (303 mg, 1.5 mmol, 1.5 eq), Cs2C03 (975 mg, 3.0 mmol, 3.0 eq) was added and reaction mixture was stirred at RT for 12h. Reaction was concentrated to get crude compound, purified by reverse phase on grace instrument 0.1% FA and AcN, to get 5-bromo-1-(2-(3,5-dimethyl-1H- pyrazol-1-yl)ethyl)-1H-pyrrolo[2,3-c]pyridine (140 mg, 44%).
LC-MS (method 23): R, = 1.83 min; m/z = 319.21 (M+H+).
REFERENCE EXAMPLE 36
5-bromo-N,N-diethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
To a stirred solution of crude 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (1.8 g,7.5mmol, 1.0 eq) in DMF was added diethyl amine (0.548g, 7.5mmol, 1.0 eq), TEA (3.78g, 37.5mmol, 5.0 equiv) and T3P (7.15g, 22.5mmol, 3.0 equiv) at 0°C and allowed to stir at RT for 16h. T e progress of the reaction was monitored by LCMS. Water was added to the reaction mixture and extracted with EtOAc. The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was washed with n-pentane and dried to get S-bromo-N.N-diethyl-IH-pyrroloP.S-clpyridine^-carboxamide (1.2 g, 54%).
LC-MS (method 23): Rt = 1.80 min; m/z = 296.05 (M+H+).
Following a similar procedure to that described in reference example 36, but using the corresponding starting materials, the following compound was obtained:
Figure imgf000093_0001
REFERENCE EXAMPLE 37
tert-butyl 3-(6-bromo-3-butyl-1 H-pyrrolo[3,2-c]pyridin-1 -yl)pyrrolidine-1 -carboxylate
To a stirred solution of 6-bromo-3-butyl-1H-pyrrolo[3,2-c]pyridine (500 mg, 01.975mmol) in DMF (50 mL) was added CS2CO3 (2.24g, 6.9mmol) at RT. Resulting reaction mixture was allowed to stir at 100°C for 1 h, then was added tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1 -carboxylate in DMF (1.04g, 3.95mmol), then heated for 2 h. The reaction was monitored by LCMS. The reaction mixture was cooled, 20 mi ice cold water was added and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate. The crude was purified by flash column chromatography in devisal silica using 25-30% EtOAc/pet ether to get tert-butyl 3-(6- bromo-3-butyl-1 H-pyrrolo[3,2-c]pyridin-1 -yl)pyrrolidine-1 -carboxyiate (0.39 g, 46.8 %) as pale yellow gum. LC-MS (method 23): Rt = 2.43 min; m/z = 423.55 (M+H+).
Following a similar procedure to that described in reference example 37, but using the corresponding starting materials, the following compound was obtained:
Figure imgf000094_0001
(*) Nai was added to the reaction mixture
REFERENCE EXAMPLE 38
5-bromo-N-ethyl-1 -propyl-1 H-pyrrolo[2,3-c]pyridine-2-carboxamide
To a stirred solution of crude 5-bromo-N-ethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (500 mg, 1.9 mmol, 1eq) in ACN was added CS2CO3 (1.8572 mg, 5.7 mmol, 3.0 eq) and 1-bromopropane (0.467 mg, 3.8 mmol, 2 eq) and allowed to stir at 50°C for 24h. The progress of the reaction was monitored by LCMS. Water was added to the reaction mixture and extracted with EtOAc. The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was washed with n-pentane and dried to get 5-bromo-N-ethyl-1-propyl-1 H-pyrrolo[2,3-c]pyridine-2-carboxamide (350 mg, 60%).
LC-MS (method 23): Rt = 1.88 min; m/z = 310.08 (M+H+).
Following a similar procedure to that described in reference example 38, but using the corresponding starting materials, the following compound was obtained:
Figure imgf000094_0002
Figure imgf000095_0001
REFERENCE EXAMPLE 39
4-((5-bromo-1-propyl-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)morpholine
To a stirred solution of 5-bromo-1-propyl-1H-pyrrolo[2,3-c]pyridine (700 mg, 2.9 mmol) in n-butanol (30 mL) was added HCHO (30%) (0.87g, 29 mmol), morpholine (2.52g, 29 mmol) and 0.5 mL of con. HCI was added stirred at 110°C 16 h. The reaction was monitored by TLC and LCMS. The crude was concentrated, diluted with EtOAc, washed with 10% NaOH solution and the organic layer was concentrated. The crude was purified by flash column chromatography 10% MeOH/DCM to get 4-((5-bromo-1-propyl-1H-pyrrolo[2,3-c]pyridin-3- yl)methyl)morpholine (800 mg, 80%) as pale yellow gummy.
LC-MS (method 23): Rt = 1.35 min; m/z = 338.21 (M+H+).
Following a similar procedure to that described in reference example 39, but using the corresponding starting materials, the following compound was obtained:
Figure imgf000095_0002
REFERENCE EXAMPLE 40
10-(5-bromo-1 H-pyrrolo[2,3-c]pyridin-1 -yl)decanenitrile
To a stirred solution of 5-bromo-1-(9-bromononyl)-1H-pyrrolo[2,3-c]pyridine (600 mg, 1.49 mmol) in DMF (10 mL) NaCN (109 mg, 2.23 mmol), was added at RT. Reaction was heated to at 80°C for 2 h. The progress of the reaction was monitored by LCMS. The reaction was allowed to stir at RT. The reaction mixture was poured into crushed ice, then diluted with EtOAc (2 x 80 mL). The organic layer separated and dried over anhydrous Na2SO4, filtered and filtrate was concentrated. The crude compound was purified by column chromatography on 230-400 silica eluted with 15 % of EtOAc/ pet-ether to afford 10-(5-bromo-1H-pyrrolo[2,3-c]pyridin-1- yl)decanenitrile (400 mg, 76%) as a gummy liquid.
LC-MS (method 23): R, = 2.30 min; m/z = 348.21 (M+H+).
REFERENCE EXAMPLE 41
tert-butyl 3-((6-bromo-3-butyl-1 H-pyrrolo[3,2-c]pyridin-1 -yl)methyl)azetidine-1 -carboxylate Step a. tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1 -carboxylate
To a stirred solution of tert-butyl 3-(hydroxymethyl)azetidine-1 -carboxylate (5 g, 1 equiv), triethylamine in DCM at 0°C, methane sulfonyl chloride (1.5 equiv) was added and allowed to stir at RT for 4 h. The reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice water (50 mL) and extracted with DCM (2 x 150 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrated concentrated to get tert-butyl 3-((methylsulfonyloxy)methyl)azetidine-1-carboxylate (6.5 g, 91.74%) as a gummy solid.
LC-MS (method 23): F¾ = 1.80 min; m/z = 288.09 (M+Na+).
Step b. tert-butyl 3-((6-bromo-3-butyl-1 H-pyrrolo[3,2-c]pyridin-1 -yl)methyl)azetidine-1 -carboxylate
To a stirred solution of 6-bromo-3-butyl-1 H-pyrrolo[3,2-c]pyridine, reference example 17, (0.500g, 1.975mmol) in DMF (50 mL) was added CS2CO3 (3.211g,9.88mmol) at RT. Resulting reaction mixture was allowed to stir at 100°C for 1 h, then was added tert-butyl 3-((methylsulfonyloxy)methyl)azetidine-1 -carboxylate in DMF (1.04 g, 3.95mmol), then heated for 2 h. The reaction was monitored by LCMS. The reaction mixture was cooled, 20 ml ice cold water was added, and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrated concentrated. The crude was purified by flash column chromatography in devisal silica using 25-30% EtOAc/pet ether to get tert-butyl 3-((6-bromo-3-butyl-1H-pyrrolo[3,2-c]pyridin-1- yl)methyl)azetidine-1 -carboxylate as pale yellow gum.
LC-MS (method 23): R, = 2.39 min; m/z = 422.20 (M+H+).
Following a similar procedure to that described in reference example 41, but using the corresponding starting materials, the following compound was obtained:
Figure imgf000096_0002
REFERENCE EXAMPLE 42
4-(2-bromoethyl)benzonitrile
To a stirred solution of 4-(2-hydroxyethyl)benzonitrile (1.0g ,6.8mmol,1eq.) in DCM (20 mL) was added CBr4
(4.5016g, 13.6mmol, 2.0 eq) and TPP (3.835g, 13.6mmol, 2.0 eq). The resulting solution was stirred at RT for 5h. Reaction was monitored TLC. Reaction was diluted with water and extracted with EtOAc. Organic layer was dried over sodium sulfate, filtered and the filtrated concentrated. The crude compound was isolated by column chromatography to get pure 4-(2-bromoethyl)benzonitrile (1.3 g, 91%).
LC-MS (method 23): Rt = 2.01 min; m/z = 210.05 (M+H+).
EXAMPLE 1
Methyl 2-(1-(3-aminopropyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate hydrochloride
Figure imgf000096_0001
Step a. Methyl 2-(1-(3-(fert-butoxycarbony!amino) propyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate
In a pressure tube, to a stirred solution of reference example 2 (900 mg, 2.549 mmol) in 1, 4-dioxane (15 mL), reference example1 (920 mg, 3.059 mmol), and CsF (775 mg, 5.098 mmol) were added followed by Cul (97 mg, 0.509 mmol). The resulting reaction mixture was degassed, and Pd(PPh3)4 (295 mg, 0.254 mmol) was added and heated to 110°C for 16h. The reaction mixture was cooled to RT, diluted with EtOAc (200 mL), filtered through the Celite pad and the filtrate was concentrated. The crude compound was purified by column chromatography using silica gel and eluted with 5% MeOH/DCM to afford the title compound (510 mg, 49%) as a brown solid.
LC-MS (method 1): Rt = 1.70 min; m/z = 411.33 (M+H+)
Step b. Methyl 2-(1-(3-aminopropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate hydrochloride
To a stirred solution of the compound obtained in the previous section, step a (500 mg, 1.219 mmol) in 1,4- dioxane (1 mL), 4M HCI in 1, 4-dioxane (3 mL) was added at 10°C. The reaction mixture was allowed to stir at RT for 4 h. Then, it was concentrated; and the residue was triturated with diethyl ether and dried under reduced pressure to afford the title compound (410 mg) as a hydrochloride salt.
LC-MS (method 1): R, = 0.96 min; m/z = 311.19 (M+H+)
Following a similar procedure to that described in example 1, but using the corresponding starting material, the following compound was obtained:
Figure imgf000097_0001
Figure imgf000098_0002
EXAMPLE 2
Methyl 2-(1 -(3-(diethylamino)propyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate
Figure imgf000098_0001
To a stirred solution of example 1 (360 mg, 1.161 mmol) in methanol (4 ml_), acetaldehyde (522 mg, 11.612 mmol) and 4 A molecular sieves were added, followed by AcOH (0.03 mL) at 0°C. The mixture was stirred for 10 min, then NaCNBH3 (219 mg, 3.483 mmol) was added at 0°C. The resulting reaction mixture was allowed to stir at RT for 16h. It was concentrated; and the residue was dissolved in DCM (100 mL), filtered through the Celite pad, and the filtrate was dried over anhydrous Na2SO4. The organic solvents were evaporated to dryness to afford the title compound (400 mg, 94%) as a white solid.
LC-MS (method 1): Rt= 1.06 min; m/z: = 367.20 (M+H+)
Following a similar procedure to that described in example 2, but using the corresponding starting material, the following compound was obtained:
Figure imgf000099_0002
2-(1H-Pyrrolo[2,3-c]pyridin-5-yl)isonicotinamide
Figure imgf000099_0001
Step a. 2-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinonitrile
To a stirred solution of reference example 8 (2.2 g, 6.74 mmol) in 1,4-dioxane (20 mL), reference example 1a (2.17 g, 8.09 mmol), and CsF (2.0 g, 13.49 mmol) were added followed by Cul( 0.25 g, 1.34 mmol). The reaction mixture was degassed using N2 gas and then Pd(PPt¾)4 (0.8 g, 0.67 mmol) was added. The reaction mixture was again degassed with N2 gas and heated to 110 °C for 16h. It was cooled to RT and diluted with water (70 mL), extracted with EtOAc (2 x 70 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 50% EtOAc/ pet ether to afford the title compound (0.9 g, 38%) as an off white solid.
LC-MS (method 1 ): Rt = 2.09 min; m/z = 351.32 (M+H+)
Step b. 2-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinamide
To a stirred solution of the compound obtained in the previous section, step a, (0.35 g, 1.00 mmol) in MeOH (10 mL), NaOH (0.12 g, 3.00 mmol) and 30% H2O2 (0.36 g, 3.00 mmol) were added at RT. The resulting reaction mixture was stirred at 70 °C for 2h. It was evaporated under reduced pressure and the crude compound was dissolved with EtOAc (70 mL), and washed with 10% NaOH solution (2 x 30 mL). The organic layer was dried over Na2SO4 and concentrated to obtain the title compound (0.25 g, 68%) as an off white solid.
LC-MS (method 1): Rt = 1.68 min; m/z = 369.32 (M+H+)
Step c. 2-(1H)-Pyrrolo[2,3-c]pyridin-5-yl)isonicotinamide To a stirred solution of the compound obtained in the previous section, step b, (0.25 g, 0.67 mmol) in THF (5mL), 1M TBAF in THF (2 mL) was added. The resulting reaction mixture was stirred at 70 °C for 16h. The reaction mixture was evaporated under reduced pressure; the crude compound was dissolved in EtOAc (50mL), and treated with aqueous ammonia to reach pH ~ 8. Solids were collected by filtration and dried. The crude compound was purified by preparative HPLC to obtain the title compound (50 mg, 31 %) as a white color solid.
LC-MS (method 10): Rt = 1.46 min; m/z = 239,2 (M+H+).
Preparative HPLC conditions: Column: YMC TRAIT, C18 150*25mm 10.0μ Pump(A) : acetonitrile Pump(B) : 10mm ammonium bicarbonate in aqueous Flow : 18.0 ml/min Gradient : % of Pump(B)- 0/90,2.5/90, 11/100, 11.1/100, 3/100, 13.1/90, 15/90, max : 215nm.
EXAMPLE 4
Methyl 2-(1-(3-phenylpropyl)-1 H-pyrrolo [2,3-c]pyridin-5-yl)isonicotinate
Figure imgf000100_0001
In a pressure tube, to a stirred solution reference example 3a (1 g, 3 mmol) in 1, 4-dioxane (10 mL), reference example 1 (1.1 g, 3 mmol), CsF (0.9 g, 6 mmol) were added followed by Cul (0.1 g, 0.6 mmol). The resulting solution was degassed with nitrogen for 5 minutes and then Pd(PPh3)4 (0.3 g, 0.3 mmol) was added. The resulting mixture was again degassed for another 5 minutes and then heated to 110°C for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to RT, filtered through the Celite, washed with EtOAc (2 x 50 mL). The filtrate was concentrated to get a crude compound that was purified by column chromatography using silica gel and eluted with 40%EtOAc: pet ether to afford the title compound (520 mg, 47%) as an off-white solid.
LC-MS (method 1): Rt = 1.83 min; m/z = 372.31 (M+H*)
Following a similar procedure to that described in example 4, but using the corresponding starting materials in each case, the following compounds were obtained:
Figure imgf000100_0002
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0002
2-{1-(3-Phenylpropyl)-1H-pynOlo[2,3-c]pyridin-5-yl)isonicotinamide
Figure imgf000118_0001
To a stirred solution of example 4 (130 mg, 0.35 mmol) in MeOH (2 mL), a solution of 7N NH3 in methanol (5 mL) was added at 0°C. The resulting reaction mixture was heated at 80°C for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated and the crude compound was triturated with diethyl ether and dried under reduced pressure to afford the title compound (70 mg, 56%) as a pink solid. LC-MS (method 1): Rt = 1.52 min; m/z = 357.33 (M+H+)
Following a similar procedure to that described in example 5, but using the corresponding starting materials in each case, the following compounds were obtained:
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0002
2-(1 -(3-Phenylpropyl)-1 H-pyrrolo[2,3-c]pyriclin-5-yl)isonicotinicacid acid
Figure imgf000122_0001
To a stirred solution of example 4 (150 mg, 0.40 mmol in MeOH-THF-H20 (1:4:1, 3 mL), LiOH.H20 (50 mg, 1.21 mmol) was added at 10°C. The reaction mixture was allowed to stir at RT for 4h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated; the residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with aqueous saturated, citric acid solution, and the precipitated solid was filtered, washed with pet ether and dried in vacuum to afford the title compound (90 mg, 62%) as a white solid.
LC-MS (method 1): Rt = 1.62 min; m/z = 358.30 (M+H+)
Following a similar procedure to that described in example 6, but using the corresponding starting materials in each case, the following compounds were obtained:
Figure imgf000122_0003
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0002
EXAMPLE 7
2-(1 -(Piperidin-3-ylmethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid hemipentahydrochloride
Figure imgf000141_0001
Step a. Methyl 2-(1-((1-(feit-butoxycarbonyl)piperidin-3-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-5- yl)isonicotinate
To a stirred solution of reference example 11 (1.5 g, 3.80 mmol) in 1,4-dioxane (20 mL), reference example 1 (1.48 g, 4.94 mmol), CsF (1.15 g, 7.61 mmol), and Cul (0.14 g, 0.76 mmol) were added. The resulting solution was degassed using nitrogen gas, then Pd(PPh3)4 (0.44 g, 0.38 mmol) was added. The reaction mixture was again degassed and heated to 110 °C for 16h. It was cooled to RT, diluted with water (70 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layers were dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 70% EtOAc/ pet ether to afford the title compound (0.6 g, 35%) as a brown color solid.
LC-MS (method 1): Rt = 1.78 min; m/z = 451.26 (M+H+)
Step b. 2-(1-((1-(7ert-butoxycarbonyl)piperidin-3-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonico-tinic acid
To a stirred solution of the compound obtained in the previous section, step a, (0.3 g, 0.66 mmol) in THF (3 mL), MeOH (3 mL), and LiOH.H20 (84 mg, 1.99 mmol) in 1 mL of water, were added at RT. The reaction mixture was stirred at RT for 3h and then it was evaporated under reduced pressure. The residue was dissolved in water (10 mL) and acidified (pH~ 4) with aqueous saturated citric acid solution. Then, the solid was filtered, separated, and dried to obtain to obtain the title compound (0.15 g, 52%) as a white color solid.
LC-MS (method 8): Rt = 1.72 min; m/z: 437.32 (M+H+)
Step c. 2-(1-(Piperidin-3-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid hemipentahydrochloride
To a stirred solution of the compound obtained in the previous section, step b, (0.1 g, 0.22 mmol) in DCM (2 mL), 2M HCI in diethylether (3 mL) was added at 0 °C. T the resulting solution was stirred at RT for 3h. The reaction mixture was evaporated under reduced pressure; the solid residue was triturated with acetonitrile (5 mL), diethyl ether (2 x 10 mL) and dried to afford the title compound (70 mg) as a hydrochloride salt, pale yellow solid.
LC-MS (method 9): Rt = 3.38 min; m/z = 337.2 (M+H*)
Following a similar procedure to that described in example 7, but using the corresponding starting materials in each case, the following compounds were obtained:
Figure imgf000142_0002
EXAMPLE 8
2-(1-(Piperidin>3-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinamide dihydrochloride
Figure imgf000142_0001
Step a. Terf-butyl 3-((5-(4-carbamoylpyridin-2-yl)-1 H-pyrrolo[2,3-c]pyridin-1 -yl)methyl)piperidine-1 - carboxylate
In a sealed tube, to a stirred solution of the compound obtained in example 7, section a (0.3 g, 0.6 mmol) in MeOH (2 mL), a solution of 7N NH3 in methanol (7 mL) was added at 0 °C. The resulting solution was heated at 80 °C for 16h. The reaction mixture was cooled to RT, evaporated under reduced pressure, and the crude compound was dissolved in EtOAc (50 mL), and washed with 10% NaOH solution (2 x 30 mL). The organic layer was dried over Na2SO4 and concentrated to get a solid residue that was washed with n-pentane (10 mL) and dried to obtain the title compound (0.14 mg, 48%) as an off white solid.
LC-MS (method 1): F¾ = 1.57 min; m/z = 436.35 (M+H+).
Step b.2-(1-(Piperidin-3-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinamide dihydrochloride
To a stirred solution of the compound obtained in the previous section, step a, (90 mg, 0.20 mmol) in DCM (3 mL). 2M HCI in diethyl ether (5 mL) was added at 0 °C. The resulting solution was stirred at RT for 3h. The reaction mixture was evaporated under reduced pressure. The solid residue was triturated with acetonitrile (5 mL), pentane (5 mL) and dried to obtain the title compound (65 mg, 79%) as a dihydrochloride salt. LC-MS (method 1): Rt = 0.83 min; m/z = 336.21 (M+H+)
Following a similar procedure to that described in example 8, but using the corresponding starting materials in each case, the following compounds were obtained:
Figure imgf000143_0002
EXAMPLE 9
2-(1 -(3-Aminopropyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinamide dihydrochloride
Figure imgf000143_0001
Step a. Terf-butyl N-[(fert-butoxy)carbonyl]-N-{3-[5-(4- cyanopyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1- yl]propyl}carbamate
To a stirred solution of reference example 5 (0.8 g, 1.44 mmol) in 1,4-dioxane (10 mL), reference example 1a (0.46 g, 1.72 mmol), CsF (0.43 g, 2.88 mmol) were added followed by Cul (55 mg, 0.28 mmol). The resulting mixture was degassed using N2 gas and then Pd(PPI¾)4 (0.16 g, 0.14 mmol) was added. The reaction mixture was again degassed and heated to 110 °C for 16h. The reaction mixture was cooled to RT, diluted with water (70 mL), and extracted with EtOAc (2 x 70 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 40% EtOAc/ pet ether to afford the title compound (0.5 g, 60%) as an off white solid.
LC-MS (method 1): Rt = 2.09 min; m/z = 478.43 (M+H+)
Step b. Tert-butyl 3-(5-(4-carbamoylpyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)propylcarbamate To a stirred solution of the compound obtained in the previous section, step a, (0.2 g, 0.41 mmol) in MeOH (5 mL), NaOH (34 mg, 0.83 mmol) and 30% H202 (0.14 g, 1.25 mmol) were added at RT. The resulting reaction mixture was heated at 70 °C for 2h. The reaction mixture was evaporated under reduced pressure and the crude compound was dissolved with EtOAc (70 mL) and washed with 10% NaOH solution (2 x 30 mL). The organic layer dried over Na2SO4 and concentrated to obtain the title compound (0.12 g, 75%) as an off white solid.
LC-MS (method 1): Rt = 1.35 min; m/z = 396.32 (M+H+)
Step c. 2-(1-(3-Aminopropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinamide dihydrochloride
To a stirred solution of the compound obtained in the previous section, step b, (0.12 g, 0.30 mmol) in 1,4- dioxane (3 mL), 4M HCI in 1,4-dioxane (5 mL) was added at 0 °C. The reaction mixture was allowed to stir at RT for 3 h. The reaction mixture was evaporated under reduced pressure and the crude compound was triturated with diethyl ether (10 mL) and dried to obtain the title compound (75 mg) as a dihydrochloride salt. LC-MS (method 10): Rt = 1.24 min; m/z = 296.2 (M+H+)
.EXAMPLE 10
2-(1 H-Pyrrolo[2,3"C]pyridin-5-yl)isonicotinic acid
Figure imgf000144_0001
Step a. Methyl 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3"C]pyridin-5-yl)isonicotinate
To a stirred solution of reference example 8 (1g, 3.05 mmol) in toluene (20 mL), reference example 1 (1.19 g, 3.97 mmol), CsF (929 mg, 6.11 mmol) and Cul (116 mg, 0.61mmol) were added. The resulting reaction mixture was degassed and Pd (PPt¾)4 (353 mg, 0.305 mmol) was added. The resulting mixture was heated at 100°C for 16h. The reaction mixture was cooled to RT, filtered through the Celite pad and washed with EtOAc (50 mL). The filtrate was concentrated and the crude compound was purified by column chromatography using silica gel. The product was eluted with 50% EtOAc: pet ether. The obtained compound was further purified by prep.HPLC to afford the title compound (300 mg, 25%) as a pale yellow liquid.
Preparative HPLC conditions: Column: X-Select C18 19 x 150 mm, 5.0μ; Buffers: pump (A): 10 mm NH4HCO3 in water, (B): Acetonitrile; Isocratic: % of B: 70%; Flow: 18.0 mL/min; Max: 215 nm.
LC-MS (method 6): Rt = 2.58 min; m/z = 384.74 (M+H+)
Step b. 2-(1H-Pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid To a stirred solution of the compound obtained in the previous section, step a, (290 mg, 0.75 mmol) in THF (5 mL), TBAF (1M solution in THF) (1 mL) was added at 0°C. The reaction mixture was refluxed for 18h. The reaction mixture was cooled to RT and concentrated to dryness. The crude compound was purified by prep.HPLC to afford the title compound in quantitative yield.
LC-MS (method 6): Rt = 1.66 min; m/z = 240.06 (M+H+) Preparative HPLC conditions: Column: Atlantis T3; Buffers: pump (A): 0.1% formic acid in aqueous, (B): Acetonitiile; Gradient: A/B: 0/5, 2/5, 10/30, 15/98; Flow: 18.0 mL/min; Max: 215 nm.
Following a similar procedure to that described in example 10, but using the corresponding starting material, the following compound was obtained:
Figure imgf000145_0003
EXAMPLE 11
Methyl 2-(1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate
Figure imgf000145_0002
To a stirred solution of example 10 (190 mg, 0.79 mmol) in methanol (5 mL), concentrated H2S04 (0.2 mL) was added at RT. The reaction mixture was refluxed for 18h. It was cooled to RT and concentrated. The crude residue was basified with aq.NaHCO3 solution and extracted with 1-butanol-EtOAc (1:1) (2 x 25 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated. The crude compound was purified by prep. HPLC to afford the title compound (18 mg, 9%) as a pale pink solid.
LC-MS (method 6): Rt = 1.81 min; m/z = 254.18 (M+H+)
Preparative HPLC conditions: Column: X-Select C18 19 x 150 mm, 5.0μ; Buffers: pump (A): 10 mm NH4HCO3 in water, (B): Acetonitiile; Gradient: time/% of B: 0/10, 2/10, 10/55, 15/98; Flow: 18.0 mL/min; Max: 215 nm. Following a similar procedure to that described in example 11, but using the corresponding starting material, the following compound was obtained:
Figure imgf000145_0004
Methyl 2-(1 H-pyrazolo[4,3-c]pyridin-6-yl)isonicotinate
Figure imgf000145_0001
Step a. Methyl 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)isonicotinate in a sealed tube, to a stirred solution of reference example 13 (750 mg, 2.65 mmol), and reference example 1
(954 mg, 3.19 mmol) in toluene (20 mL), Pd(PPh3)4 (307 mg, 0.26 mmol) was added at RT. The resulting suspension was degassed with nitrogen for 10 min. The reaction mixture was heated to 110 °C for 24 h. It was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resultant crude compound was purified by flash column chromatography using 35% EtOAc in petroleum ether as an eluent to afford the title compound (180 mg, 20%).
LC-MS (method 6): F¾ = 2.46 min; m/z = 339.22 (M+H+)
Step b. Methyl 2-(1H-pyrazolo[4,3-c]pyridin-6-yl)isonicotinate
In a sealed tube, to a stirred solution of the compound obtained in the previous section, step a, (180 mg, 0.53 mmol) in DCM (5 m L), 4M HCI in 1,4-dioxane (1 mL) was added at RT. The resulting solution was stirred for 24 h The reaction mixture was concentrated under reduced pressure, the obtained residue was diluted with water (10 mL). The pH was adjusted to ~8 with saturated NaHC03 solution and extracted with EtOAc (3X 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered; and the filtrate was concentrated under reduced pressure. The crude compound was purified by Grace column chromatography (reverse phase) using with 30% of acetonitrile in 0.1% aqueous formic acid as an eluent to afford the title compound (40 mg, 29%) as pale brown solid.
LC-MS (method 6): R, = 1.82 min; m/z = 255.11 (M+H+)
EXAMPLE 13
2-(1 H-Pyrazolo[4,3-c]pyridin-6-yl)isonicotinic acid
Figure imgf000146_0001
To a stirred solution of example 12 (120 mg, 0.47 mmol) in MeOH:H20 (5 mL:5mL), UOH.H2O (99 mg, 2.36 mmol) was added at RT. The resulting solution was stirred at RT for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (10 mL) and washed with EtOAc (10 mL). The aqueous layer pH was adjusted to ~5 with 10% citric acid solution. Then, the precipitated solid was filtered, washed with water and dried under vacuum to afford the title compound as an off-white solid. LC-MS (method 12): Rt = 4.95 min; m/z = 241.2 (M+H+)
EXAMPLE 14
2-(1H-Pyrazolo[4,3-c]pyridin-6-y!)isonicotinamide
Figure imgf000146_0002
Step a. 2-(1-(Tetrahydro-2H-pyran-2-yl)-1 H-pyrazolo[4,3-c]pyridin-6-yl)isonicotinonitrile
In a sealed tube, to a stirred solution of reference compound 13 (800 mg, 2.83 mmol), and reference compound 1a (908 mg, 3.40 mmol) in toluene (30 m L), Pd(PPh3)4 (785 mg, 0.68 mmol) was added at RT. The resulting suspension was degassed with nitrogen for 5 min. The reaction mixture was heated to 110 °C for 16 h and the it was allowed to cool to RT, filtered through a Celite and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash column chromatography eluting with 30% ethyl acetate in pet ether to afford the title compound (330 mg, 38%).
LC-MS (method 6): Rt = 2.64 min; m/z = 306.17 (M+H+)
Step b. 2-(1H-Pyrazolo[4,3-c]pyridin-6-yl)isonicotinonitrile
To a stirred solution of the compound obtained in the previous section, step a, (330 mg, 1.08 mmol) in DCM (5 mL), TFA ( 5 mL) was added at RT. The resulting solution was stirred for 48 h and then it was concentrated under reduced pressure. The resultant residue was diluted with water (5 mL) and the pH adjusted to ~8 with saturated NaHC03 solution, and extracted with EtOAc (3X15 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated under reduced pressure and the obtained crude compound was triturated with diethyl ether to afford the title compound (200 mg, 84%) as an off-white solid.
LC-MS (method 6): Rt = 1.65 min; m/z = 222.13 (M+H+)
Step c. 2-(1H-Pyrazolo[4,3-c]pyridin-6-yl)isonicotinamide
To a stirred solution of the compound obtained in the previous section, step b, (65 mg, 0.294 mmol) in i-BuOH (5 mL), KOH (41 mg, 0.735 mmol) was added at RT and the resulting suspension was stirred at 100°C for 30 min. The reaction mixture was concentrated under reduced pressure and the obtained crude compound was purified by prep HPLC method to afford the title compound (35 mg, 49%) as an off-white solid.
LC-MS (method 13): Rt = 6.26 min; m/z = 240.0 (M+H+)
Preparative HPLC Conditions: Column: Inertsil ODS-3 250*20mm 5.0μ, Mobile phase (Buffers): A: 10mM Amonium Bicarbonate in Aq. B: Acetonitrile; Gradient Method (A/B): 0/10, 2/10, 15/80, 20/98, Flow rate: 18.0 mL/min; Detectors (Wave length) : 215 nm
EXAMPLE 15
2-(1H-Pyrrolo[3,2-c]pyridin-6-yl)isonicotinamide
Figure imgf000147_0001
Step a. 2-(1-((2-(Trimethylsilyl) ethoxy)methyl)-1H pyrrolo [3,2-c] pyridin-6-yl) isonicotinonitrile
To a stirred suspension of reference compound 1a (600 mg, 2.238 mmol), reference compound 8a (732 mg, 2.238 mmol), Cul (85 mg, 0.447mmol), in dioxane (20 mL), Pd(PPh3)4(257 mg, 0.223 mmol) and CsF (679 mg, 4.476 mmol) were added. The reaction mixture was degassed under nitrogen and heated at 100°C for 24 h. Then, it was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to obtain a crude compound: It was purified by Grace chromatography (reverse phase) using 0.1% formic acid (aq) in acetonitrile as an eluent to afford the title compound (400 mg, 51.08%).
LC-MS (method 6): Rt = 2.51 min; m/z = 351.68 (M+H+)
Step b. 2-(1-(Hydroxymethyl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinonitrile To a stirred solution of the compound obtained in the previous section, step a, (30 mg, 0.085 mmol) in DCM (5 mL), TFA (1 mL) was added at RT and stirred for 24 h. The reaction mixture was concentrated under reduced pressure and the obtained crude compound was triturated with DCM to afford the title compound (20 mg, 95%). LC-MS (method 15): Rt = 1.12 min; m/z = 251.05 (M+H+)
Step c. 2-(1H-Pyrrolo[3,2-c]pyridin-6-yl)isonicotinamide
a stirred solution of the compound obtained in the previous section, step b, (380 mg, 1.520 mmol) in MeOH (15 mL), 2% aq NaOH solution (25 mL) was added at RT and stirred for 6 h. The reaction mixture was concentrated under reduced pressure and the obtained crude compound was purified by Prep HPLC method to afford the title compound (20 mg, 5%).
LC-MS (method 6): R, = 1.42 min; m/z, 239.13 (M+H+)
EXAMPLE 16
Methyl 2-(1-butyl-1 H-pyrrolo [2,3-c]pyridin-5-yl)-5-fluoroisonicotinate
Figure imgf000148_0001
In a pressure tube, to a stirred solution of reference example 15 (400 mg, 1.183 mmol) in 1, 4-dioxane (10 mL), methyl 2-bromo-5-fluoroisonicotinate (275 mg, 1.183 mmol), CsF (359 mg, 2.366 mmol) and Cul (112 mg, 0.591 mmol) were added. The resulting solution was degassed with N2, and Pd(PPh3)4 (136 mg, 0.118 mmol) was added. The resulting mixture was heated to 110°C for 16h. The reaction mixture was diluted with 10%MeOH/DCM and filtered through celite pad; the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted at 20% EtOAc in pet ether to afford the title compound (150 mg, 38%) as an off white solid;
LC-MS (method 3): R, = 1.85 min; m/z, = 328.26 (M+H+)
Following a similar procedure to that described in example 16, but using the corresponding starting material, the following compound was obtained:
Figure imgf000148_0002
EXAMPLE 17
2-(1-Butyl-1H-pyrrolo [2, 3-c] pyridin-5-yl)-5-fluoroisonicotinic acid
Figure imgf000149_0001
Following a similar procedure to that described in example 6, but using example 16 instead of example 4, the desired compound was obtained (28% yield).
LC-MS (method 4): Rt = 1.24 min; m/z = 314.24 (M+H+).
Following a similar procedure to that described in example 17, but using the corresponding starting material, the following compound was obtained:
Figure imgf000149_0003
Methyl 2-(1 -butyl-3-(1 -methylpiperidin-4-yl)-1 H-pyrrolo [2,3-c]pyridin-5-yl)isonicotinate
Figure imgf000149_0002
To a stirred solution of example 4am (500 mg, 1.237 mmol) in MeOH (10 mL) Pd/C (500 mg) was added under nitrogen atmosphere. The reaction mixture was stirred under H2 balloon pressure at RT for 36h. The reaction mixture was diluted with MeOH and filtered through a celite pad; the filtrate was concentrated under reduced pressure to afford the title compound (380 mg, 75%) as a pale yellow solid.
LC-MS (method 19): Rt = 0.68 min; m/z = 407.67 (M+H*).
Following a similar procedure to that described in example 18, but using the corresponding starting material, the following compound was obtained:
Figure imgf000149_0004
EXAMPLE 19 2-(1 -Butyl-3-(1 -methylpiperidin-4-yl)-1 H-pyrrolo [2,3-c]pyridin-5-yl)isonicotinic acid
Figure imgf000150_0001
Following a similar procedure to that described in example 6, but using example 18 instead of example 4, the desired compound was obtained.
LC-MS (method 23): Rt = 1.28 min; m/z = 393.40 (M+H+).
EXAMPLE 20
2-(1 -(2-Aminoethyl)-3-butyl-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate hydrochloride
Figure imgf000150_0002
Step a. Methyl 2-(1-(2-(tert-butoxycarbonylamino)ethyl)-3-butyl-1H-pyrrolo[3,2-c]pyridin-6- yl)isonicotinate
Following a similar procedure to that described in example 1, but using reference example 27 instead of reference example 2, the desired compound was obtained (yield :80) as off-white gummy solid.
LC-MS (method 23): Rt = 1.86 min; m/z = 453.33 (M+H+).
Step b. Methyl 2-(1-(2-aminoethyl)-3-butyl-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate hydrochloride
Following a similar procedure to that described in example 1 , step b, but using example the compound obtained in the previous section, step athe desired compound was obtained.
LC-MS (method 23): R, = 1.36 min; m/z = 353.22 (M+H+).
Following a similar procedure to that described in example 20, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000151_0004
EEXAMPLE 21
2-(1-(2-aminoethyl)-3-butyl-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid
Figure imgf000151_0001
Following a similar procedure to that described in example 6, but using example 20 instead of example 4, the desired compound was obtained.
LC-MS (method 30): Rf = 1.31 min; m/z = 339.22 (M+H+).
EXAMPLE 22
Methyl 2-(3-butyl-1 -(2-cyanopyrimidin-5-yl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate
Figure imgf000151_0002
To a stirred solution of example 4ay (350 mg, 1.13 mmol) in toluene (25 mL), 5-bromopyrimidine-2-carbonitrile (416 mg, 2.26 mmol), Cs2C03 (737 mg, 2.62 mmol), and Cul (107 mg, 0.56 mmol) were added. The resulting suspension was degassed with nitrogen gas for 5 min followed by addition of trans-N.N'-dimethylcyclohexane- 1,2-diamine (80 mg, 0.56 mmol). The reaction mixture was stirred at 110°C for 16 h. Then, it was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered; and the filtrate was evaporated under reduced pressure to obtain a crude compound that was purified by flash column chromatography using 20% ethyl acetate in pet ether as an eluent. The title compound (150 mg, 32%) was afforded as an off white solid.
LC-MS (method 23): Rt = 2.29 min; m/z = 413.27 (M+H+).
EXAMPLE 23
2-(3-Butyl-1 -(2-cyanopyrimidin-5-yl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid
Figure imgf000151_0003
Following a similar procedure to that described in example 6, but using example 22 instead of example 4, the desired compound was obtained. LC-MS (method 30): Rt = 1.99 min; m/z = 399.27 (M+H+).
EXAMPLE 24
Methyl 2-(1-(2-(1-acryloylpiperidin-4-yl)ethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate (
Figure imgf000152_0001
To a stirred solution of example 20a (250 mg, 0.625 mmol) in DCM (5 mL), TEA (347 mg, 3.12 mmol) and acryloyl chloride (124 mg, 1.24 mmol) at 0°C were added. The resulting mixture was allowed to stir at RT for 16 h.The reaction mixture was diluted with water, extracted with DCM, and the combined organics were dried over Na2SO4 and filtered. The solution was evaporated under reduced pressure to obtain the title compound (200 mg, 76%) as brown solid.
LC-MS (method 30): R, = 1.57 min; m/z = 419.26 (M+H+).
Following a similar procedure to that described in example 24, but using the corresponding starting material, the following compound was obtained:
Figure imgf000152_0003
EXAMPLE 25
2-(1 -(2-(1 -Acryloylpiperidin-4-yl)ethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid
Figure imgf000152_0002
To a stirred solution of example 24 (200 mg, 0.47 mmol) in THF: MeOH: H20 (5 mL: 5 mL: 3 mL), UOH.H20 (59 mg, 1.43 mmol) was added at 0°C. The resulting solution was stirred at room temperature for 3h. The reaction mixture was evaporated under reduced pressure, diluted with water, and washed with ethyl acetate. Aqueous layer's pH was adjusted to 5.0 with citric acid, extracted with 10% methanol in DCM and the combined organic layers were dried over Na2SO4 and filtered. The solution was evaporated under reduced pressure to obtain a crude compound that was purified by prep HPLC followed by lyophilisation to afford the title compound (95 mg, 49%) as an off white solid.
LC-MS (method 30): Rt = 1.44 min; m/z = 405.26 (M+H+). Prep HPLC conditions: Column/dimensions: Prontosil C18 (19 x250 mm), 10.0 μ, Mobile phase: 0.1% FA in H20: Acetonitrile (A:B), Gradient (Time /% B) : 0/10, 2/25, 7/25, 7.1/100, 8/100, 8.1/10, 11/10, Flow rate : 20 ml/min.
Following a similar procedure to that described in example 25, but using the corresponding starting material, the following compound was obtained:
Figure imgf000153_0003
EXAMPLE 26 & 26a
2-(1-Butyl-3-(cyanamidomethyl)-1H-pyrrolo[2,3-c]pyridin-S-yl)isonicotinic acid
Figure imgf000153_0001
and 2-(1-butyl-3-(ureidomethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid
Figure imgf000153_0002
Step a. Methyl 2-(1-butyl-3-formyl-1H-pyrrolo [2, 3-c] pyridin-5-yl) isonicotinate
To a stirred solution of example 4b (1.8 g, 5.81 mmol) in DCE (10 ml) and nitromethane (10 ml) at 0°C, dichloro (methoxy)methane (3.35 g, 29.12 mmol), and AICI3 (2.3 g, 17.47 mmol) were added. The reaction mixture was allowed to stir at RT for 6 h. Then, it was cooled at 0°C, and slowly quenched with MeOH (10 mL) at 0°C, cold water (20 mL) and basified with cooled sat.Na2C03 solution (0°C). The resulting mixture was stirred for 10 min and then extracted with DCM (3 x 30 mL), dried over is^SCU, and evaporated to get a crude compound. This solid was triturated with diethyl ether and dried to afford 1.2 g (61%) of the title compound, as a yellow solid.
LC-MS (method 23): Rt = 1.86 min; m/z = 338.13 (M+H+). Step b. Methyl 2-(1-butyl-3-((cyanoimino)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate
To a stirred solution of the compound obtained in the previous section, step a, (200 mg,0.59 mmol) in toluene, cyanamide (74 mg, 1.77 mmol) and PTSA (10 mg ,0.059mmol) were added. Then it was heated to 110°C for 16 h. The reaction mixture was evaporated in vacuum to get 220 mg of the title compound as a brown solid. LC-MS (method 23): Rt = 2.01 min; m/z = 362.19 (M+H+).
Step c. Methyl 2-(1-butyl-3-(cyanamidomethyl)-1H-pyrrolo [2,3-c]pyridin-5-yl)isonicotinate
To a stirred solution of the compound obtained in the previous section, step b, (220 mg, 0.60 mmol) in MeOH, NaCNBH3 (76 mg, 1.2 mmol) was added at 0°C and then allowed to stir at RT for 4 h. The reaction mixture was evaporated in vacuum to get a crude compound. This crude compound was poured in to ice water (10 mL) and stirred for 30 min. The precipitated solid was filtered and dried to afford 200 mg (over two steps 92%) of the title compound, as a brown solid.
LC-MS (method 23): R, = 1.55 min; m/z = 364.18 (M+H+).
Step d. 2-(1-Butyl-3-(cyanamidomethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid
and 2-(1 -butyl-3-(ureidomethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid
To a stirred solution of the compound obtained in the previous section, step c, (150 mg, 0.41 mmol) in THF: H20 (2:1 , 2mL), LiOH.H20 (51 mg, 1.23 mmol) was added at 0°C and it was allowed to stir at 10°C for 1 h. The reaction mixture was acidified to pH-3 using saturated citric acid solution at 0°C, and evaporated completely to get a crude compound. This crude compound was purified by prep.HPLC to afford 6 mg (4%) of example 26 as an off white solid and 20 mg (13%) of example 26a as a light pink solid.
Example 26: LC-MS (method 30): Rt = 1.45 min; m/z = 348.18 (M-H+).
Example 26a: LC-MS (method 23): Rt = 1.40 min; m/z = 368.24 (M+H+).
Preparative HPLC Conditions: Column/dimensions : ATLANTIS T3 (19 x250 mm), 5.0 pm, Mobile phase : 0.1 % FA in H20 : Acetonitrile (A:B);,Gradient(Time 1% of B) : 0/10,6/55, 6.1/100,9/100,9.1/10,12/10, Flow rate : 20 ml/min, UV:215 nm & 254 nm.
EXAMPLE 27
2-(3-butyl-1-(2-(vinylsulfonarnido)ethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid
Figure imgf000154_0001
Step a. methyl 2-(3-butyl-1-(2-(vinylsulfonamido)ethyl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate:
To a stirred solution of example 20 (150 mg, 0.38 mmol) and 2-chloro-ethanesulfonyl chloride (62.87 mg, 0.38 mmol) in DCM (5 mL) was added TEA (0.16 mL, 1.15 mmol) at -50°C and allowed to stir at -50°C for 1 h. The reaction mixture was poured into ice water (10 mL) and extracted with DCM (2 x 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrated concentrated to get 180 mg (crude) of methyl 2-(3-butyl- 1-(2-(vinylsulfonamido)ethyl)-1H-pynOlo[3,2-c]pyridin-6-yl)isonicotinate, as a gummy solid.
LC-MS (method 23): Rt = 1.77 min; m/z = 443.26 (M+H+).
Step b.2-(3-butyl-1-(2-(vinylsulfonamido)ethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid :
To a stirred solution of methyl 2-(3-butyl-1-(2-(vinylsulfonamido)ethyl)-1H-pyrrolo[3,2-c]pyridin-6- yl)isonicotinate, (180 mg, 0.40 mmol) in THF (5 mL) was added Potassium trimethylsilanolate (104 mg, 0.81 mmol) at 0°C and allowed to stir at 10°C. The solvent was evaporated to get crude residue, was acidified by citric acid solution at 0°C extracted with 10 % MeOH/DCM (2 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrated concentrated to get crude. The crude compound was purified by Prep.HPLC and fraction was lyophilized to afford 2-(3-butyl-1-(2-(vinylsulfonamido)ethyl)-1H-pyrrolo[3,2- c]pyridin-6-yl)isonicotinic acid (28 mg, 16 %) of as a light pink solid.
LC-MS (method 23): R, = 1.64 min; m/z = 429.59 (M+H+).
Preparative HPLC Conditions: Column/dimensions: X SELECT C18 (19x150 mm), 5:0 μπι, Mobile phase: 0.1 % FA in H20: Acetonitrile (A: B) Gradient (Time /% B): 0/10,3/25,7/25,7.1/100,10/100, 10.1/10, 12/10., Flow rate: 25 ml/min, UV: 215nm & 254 nm.
Following a similar procedure to that described in example 27, but using the corresponding starting material, the following compound was obtained:
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0002
EXAMPLE 28
(E)-2-(3-butyl-1-(2-(4-(dimethylamino)but-2-enamido)ethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)isoni acid formate
Figure imgf000157_0001
Step a: (E)-methyl 2-(3-butyl-1-(2-(4-(dimethylamino)but-2-enamido)ethyl)-1 H-pyrrolo[3,2-c]pyridin-6- yljisonicotinate:
To a stirred solution of example 20 (120 mg, 0.30 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (47 mg, 0.37 mmol) in DMF (5 mL) was added T3P (0.29 mL, 0.92 mmol), TEA (0.156 mL, 1.54 mmol) at 0°C and allowed to stir at RT for 16 h. The reaction was diluted with DCM (20 mL) and washed with water (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrated concentrated to get 110 mg (crude) of (E)-methyl 2-(3-butyl-1 -(2-(4-(dimethylamino)but-2-enamido)ethyl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate, as brown gummy solid.
LC-MS (method 23): Rt = 1.49 min; m/z = 464.40 (M+H+).
Step b (E)-2-(3-butyl-1-(2-(4-(dimethylamino)but-2-enamido)ethyl)-1 H-pyrrolo[3,2-c]pyridin-6- yl)isonicotinic acid formate:
To a stirred solution of the compound obatained in pevious section step a (110 mg, 0.23 mmol) in MeOH:THF:H20 (1:1.5:1.5, 10mL) was added UOH.H20 (29 mg, 0.71 mmol) at 0°C) at 0°C and allowed to stir at 10°C for Ih.The reaction was evaporated in vacuum then acidified with citric acid solution at at 0°C and extracted with 10% MeOH/DCM, then dried over anhydrous ^SO*. filtered and filtrate was concentrated to get 125 mg of crude, The crude was purified by prep.HPLC, and lyophilized to afford 21 mg of (E)-2-(3-butyl-1- (2-(4-(dimethylamino)but-2-enamido)ethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid, as a pink solid.
LC-MS (method 23): Rt = 1.41 min; m/z = 450.32 (M+H+).
Preparative HPLC Conditions: Column/dimensions: YMC C8(25x150 mm), 5.0 μm, Mobile phase: 0.1 % FA in H20: Acetonitrile (A: B) Gradient (Time /% B): 0/10, 1/10,5/25,8/25,8.5/100,11/100,11.1/10,13/10., Flow rate: 25 ml/min, UV: 215nm & 254 nm.
[EXAMPLE 29
2-(3-butyM -(2-(3-oxobutanamido)ethyl)-1 H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid
Figure imgf000158_0001
Step a. Methyl 2-(1-(2-but-2-ynamidoethyl)-3-butyl-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate:
To a stirred solution of example 20 (120 mg, 0.30 mmol) and but-2-ynoic acid (31 mg, 0.37 mmol) in DMF (5 mL) was added HATU (176 mg, 0.46 mmol), DIPEA (119 mg, 0.92 mmol) at 0°C and allowed to stir at RT for 4 h. The reaction was diluted with DCM (20 mL) and washed with water (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrated concentrated to get 120 mg (crude) as brown gummy solid. LC-MS (method 23): Rt = 1.73 min; m/z = 419.37 (M+H+).
Step b. 2-(3-butyl-1-(2-(3-oxobutanamido)ethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinic acid:
To a stirred solution of methyl 2-(1-(2-but-2-ynamidoethyl)-3-butyl-1H-pyrrolo[3,2-c]pyridin-6-yl)isonicotinate (120 mg, 0.28 mmol) in MeOH:THF:H20 (1:1.5:1.5, 10mL) was added LiOH.H20 (36 mg, 0.86 mmol) at 0°C and allowed to stir at 10°C for Ih.The reaction was evaporated in vacuum then acidified with citric acid solution at 0°C and extracted with 10% MeOH/DCM, then dried over anhydrous Na2SO4, filtered and filtrate was concentrated to get crude. The crude compound was purified by prep.HPLC to afford 16 mg of 2-(3-butyl-1-(2- (S-oxobutanamidoJethylJ-IH-pyrroloP^-clpyridin-6-ylJisonicotinic acid, as an off white solid.
LC-MS (method 23): Rt = 1.55 min; m/z = 423.28 (M+H+).
Preparative HPLC Conditions: Column/dimensions: YMC C8 (25x150 mm), 5.0 μητι, Mobile phase: 0.1 % FA in H20: Acetonitrile (A: B) Gradient (Time /% B): 0/10,6/40,10/40,10.5/100,12/100,12.1/10,14/10., Flow rate: 25 ml/min, UV: 215nm & 254 nm.
EXAMPLE 30
2-(1 -(5-acrylamidopentyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid hemipentaacetate
Figure imgf000159_0001
Step a. methyl 2-(1-(5-acrylamidopentyl)-1H-pyrrolo[2,3-c]pyridin-5>yl)isonicotinate
To a stirred solution of Example 1b (0.2 g, 0.5 mmol eq) in DCM (15 mL) was added trimethylamine (0.2 g, 2 mmol) at 0°C then acrolyl chloride (78 mg, 00.8 mmol) was added slowly at 0°C and allowed to stir at RT for 3h. The reaction mixture was poured into ice water (10 mL) and extracted with 10 % MeOH/DCM (2 x 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated to get 200 mg (crude) of methyl 2- (1-(5-acrylamidopentyl)-1H-pynOlo[2,3-c]pyridin-5-yl)isonicotinate as brown gummy
LC-MS (method 31): Rt = 3.02 min; m/z = 393.35 (M+H+).
Step b. 2-(1-(5-acrylamidopentyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid hemipentaacetate
To a stirred solution of methyl 2-(1-(5-acrylamidopentyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate (200 mg, 0.5 mmol) in MeOH:THF:H20 (1 :1.5:1.5, 10mL) was added L1OH.H2O (37 mg, 0.9 mmol) at 0°C and allowed to stir at 10°C for 1 h. The progress of the reaction was monitored by TLC and LCMS. The solvent was evaporated to get crude, added saturated citric aid solution to a pH 2-3 and the crude was concentrated to get a pink solid. The crude compound was purified by prep.HPLC to afford 18 mg of 2-(1-(5-acrylamidopentyl)-1H-pyrrolo[2,3- c]pyridin-5-yl)isonicotinic acid hemipentaacetate, as an pink solid.
LC-MS (method 23): Rt = 1.39 min; m/z = 379.28 (M+H+).
Preparative HPLC Conditions: column/dimensions : XBRIDGE C18 (30x150 mm), 5μm. Mobile phase : 10 Ammonium Acetate Acetonitrile:MeOH(1:1) (A:B). Gradient (Time /% B):
0/10,4/40,7/40,7.1/100,9/100,9.1/10,12/100. Flow rate : 25 ml/min. Diluent : ACN+H2O.
Following a similar procedure to that described in example 30, but using the corresponding starting material, the following compounds were obtained:
Figure imgf000159_0002
Figure imgf000160_0002
EXAMPLE 31
2-(1-(9-cyanononyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid
Figure imgf000160_0001
To a stirred solution of example 4abv (70 mg, 0.17 mmol) in THF was added potassium trimethylsilanolate (44 mg, 0.34 mmol) at 0°C and allowed to stir at 10°C for 1 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was evaporated to get crude residue, and was acidified with citric acid solution at 0°C, precipitated solid was stirred for 30 min then filtered and dried. The solid compound was triturated in diethyl ether, filtered and dried. The solid obtained was dissolved in ACN/H2O then lyophilized to afford 2-(1-(9- cyanononyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid (17 mg, 25%) as an off white solid
LC-MS (method 35): Rt = 2.53 min; m/z = 391.40 (M+H+).
Following a similar procedure to that described in example 31, but using the corresponding starting material, the following compounds were obtained:
Figure imgf000161_0003
EXAMPLE 32 AND 32a
2-(1 -butyl-3-((cyanomethyl)carbamoyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid (32)
Figure imgf000161_0002
and 2-(1-butyl-3-carbamoyl-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid hemiformate (32a)
Figure imgf000161_0001
Step a. methyl 2-(1-butyl-3-formyl-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate
To a stirred solution of reference example 10 (1.7 g, 0.005 mmol) in DCE (7.5ml) was added nitromethane (7.5 ml) then cooled to 0°C, followed by dichloro(methoxy)methane (2.52 g, 0.02 mol), AICI3 (2.19 g, 0.016 mol) were added, the reaction was allowed to stir at RT for 6 h. The reaction was cooled at 0°C, slowly quenched with MeOH (10 mL) at 0°C, cold water (20 mL) and basified with sat.Na2C03 solution at 0°C and stirred for 10 min, then extracted with DCM (3 x 100 mL), dried over Na2SO4 and evaporated. The crude compound was triturated with diethyl ether and dried to afford methyl 2-(1-butyl-3-fbrmyl-1H-pyrrolo[2,3-c]pyridin-5- yl)isonicotinate (1.2 g, 64%) as a brown solid.
LC-MS (method 23): Rt = 1.82 min; m/z = 338.10 (M+H+).
Step b. l-butyl-S-i^imethoxycarbonylJpyridin^-ylJ-IH-pyrrolop.S-clpyridine-S-carboxylic acid
To a stirred solution of methyl 2-(1-butyl-3-formyl-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate (200 mg, 0.6 mmmol) in Acetone: H2O (2:1, 5mL) was added KMNO4 (189 mg, 1.2 mmol) at 0°C and allowed to stir at RT for 4 h. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated, the crude compound dissolved in water (5 mL), acidified with citric acid and extracted with 10 % MeOH/DCM (2 x 25 mL), then dried over anhydrous isfeSCU, filtered and filtrate was concentrated to get 0.15 g of 1-butyl-5-(4- (methoxycarbonyl)pyridin-2-yl)-1 H-pyrrolo[2,3-c]pyridine-3-carboxylic acid, as a gummy solid.
LC-MS (method 23): R, = 1.63 min; m/z = 354.12 (M+H+).
Step c. methyl 2-(1-butyl-3-(cyanomethylcarbamoyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate
To a stirred solution of 1-butyl-5-(4-(methoxycarbonyl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (140mg, 0.39mmol) in DMF (15 mL) was added EDC.HCI (91 mg, 0.43 mmol), HOBt (80 mg, 0.47 mmol), TEA (0.165 mL, 1.18 mmol), then stirred for 10 min then was added 2-aminoacetonitrile hydrochloride (40 mg, 0.43 mmol) at 0°C and allowed to stir at RT for 16 h. The reaction mixture was poured into ice water (20 mL) and extracted with EtOAc (2 x 80 mL). The organic layer was washed with brine solution (2 x 30 mL), then dried over anhydrous Na2SO4, filtered and the filtrated concentrated to get 120 mg of methyl 2-(1-butyl-3- (cyanomethylcarbamoyl)-l H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate as a gummy solid.
LC-MS (method 23): Rt = 1.66 min; m/z = 392.29 (M+H+).
Step d. 2-(1-butyl-3-((cyanomethyl)carbamoyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid (32)
Figure imgf000162_0001
and 2-(1-butyl-3-carbamoyl-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid hemiformate (32a)
Figure imgf000162_0002
To a stirred solution of methyl 2-(1-butyl-3-(cyanomethylcarbamoyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate (190 mg, 0.485 mmol) in THF (5 mL) was added Potassium trimethylsilanolate (2.0 equiv) at 0°C and allowed to stir at 10°C. The progress of the reaction was monitored by TLC and LCMS. The reaction was evaporated in vacuum then acidified with citric acid solution at at 0°C and extracted with 10 % MeOH/DCM (3 x 120 mL), then dried over anhydrous Na2SO4, filtered and filtrate was concentrated. The crude compound was purified by Prep.HPLC and lyophilized to afford 6mg of 2-(1-butyl-3-(cyanomethylcarbamoyl)-1H-pyrrolo[2,3-c]pyridin-5- yl)isonicotinic acid (32), along with 8 mg of 2-(1 -butyl-3-car amoyl-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinic acid hemiformate (32a).
Example 32: LC-MS (method 23): Rt = 1.45 min; m/z = 378.19 (M+H+).
Example 32a: LC-MS (method 23): Rt = 1.37 min; m/z = 337.12 (M-H*).
Preparative HPLC Conditions: Column: X SELECT C18 (19x150 mm), 5.0μ, Mobile phase: 0.1 % FA in H20: Acetonitiile (A:B), Gradient (Time /% B) : 0/10,3/20,8/20,8.1/100,10/100,10.1/10,12/10., Flow rate : 20 ml/min, UV : 215 nm & 254 nm
EXAMPLE 33
Methyl 2-(1 -(4-aminophenethyl)-1 H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate
Figure imgf000163_0001
Step a. 5-bromo-1-(4-nitrophenethyl)-1H-pyrrolo[2,3-c]pyridine
To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine (1.0 g, 5.1 mmol, 1 equiv) in ACN (50 mL) was added 1-(2-bromoethyl)-4-nitrobenzene (2.34 g, 10.2 mmol, 2.0 equiv) and 2CO3 (2.11 g, 15.3 mmol, 3.0 eq). Reaction was stirred at 60°C for 10h. Reaction was monitored by LCMS and TLC. After 3h TLC showed 1-(2- bromoethyl)4-nitrobenzene was consumed, 5-bromo-1H-pyrrolo[2,3-c]pyridine was present in a 24% and an undesired product in a 67% in RM. 1-(2-bromoethyl)-4-nitrobenzene (2.0 equiv) was added to the reaction mixture and was stirred at same temperature for 12h. LCMS showed 20% formation desired product and 1-(2- bromoethyl)-4-nitrobenzene (2.0 equiv) was added to reaction mixture. LCMS showed 24% formation desired product, and the reaction was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (100-200 mesh) using 1-50 % EtOAc in pet ether as solvent eluent to isolate 5- bramo-1-(4-nitrophenethyl)-1H-pyrrolo[2,3-c]pyridine (1.2 g, 68%).
LC-MS (method 23): Rt = 2.13 min; m/z = 346.01 (M+H+).
Step b. Methyl 2-(1-(4-nitrophenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate
To a stirred solution of 5-bromo-1-(4-nitrophenethyl)-1 H-pynOlo[2,3-c]pyridine (600 mg, 0.57 mmol, 1 eq) in 1, 4-dioxane (10 mL) was added methyl 2-(trimethylstannyl)isonicotinate (174 mg, 0.57 mmol, 1.0 eq), CsF (174 mg, 1.15 mmol, 2 eq) and followed by Cul (22 mg, 0.11 mmol, 0.2 eq). The resulting solution was degassed with nitrogen for 30 minutes, then Pd(PPh3)4 (66 mg, 0.057 mmol, 0.1 eq) was added and then heated at 110 °C for 16 h. The reaction mixture was cooled to RT and diluted with EtOAc and filtered through celite pad. The filtrate was concentrated under reduced pressure. The crude was purified by silica gel column chromatography (100-200 mesh) using 20-80 % EtOAc in pet ether as solvent eluent to isolated 350 mg of methyl 2-(1-(4- nitrophenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate.
LC-MS (method 31): Rt = 3.15 min; m/z = 403.32 (M+H+). Step c. Methyl 2-(1-(4-aminophenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate
To a stirred solution of methyl 2-(1-(4-nitrophenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate (200 mg, 0.5 mmol, 1 eq) in EtOH (3 mL) was added tin chloride (283 mg, 1.5 mmol, 3.0 eq) and the reaction was refluxed for 5h. The reaction was concentrated, diluted with water and NaHC03 and then extracted with ethyl acetate. Organic layer was dried, filtered and the filtrate was concentrated. The crude was purified by Prep HPLC to get 6 mg of methyl 2-(1-(4-aminophenethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate.
LC-MS (method 23): Rt = 1.40 min; m/z = 373.24 (M+H+).
Preparative HPLC Conditions: Column: PROTONSIL C18 (25x250 mm), ΙΟμιπ, Mobile phase : 0.1% FA in H20 : Acetonitrile (A :B), Gradient (Time/%B) : 0/10, 6/45, 6.1/100,10/100,10.1/10,13/10; Flow rate : 20 ml/min; Diluent : Methanol+H20+Acetontrile+THF.
EXAMPLE 34
Methyl 2-(1-butyl-3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate
Figure imgf000164_0001
To a stirred solution of example 18a (280 mg, 1 eq) in DCM (5 mL) was added HCI in 1,4-dioxane (5 ml). The resulting solution was stirred at RT for 3h. The reaction was concentrated and the crude was washed with n- pentane to get 260 mg of methyl 2-(1-butyl-3-(piperidin4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinate.
LC-MS (method 32): R, = 2.11 min; m/z = 393.2 (M+H+).
EXAMPLE 35
2-(1-(10,10,10-trit1uorodecyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)isonicotinamide
Figure imgf000164_0002
To a stirred solution of example 6aau (50 mg, 0.115 mmol) in THF was added 1 , 1 '-Carbonyldiimidazole (55 mg, 0.345 mmol) stirred at 40°C for 1 h then hydroxylamine hydrochloride (20 mg, 0.287 mmol) was added and allowed to stir at the same temperature for 16 h. Reaction was monitored by LCMS and TLC. The crude was concentrated. The crude was purified by prep. HPLC and lyophilized to afford 2-( 1 -( 10, 10, 10-trifluorodecyl)-1 H- pyrazolo[3,4-c]pyridin-5-yl)isonicotinamide (5 mg, 10%).
LC-MS (method 35): Rt = 3.79 min; m/z = 434.48 (M+H+).
The Prep HPLC conditions: Column :XSELECT C18(19x150 πιιτι),5μm; Mobile phase : 0.1% FA in H20 :Acetonitrile (A:B); Gradient (Time /% B) : 0/20,1/20,4/70,7/70,7.1/98,10/98,10.1/20,12/20; Flow rate : 20 ml/min; Diluent : MeOH +ACN+ THF+ H20 Further examples of compounds of Formula (I) are shown below, which may be prepared following the general synthetic procedures described herein:
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
EXAMPLE 36
IN VITRO KDM ENZYME INHIBITION ASSAYS
The ability of test compounds to inhibit the activity of KDM4C.KDM5B and KDM6B can be determined using the AlphaLISA technology, using human recombinant proteins, following the procedures described herein. Reagents source and assay conditions for each KDM are listed in the tables below. For IC50 determination, inhibitors are tested at eight logarithmic serial dilutions.
Figure imgf000171_0002
Figure imgf000172_0001
Figure imgf000172_0002
General method:
The demethylase assay is performed in 384-well light gray plates (Perkin Elmer #6005350) + TopSeal-A Black Sealing Film (Perkin Elmer #6050173) at room temperature.
5 ul of enzyme in Enzyme Buffer is incubated with 2.5 ul of test compound in 2% DMSO at the desired concentration for 10 minutes. Reaction is started with 2.5 ul of substrate/cofactors mix in Assay Buffer. At the end of the reaction time, 5 ul of acceptor beads in 1X AlphaUSA Epigenetics Buffer 1 (Perkin Elmer # AL008) are added. After 60 minutes incubation at room temperature, 10 ul of Alpha streptavidin donor beads in 1X AlphaUSA Epigenetics Buffer 1 (Perkin Elmer # AL008) are added under a green filtered light (#389 Chroma Green, Rosco) and incubated for 120 minutes at room temperature. The luminescence signal is measured with an Ensight muitimode plate reader (Perkin Elmer HH34000000) in Alpha mode.
The control of demethylase activity is obtained in the absence of test compounds (with 0.5% DMSO) after background subtraction, while the negative control is represented by the reaction mix in the absence of the enzyme, after background subtraction. Percentage of inhibition is calculated as a fraction of the control activity. ICso is calculated by nonlinear regression curve fitting with GraphPad Prism version 5.01 (GraphPad Software, San Diego, CA). The results obtained in the above assays with compounds of the invention are shown in the table below:
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
EXAMPLE 37 IN VITRO CELL-BASED ASSAY In order to test the histone lysine-demethylase inhibitory effects of the compounds of the invention in cells, global levels of tri-methylation on lysine 4 of histone 3 (H3K4me3) were assessed by western blot in the breast cancer BT474 cell line.
For this, 2x106 cells were seeded in T75 flasks and grown in RPMI-1640 medium (Sigma) supplemented with 10% FBS and 2mM glutamine (Life Technologies) without antibiotics, incubated at 37°C and 5% CO2. 24 hours after seeding, cells were treated with 1μΜ of the test compound or vehicle (DMSO, at 0.1%), incubated for five days and harvested by trypsinisation. Pellets of 2x106 cells were used for histone purification (EpiQuick, Epigentek) following manufacturer s instructions, and 1 pg of purified histone extracts were loaded into 12% NUPAGE gels (Life Technologies) for H3K4me3 detection by Western blot (a-H3K4me3 antibody, Active Motif #39159, 1:2000 dilution).
H3K4me3 western blot signal and total H3 intensity from ponceau staining were quantified by band densitometry using the ImageJ software. H3K4me3 signals were normalized by their corresponding total H3 levels, and made relative to the vehicle (DMSO)..
The results obtained in this cell assay with compounds of the invention are shown below, wherein compounds are classified based on their potency to increase H3K4me3 levels compared to the vehicle after 5 days of incubation at 1 μΜ . Score ** means that H3 normalised H3K4me3 fold induction relative to vehicle is≥2 and Score * means that M3 normalised H3K4me3 fold induction relative to vehicle is <2.
Figure imgf000179_0001
Figure imgf000179_0002
Figure imgf000179_0003
Figure imgf000180_0001
Figure imgf000180_0002
Figure imgf000180_0003
Figure imgf000181_0002
The data provided in Examples 36 and 37 indicate that compounds of Formula (I) exhibit histone lysine- demethylase inhibitory activity.
In particular, those compounds of Formula (I) wherein R1 is -OH
Figure imgf000181_0001
is selected from a group of formula (i), (ii), (iv) and (v), and preferably is selected from (i) and (ii); and R4is selected from C1-16 alkyl, C1-16 haloalkyl, -L1-carbocyclyl and -L1-aryl (wherein the carbocyclyl in -L1-carbocyclyl and the aryl in -L1-aryl are each optionally substituted as previously described) were found to exhibit potent biochemical KDM inhibitory activity as well as cellular activity, and are a preferred embodiment of the invention. Particularly preferred are those compounds within this embodiment wherein R4 is selected from C1-16 alkyl, C1-16 haloalkyl, -C1-10 alkylene-C3-7 cycloalkyl and -C1-10 alkylene-phenyl (wherein the C3-7 cycloalkyl in -C1-10 alkylene-C3-7 cycloalkyl and the phenyl in -C1-10 alkylene-phenyl are each optionally substituted as previously described), including those where additionally R6 is hydrogen and/or R5 is hydrogen. For selected compounds within this preferred genus, the levels of tri-methylation on H3K4 at decreasing concentrations of the compound were tested and a dose- response was observed, with an increase in H3K4me3 vs vehicle at concentrations below 100 nM.
These results are particularly relevant since it has been reported in the scientific literature that difficulties are encountered in the development of JmjC-KDM inhibitors in translating biochemical in vitro activity into cellular activity, particularly for JmjC-KDM inhibitors containing carboxylic acid groups.

Claims

CLAIMS 1. A compound of Formula (I) or a salt thereof:
Figure imgf000182_0001
wherein
R1 is selected from -OH, -OR7 and -NR8R9;
R2 is selected from hydrogen, halo and methyl;
R3 is selected from hydrogen and halo;
Figure imgf000182_0002
Figure imgf000183_0001
R4 and R5 are each independently selected from hydrogen, C1-16 alkyl, C1-16 haloalkyl, -L1-carbocyclyl, -L1-aryl, -L1-heterocyclyl, -L1-heteroaryl, -(C1-16 alkylene)-OR10, -(C1-16 alkylene)-NR11Ri2, .( C1-16 alkylene)-CONR13R14, -(C2-16 alkenylene)-CONR13R14, -(C1-16 alkylene)-NR15COR16, -(C1-16 alkylene)-NR15CONR17Rie, -( C1-16 alkylene)- NR16S02R19, -CONR13R14 and -COR16, wherein the carbocyclyl in -L1-carbocyclyl, the aryl in -L1-aryl, the heterocyclyl in -L1-heterocyclyl and the heteroaryl in -L1-heteroaryl are each optionally substituted with one or more R20;
R6 is selected from hydrogen, C1-10 alkyl, C1-10 haloalkyl, -L2-carbocyclyl, -L2-aryl, -L2-heterocyclyl, -L2- heteroaryl, -( C1-10 alkylene)-OR21, -(C1-10 alkylenej-NR^R23, -( C1-10 alkylene)-CONR24R25, -(C2-10 alkenylene)- CONR24R25, -( C1-10 alkylene)-NR26COR27, -(C1-10 alkyleneJ-NR^CONR^R29, -(C1-10 alkylene)-NR26S02R3°, -CONR24R25 and -COR27, wherein the carbocyclyl in -L2-carbocyclyl, the aryl in -L2-aryl, the heterocyclyl in -L2- heterocyclyl and the heteroaryl in -L2-heteroaryl are each optionally substituted with one or more R31;
R7 is selected from C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-OR32, -(C1-6 alkylenej-NR^R34, -(C1-6 alkylene)- CONR35R36, -(C1-6 alkylene)-OCONR35R36, -(C1-6 alkyleneJ-OCOR37, -(C1-6 alkylene)-OCOOR37, -L3-carbocyclyl, -L3-aryl, -L3-heterocyclyl and -LAheteroaryl, wherein the carbocyclyl in -lAcarbocyclyl, the aryl in -lAaryl, the heterocyclyl in -L3-heterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R38,
R8and R9 are each independently selected from hydrogen, C1-6 alkyl and C1-6 haloalkyl;
R10 is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -L4-carbocyclyl, -L4-aryl, -L4-heterocyclyl and -L4- heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R39;
R11 and R12 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -CN, -L4-carbocyclyl, -L4- aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R39;
R13 and R14 are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -CR40R41-CN, -L4-carbocyclyl, -L4-aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R39, or R13 and R14 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C1-6 alkyl, -OH, -NH2L -NH(C1-6 alkyl), and -N(C1-6 alkyl)2;
each R15, R17, R18, R26, R28, R29, R∞, R5Z, R53 and R57 is independently selected from hydrogen and C1-6 alkyl; each R16 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C2-6 haloalkenyl, -COR42, -CH=CH-CH2-NR43R44, -L4-carbocyclyl, -L4-aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4- heteroaryl are each optionally substituted with one or more R39;
each R19 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -L4-carbocyclyl, -L4-aryl, -L4- heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R39;
each R20 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C%6 alkoxy, C1-6 haloalkoxy, -OH, -NR45R46 ^CN, -COR47, -CONR^R49, -OCOR47, -NR50COR47, -NRMCONR+SR49, -NR5°S02R51, -S02NR48R49, -SO2R51, -L5-carbocyclyl, -L5-aryl, -L5-heterocyclyl and -L5-heteroaryl, wherein the carbocyclyl in -lAcarbocyclyl, the aryl in -L5-aryl, the heterocyclyl in -lAheterocyclyl and the heteroaryl in -lAheteroaryl are each optionally substituted with one or more R39;
each R21 is independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl;
R22 and R23 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl and -CN;
R24 and R25 are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and
_CR4OR4I.CN, or R24 and R25 taken together with the N atom to which they are attached form a saturated 4- to
7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and
S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C1-6 alkyl, -OH, -NH2, -NH(C1-6 alkyl), and -N(C1-6 alkyl)2;
each R27 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C2-6 haloalkenyl,
-COR42 and -CH=CH-CH2-NR43R44;
each R30 is independently selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R31 and R39 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -OH, -NR45R46, -CN, -COR47, -CONR48R49, -OCOR47, -NR50COR47, -NR5°CONR48R49, -NR50SO2R51, -S02NR48R49, and -SO2R51;
each R32, R33 and R34 is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -L4-carbocyclyl, -L4- aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R38;
R35 and R36 are each independently selected from hydrogen, C1-6 alkyl, -L4-carbocyclyl, -L4-aryl, -LAheterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4- heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R38, or R35 and R36 taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7- membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C1-6 alkyl, -OH, -NH2, -NH(C1-6 alkyl), and -N(C1-6 alkyl)2;
each R37 is independently selected from C1-6 alkyl, -L4-carbocyclyl, -L4-aryl, -L4-heterocyclyl and -L4-heteroaryl, wherein the carbocyclyl in -L4-carbocyclyl, the aryl in -L4-aryl, the heterocyclyl in -L4-heterocyclyl and the heteroaryl in -L4-heteroaryl are each optionally substituted with one or more R38;
each R38 is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -OH, -NR^R53 ,-CN, -COR54, -CONRSR56, -OCOR54, -NR^COR54, -NR^CONR^R56, -NR57S02R54 -S02NR55R56 and -S02R54;
R40 and R41 are each independently selected from hydrogen and methyl, or taken together with the C atom to which they are attached form a cyclopropyl ring;
each R42 is independently selected from C1-6 alkyl;
R43 and R44 are each independently selected from hydrogen and C1-6 alkyl, or taken together with the N atom to which they are attached form a saturated 4- to 7-membered monocyclic heterocyclic ring optionally containing one further heteroatom selected from N, 0 and S, wherein said 4- to 7-membered monocyclic heterocyclic ring is optionally substituted with one or more groups independently selected from halo, C1-6 alkyl, -OH, -NH2, -NH(C1-6 alkyl), and -N(C1-6 alkyl)2;
R45 and R46 are each independently selected from hydrogen, C1-6 alkyl and -CN;
each R47 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and -COR42;
R48 and R49 are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and
-CR40R41.CN;
each R51 is independently selected from C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
each R64 is independently selected from C1-6 alkyl and -(C1-6 alkylene)-NR52R53;
RKand R56 are each independently selected from hydrogen, C1-6 alkyl and -(C1-6 alkylene)-NR52R53;
each L1, L2, L3 and L4 is independently selected from a bond and C1-10 alkylene; and
each L6 is independently selected from a bond and C1-6 alkylene.
2. The compound of claim 1 , wherein
Figure imgf000185_0001
is selected from a group of formula (i), (ii), (iv) and (v).
3. The compound of claim 1 , which is a compound of Formula (II), or a salt thereof,
Figure imgf000186_0003
wherein W is CR5 or N.
4. The compound of claim 1, which is a compound of Formula (la), or a salt thereof:
Figure imgf000186_0001
5. The compound of claim 1 , which is a compound of Formula (lb), or a salt thereof:
Figure imgf000186_0002
6. The compound of any one of claims 1 to 5, wherein R1 is selected from -OH, -O-C1-6 alkyl, -0-C1-6 haloalkyl and -NH2.
7. The compound of any one of claims 1 to 5, wherein R1 is -OH.
8. The compound of any one of claims 1 to 7, wherein R3 is hydrogen.
9. The compound of any one of claims 1 to 8, wherein R4 and R5 are each independently selected from hydrogen, C1-16 alkyl, C1-16 haloalkyl, -L1-carbocyclyl, -L1-aryl, -L1-heterocyclyl, -L1-heteroaryl, -(C1-16 alkylene)- OR10, -(C1-16 alkylene)-NR11R12, -(C1-16 alkyleneJ-CONR'W4, and -CONR13R14, wherein the carbocyclyl in -L1- carbocyclyl, the aryl in -L1-aryl, the heterocyclyl in -L1-heterocyclyl and the heteroaryl in -L1-heteroaryl are each optionally substituted with one or more R20.
10. The compound of any one of claims 1 to 8, wherein R4is selected from C1-16 alkyl, C1-16 haloalkyl, -C1-10 alkylene-carbocyclyl and -C1-10 alkylene-aryl, wherein the carbocyclyl in -C1-10 alkylene-carbocyclyl and the aryl in -C1-10 alkylene-aryl are each optionally substituted with one or more R20.
11. The compound of any one of claims 1 to 8, wherein R4 is selected from C1-16 alkyl, C1-16 haloalkyl, -C1-10 alkylene-C3-7 cycloalkyl and -C1-10 alkylene-phenyl, wherein the C3-7 cycloalkyl in -C1-10 alkylene-C3-7 cycloalkyl and the phenyl in -C1-10 alkylene-phenyl are each optionally substituted with one or more R20.
12. The compound of any one of claims 1 to 8, wherein R4 is C1-16 alkyl.
13. The compound of any one of claims 1 to 8, wherein R4 is C1-16 haloalkyl.
14. The compound of any one of claims 1 to 8, wherein R4 is -(CH2)1-4-C3-7 cycloalkyl wherein the C3-7 cycloalkyl in -(CH2)1-4-C3-7 cycloalkyl is optionally substituted with one or more R20.
15. The compound of any one of claims 1 to 8, wherein R4 is -(CH2)1-4-phenyl wherein the phenyl in -(CH2)u-phenyl is optionally substituted with one or more R20.
16. The compound of claim 15, wherein R4 is -(CH2)w-phenyl wherein the phenyl in -(CH2)u-phenyl is optionally substituted with one or more halo.
17. The compound of any one of claims 1 to 16, wherein R6 is hydrogen.
18. The compound of any one of claims 1 to 17, wherein R5 is selected from hydrogen, C1-16 alkyl and -(Ci. 16 alkylene)-NR1lR12.
19. The compound of any one of claims 1 to 18, wherein R5 is hydrogen.
20. The compound of any one of claims 1 to 19, wherein R2 is hydrogen.
21. The compound of claim 1, which is a compound selected from
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
or a salt thereof.
22. A pharmaceutical composition which comprises a compound of any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
23. A compound of any one of claims 1 to 21 , or a pharmaceutically acceptable salt thereof, for use as a medicament.
24. A compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 22, for use in the treatment of a disease associated with a JmjC-KDM.
25. A compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 22, for use in the treatment of cancer.
26. A compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 22, for use in the treatment of a viral infection.
27. A method for treating a disease associated with a JmjC-KDM, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 21 , or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
28. A method for treating cancer, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
29. A method for treating a viral infection, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
30. Use of a compound of any one of claims 1 to 21, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease associated with a JmjC-KDM.
31. Use of a compound of any one of claims 1 to 21, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.
32. Use of a compound of any one of claims 1 to 21, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a viral infection.
33. In vitro use of a compound of any one of claims 1 to 21 , or a pharmaceutically acceptable salt thereof, as a JmjC-KDM inhibitor.
Figure imgf000192_0001
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