WO2017207813A1 - Heteroaryl-carboxylic acids as histone demethylase inhibitors - Google Patents

Heteroaryl-carboxylic acids as histone demethylase inhibitors Download PDF

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Publication number
WO2017207813A1
WO2017207813A1 PCT/EP2017/063585 EP2017063585W WO2017207813A1 WO 2017207813 A1 WO2017207813 A1 WO 2017207813A1 EP 2017063585 W EP2017063585 W EP 2017063585W WO 2017207813 A1 WO2017207813 A1 WO 2017207813A1
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bipyridine
methyl
compound
carboxylic acid
amino
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PCT/EP2017/063585
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French (fr)
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Alberto ORTEGA MUÑOZ
Jorge Salas Solana
Elena CARCELLER GONZÁLEZ
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Oryzon Genomics, S.A.
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Publication of WO2017207813A1 publication Critical patent/WO2017207813A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to compounds, particularly heteroaryl-carboxyiic acids and derivatives thereof as described herein, 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.
  • HMTs histone lysine demethyltransferases
  • RDMs histone lysine demethylases
  • 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(ll)-dependent 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.
  • WO2010/043866 discloses 4-carboxy-2,2'-bipyridine derivatives as histone demethylase inhibitors of the JMJD2 (also known as KDM4) subfamily, in particular JMJD2E (KDM4E). These compounds all have an amido or ester subsb ' tuent (on the second pyridine ring) linked to the bipyridine moiety via the carbonyl group. This amido or ester substituent is always placed at position 4' of the bipyridine, i.e. at para position relative to the N atom of the second pyridine ring.
  • US2016/0068507 discloses inhibitors of histone demethylases of the JMJD2 and JARID1 families based on disubstituted pyridine compounds bearing at the 4-position a carboxy group and at the 2-position a substituted 1-pyrazolyl group.
  • the pyrazolyl group is always attached via its N1 ring atom to the pyridine ring.
  • the present invention provides a compound of Formula (I) as described below or a salt thereof:
  • Z ⁇ Z 2 , and Z 3 are each independently selected from CR 4 and N, and Z 4 and Z 5 are each independently selected from CR 2 and N, with the proviso that only one of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 can be N;
  • R 1 is selected from hydrogen, Cu, alkyl, Cu haloalkyl, -(Ci. 6 alkylene)-OR- ⁇ -(Ci. 6 alky!ene)-NR 6 R 7 , -LA carbocyclyl, -L 3 -aryl -LAheterocyclyl and -LAheteroaryl, wherein the carbocyclyl in -lAcarbocyclyl, the aryl in - lAaryl, the heterocyclyl in -L 3 -heterocyclyl and the heteroaryl in -L 3 -heteroaryi are each optionally substituted with one or more R 8 ,
  • each R 2 is independently selected from hydrogen, halo, Ci-e alkyl, C 1-6 haloalkyl, Ci e alkoxy, Ci-s hydroxyalkyi, - OH and -NH 2 ;
  • each R 4 is independently selected from hydrogen and halo
  • L' is Ci 4 alkylene, C2-4 alkenylene or C2-4 alkynylene, wherein said C1-4 alkylene, said C? 4 alkenylene and said C24 alkynylene are optionally interrupted by 0, S or NR 10 , and wherein said Cu alkylene, said C2.4 alkenylene and said C24 alkynylene are optionally substituted with one or more R 12 ;
  • L 2 is C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene, wherein said C1-6 alkylene, said C2-6 alkenylene and said C2.6 alkynylene are optionally interrupted by 0, S or NR 10 , and wherein said C%6 alkylene, said Cn alkenylene and said C2-6 alkynylene are optionally substituted with one or more R 12 ;
  • n and n are each independently selected from 0 and 1 ;
  • R 3 is selected from -NR 13 R 14 , -OR 15 and R 16 ;
  • R 6 and R 7 are each independently selected from hydrogen and C1-6 alkyl, or R 6 and R 7 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 substituents independently selected from halo, 0-6 alkyl, -OH, -NH?, -NH(C,. 6 alkyl), and -N(0 6 alkyl) 2 ;
  • each L 3 is independently selected from a bond and 0.4 alkyiene
  • R s and R ,0 are each independently selected from hydrogen, 0.6 alkyl and ⁇ ⁇ haloalkyl;
  • -R 11 - is a biradical of a 5-membered heteroaryl ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S with the proviso that at least one is a N atom, and wherein -R' 1 - is linked to -(L 1 ) m - and -(L 2 ) n - R 3 in a 1,3-disposition;
  • each R 12 is independently selected from 0.6 alkyl, halo, 0-6 haloalkyl, -L 3 -carbocyclyl, - LAary i ,-L 3 -heierocyclyl and -LAheteroaryl, wherein the carbocyclyl in -L 3 -carbocyclyl, the aryl in -L 3 -aryl, the heterocyclyl in -LA heterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R 1?
  • R 13 , R 14 and R 15 are each independently selected from hydrogen, 0. 6 alkyl, 0-6 haloalkyl, -(0-6 alkylene)-OR 18 , -LAcarbocyclyl, -L 3 -aryl,-L 3 -heterocycly! and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocycly!, the aryl in -LAaryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are optionally substituted with one or more R 1S ;
  • R 15 is selected from O s alkyl, carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein said alkyl is optionally substituted with one or more R 20 and said carbocyclyl, said aryl, said heterocyclyl and said heteroaryl are each optionally substituted with one or more R 21 ;
  • each R 22 is independently selected from Cn alkyl; and each R 5 , each R 18 , each R 23 , each R 24 , each R 25 , each R 25 and each R 27 is independently selected from hydrogen and C1-5 alky I.
  • the compounds of Formula (I) as described herein are inhibitors of JmjC-KDMs, e.g. KDM5 or KDM4 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 and/or KDM4-mediated disease.
  • the disease may be 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.
  • the 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:
  • Z ⁇ 72, and Z 3 are each independently selected from CR 4 and N, and Z 4 and Z 5 are each independently selected from CR 2 and N, with the proviso that only one of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 can be N;
  • R 1 is selected from hydrogen, d-s alkyl, Cu haloalkyl, -(Ci- 6 alkylene)-OR 5 , -(C « alkylene)-NR 3 R 7 , -LA carbocyclyl, -LAaryl -LAheterocyclyl and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in - LAaryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -L 3 -heteroaryl are each optionally substituted with one or more R 8 ,
  • each R 2 is independently selected from hydrogen, halo, Cu a!kyl, Ci-e haloalkyl, Ci-e alkoxy, Ci e hydroxyalkyl, - OH and -NH 2 ;
  • each R 4 is independently selected from hydrogen and halo;
  • L 1 is Ci-4 alkylene, C2-4 alkenylene or CM alkynylene, wherein said Cu alkylene, said C24 alkenylene and said C2-4 alkynylene are optionally interrupted by 0, S or NR 10 , and wherein said Cu alkylene, said C24 alkenylene and said C24 alkynylene are optionally substituted with one or more R 12 ;
  • L 2 is C1-6 alkylene, C2-6 alkenylene or C? e alkynylene, wherein said Cu alkylene, said C?.e a!kenyiene and said C2-6 alkynylene are optionally interrupted by 0, S or NR 10 , and wherein said Cu alkylene, said C2.5 alkenylene and said C2-6 alkynylene are optionally substituted with one or more R 12 ;
  • n and n are each independently selected from 0 and 1 ;
  • R 3 is selected from -NR ,3 R U , -OR 15 and R 16 ;
  • R 6 and R 7 are each independently selected from hydrogen and Cvs alkyl, or R 6 and R 7 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 substituents independently selected from halo, Ci-s alkyl, -OH, -NH2, -NH(Ci 6 alkyl), and -N(d.$ alkyi) 2 ;
  • each L 3 is independently selected from a bond and Cu alkylene
  • R 9 and R 10 are each independently selected from hydrogen, C1-6 alkyl and Ci s haloalky!;
  • -R 11 - is a biradical of a 5-membered heteroaryl ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S with the proviso that at least one is a N atom, and wherein -R n - is linked to -(L 1 ⁇ m - and -(L 2 ) n - R 3 in a 1 ,3-disposition;
  • each R 12 is independently selected from C1-5 alkyl, halo, Ci-3 ⁇ 4 haloalkyl, -L 3 -carbocyclyl, -L 3 -aryl,-L 3 -heterocyclyi and -L 3 -heteroaryl, wherein the carbocyclyl in -L 3 -carbocyclyl, the aryl in -LAaryl, the heterocyclyl in -L 3 - heterocyclyl and the heteroaryl in -lAheteroaryl are each optionally substituted with one or more R 17 , and wherein two groups R 12 attached to a same C atom of the alkylene, alkenylene or alkynylene group are optionally linked together to form with said C atom a C3-6 cycloalkyl group or a saturated 4- to 6-membered monocyclic heterocyclic ring containing 1 heteroatom selected from N, 0 and S, wherein said C3-6 cycloalkyl and 4- to
  • R 13 , R 14 and R 15 are each independently selected from hydrogen, Cu alkyl, C-, 6 haloalkyl, -(d.e alkylene)-OR 18 , -LAcarbocyclyl, -LAaryl -LAheterocyclyi and -lAheteroary!, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyl in -LAheterocyc!yl and the heteroaryl in -LAheteroaryl are optionally substituted with one or more R 1S ;
  • each R 22 is independently selected from Ci ⁇ alkyl
  • each R 5 , each R 18 , each R 23 , each R 24 , each R 25 , each R 26 and each R 27 is independently selected from hydrogen and Ci-6 alkyl.
  • 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.
  • Z 1 , Z 2 , and Z 3 are each independently selected from CR 4 and N
  • Z 4 and Z 5 are each independently selected from CR 2 and N, with the proviso that only one of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 can be N.
  • Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are carbon atoms (CR 4 in the case of Z ⁇ Z 2 and Z 3 , and CR 2 in the case of Z 4 and Z 5 ) or one of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 is a nitrogen atom and the remaining of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are carbon atoms (CR 4 in the case of Z ⁇ Z ? and Z 3 , and CR 2 in the case
  • One subset of the compounds of Formula (I) includes those of Formula (II):
  • a compound of Formula (II) corresponds to compounds of Formula (la), (lb) and (lc) as previously defined.
  • the present invention relates to a compound of any of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II) as defined herein, or any salt thereof.
  • the compound of Formula (I) is a compound of Formula (II), or a salt thereof.
  • the compound of Formula (II) is a compound of Formula (la), or a salt thereof.
  • the compound of Formula (II) is a compound of Formula (lb), or a salt thereof.
  • the compound of Formula (II) is a compound of Formula (lc), or a salt thereof.
  • the compound of Formula (I) or (II) is a compound of Formula (la) or (lb), or a salt thereof. Still more preferably, the compound of Formula (I) or (II) is a compound of Formula (la). Accordingly, while various embodiments described herein below relate to a compound of Formula (I), (la), (lb), (lc), (Id), (le), (!f) or (II), it is particularly preferred that the compound specified in each one of these embodiments is a compound of Formula (la) or (lb), or a salt thereof, and it is even more preferred that the respective compound is a compound of Formula (la) or a salt thereof.
  • the compounds of the invention include carboxylic acids, when in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II) R 1 is hydrogen, and esters thereof, when in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (if) or (II) R 1 is selected from Ci_ 6 alkyl, C u haloalkyl, -(Ci. 6 alkylene)-OR 5 , -(C,.
  • esters can be used as prodrugs of the corresponding carboxylic acids (i.e. a compound wherein R f is hydrogen). In addition, certain esters exhibit JmjC-KDM inhibitory activity perse.
  • R 1 is hydrogen, Ci e alkyl or Ci.6 haloalkyl.
  • R 1 is hydrogen or C1.4 alkyl, still more preferably hydrogen, methyl or ethyl.
  • R 1 is hydrogen.
  • each R 2 is independently selected from hydrogen, halo, Ci 3 alkyl, C1.3 haloalkyl and C1-3 hydroxya!kyl.
  • one of the groups R 2 is selected from hydrogen, halo, C1.3 alkyl, C1.3 haloalkyl and C1-3 hydroxyalkyl, and the remaining groups R 2 are hydrogen.
  • one of the groups R 2 is selected from hydrogen, fluoro, methyl, trifluoromethyl and -CH2OH, and the remaining groups R 2 are hydrogen.
  • each R 2 is hydrogen. More preferably, in a compound of Formula (!), (la), (lb), (Ic), (Id), (le), (If) or (II):
  • R 1 is hydrogen, d-e alkyl or C1-6 haloalkyl, preferably hydrogen or C1-4 alkyl, more preferably hydrogen, methyl or ethyl, and still more preferably hydrogen;
  • each R 2 is hydrogen
  • one of the groups R 4 is selected from hydrogen and fluoro, and the remaining groups R 4 are hydrogen.
  • each R 4 is hydrogen. More preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), each R 2 and each R 4 is hydrogen.
  • L 1 is CM alkylene, wherein said C1.4 alkylene is optionally interrupted by 0, S or NR 10 , and wherein said Cu alkylene is optionally substituted with one or more R' 2 .
  • L 1 is (CH2)i-4, wherein said (CH2)i-4 is optionally substituted with one or more (preferably one or two) R 12 .
  • L 1 is (CH 2 )i.?, wherein said (CH2>i 2 is optionally substituted with one or more (preferably one or two) R 12 .
  • U is (CH 2 )i- 2
  • SJ is CH 2 .
  • L 2 is Cu alkylene, wherein said C1 6 alkylene is optionally interrupted by 0, S or NR 10 , and wherein said C1-6 alkylene is optionally substituted with one or more R 12 .
  • L 2 is (CH2)i s, wherein said (CH 2 )i-s is optionally substituted with one or more (preferably one or two) R 12 .
  • L 2 is (CH 2 )i-4, wherein said (CH 2 )i-4 is optionally substituted with one or more (preferably one or two) R 12 . More preferably, L 2 is (CH 2 )i-4.
  • m is selected from 0 and 1, and n is 1. In some preferred embodiments, m is 0 and n is 1.
  • m is selected from 0 and 1 ;
  • L 1 is (CH 2 )i-2, preferably CH 2 ;
  • n is 1 ;
  • L 2 is (CH 2 )i_4 wherein said (CH 2 )i 4 is optionally substituted with one or more (preferably one or two) R 12 , and preferably L 2 is (CH 2 )i 4.
  • n 1 and L 2 is C 2 6 alkylene (preferably (CH 2 ) 2 - 6 ), wherein said C 2 s alkylene (or said (CH 2 ) 2 -6) is optionally interrupted by 0, S or NR 10 , and wherein said C2-6 alkylene (or said (CH 2 ) 2 -6) is optionally substituted with one or more R 12 .
  • n 1 and L 2 is (CH 2 ) 2 .
  • S preferably (CH 2 ) 2 - 4 ), wherein said (CH 2 ) 2 -5 (or said (CH 2 ) 2 .4) is optionally substituted with one or more R 12 .
  • the C1.4 alkylene, C 2 . 4 alkenylene and C2-4 alkynylene in L 1 and the Cu alkylene, Cn alkenylene and C2-6 alkynylene in L 2 can be optionally substituted with one or more R 12 , As defined above, each R 12 is independently selected from d-e aikyi, halo, Ci.
  • haloalkyl -lAcarbocyclyl, -L 3 -aryl, -L 3 -heterocyclyl and -L 3 -heteroaryl, wherein the carbocyclyl in -LA carbocyclyl, the aryl in -IAaryl, the heterocyclyl in -L 3 -heterocyclyl and the heteroaryl in -L 3 -heteroaryl are each optionally substituted with one or more R 17 .
  • two groups R 12 attached to a same C atom of the alkylene, alkenylene or alkynylene group can be optionally linked together to form with said C atom a C3-6 cycloalkyi group or a saturated 4- to 6-membered monocyclic heterocyclic ring containing 1 heteroatom selected from N, 0 and S, wherein said Cu cycloalkyi and 4- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from halo and C1-6 alkyl.
  • Examples of said C3-6 cycloalkyi or 4- to 6-membered heterocyclic ring formed by said two R 12 groups attached to a same C atom together with said C atom are shown below:
  • each ring depicted above can be optionally substituted with one or more substituents independently selected from halo and C1 6 alkyl.
  • each R 12 is independently selected from Ci .3 alkyl and -LAaryl, wherein the aryi in -LAaryl is optionally substituted with one or more R 17 .
  • said aryi is phenyl optionally substituted with one or more R 17 .
  • -R 11 - is a bi radical of a 5-membered heteroaryl ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S with the proviso that at least one is a N atom, and wherein -R 11 - is linked to the -(L 1 ) m - and -(L 2 ) n -R 3 group in a 1 , 3-d is position. Examples of such -R 11 - groups are shown in Table 1 , below.
  • these groups can be read in each of the two possible orientations, i.e. they can be linked to L 1 through the point of attachment shown on the left side in the above drawings and to L 2 through the point of attachment shown on the right side in the above drawings, or the other way around.
  • -R 11 - is a group selected from Table 1. In some embodiments, -R 11 - is
  • Y is selected from -NR 10 -, -0- and -CH 2 -.
  • Y is
  • Y is -NR 10 -.
  • L 2 is (CH2)i-6, wherein said (CH 2 )i s is optionally substituted with one or more (preferably one or two) R 12 ; with the proviso that when Y is -NR 10 - or -0- and R 3 is -NR 13 R 14 , -OR 15 or N-linked-R 15 , then n is 1 and L 2 is (CH 2 ) 2 -6, wherein said (CH 2 ) 2 .6 is optionally substituted with one or more (preferably one or two) R 12 .
  • Y is selected from -
  • Y is selected from - NR 10 -, -0- and -CH 2 -; m is selected from 0 and 1 ; n is 1 ; L 1 is (CH 2 )i-4, wherein said (CH 2 )i-4 is optionally substituted with one or more (preferably one or two) R 1?
  • L 2 is (CH 2 )i-6, wherein said (CH 2 )i-6 is optionally substituted with one or more (preferably one or two) R 12 , with the proviso that when Y is -NR 10 - or -0- and R 3 is -NR 13 R 14 , -OR 15 or N-linked-R 16 , then L 2 is (CH 2 ) 2 . 6 , wherein said (CH 2 ) 2 6 is optionally substituted with one or more (preferably one or two) R 12 .
  • Y is selected from -NR 10 -, -0- and -CH 2 -; m is selected from 0 and 1 ; n is 1 ; U is (CH 2 )i-3 ⁇ 4 and L 2 is (CH 2 )i-6, wherein said (Ch1 ⁇ 2)i-6 is optionally substituted with one or more (preferably one or two) R 12 , with the proviso that when Y is - NR 10 - or -0- and R 3 is -NR 13 R 14 , -OR 15 or N-!inked-R 16 , then L 2 is (CH 2 ) 2 . 6 , wherein said (CH 2 ) 2 6 is optionally substituted with one or more (preferably one or two) R 12 .
  • a particularly preferred group of compounds of Formula (I) are those compounds of Formula (II), and preferably of Formula (la) or (lb), wherein: Y is selected from -NR 10 -, -0- and -CH 2 -; m is selected from 0 and 1 ; n is 1 ; U is (CH 2 )i 2 , preferably CH 2 ; and L 2 is (CH 2 )i , wherein said (CH 2 )i-4 is optionally substituted with one or more (preferably one or two) R 12 , and preferably L 2 is (CH 2 )i 4.
  • m is 0.
  • Even more preferred compounds of Formula (I) are those compounds of Formula (II), preferably of Formula (la) or (lb), wherein: Y is selected from -NR 10 -, -0- and -CH 2 -; m is selected from 0 and 1 with the proviso that when m is 1 then Y is -0-; n is 1 ; L 1 is CH 2 ; and L 2 is (CH 2 )i 4, wherein said (CH 2 )I.H is optionally substituted with one or more (preferably one or two) R 12 , and preferably L 2 is (CH 2 )u. In some preferred embodiments, m is 0.
  • any aikylene depicted in the above groups can be optionally substituted with one or more (preferably one or two) R 12 as defined above.
  • Examples of groups in table 2 wherein such aikylene groups are substituted with one or more R 12 are provided in Table 3 below:
  • -(L 1 ) m -Y-(L 2 ) n - is selected from the groups listed in Table 2 or Table 3.
  • R 9 is hydrogen and R ,A is hydrogen. In some embodiments, in the groups listed in Table 2 and Table 3, R 9 is C-,s alkyl. In some embodiments, in the groups listed in Table 2 and Table 3, R 10 is CLS alkyl.
  • R 3 is selected from -NR 13 R 14 , -OR 15 and R 16 .
  • R 3 is -NR 1S R U .
  • R 13 and R 14 are each independently selected from hydrogen, Ci-s alkyl, C1-6 haloalkyl, -LA C3-7 cyc!oalkyl, -L 3 -aryl and -LAheteroaryl, wherein the C3-7 cycloalkyl in -L 3 -C3-7 cycloalkyi, the ary!
  • R 13 and R 14 are each independently selected from hydrogen, C « alky! and -LApheny!, wherein the phenyl in -LA phenyl is optionally substituted with one or more R 19 .
  • R 3 is selected from -OR 15 and R 16 ,
  • R 3 is R 16 .
  • R 3 is R 16 and R 15 is selected from C1.5 alkyl, C3-7 cycloalkyl, aryl (preferably phenyl), heterocyclyl and heteroaryl, wherein said Cn alkyl is optionally substituted with one or more R 20 and wherein said C3-7 cycloalkyl, said aryl, said phenyl, said heterocyclyl and said heteroaryl are each optionally substituted with one or more R 21 .
  • R 3 is R 16 and R 16 is selected from C3.7 cycloalkyl, phenyl, heterocyclyl and heteroaryl, wherein said C3-7 cycloalkyl, said phenyl, said heterocyclyl and said heteroaryl are each optionally substituted with one or more R 21 .
  • R 3 is R 16 and R 16 is aryl, preferably phenyl, wherein said aryl or said phenyl is optionally substituted with one or more R 21 .
  • each R 21 is independently selected from halo, alkyl, C1.6 haloalkyl and -LAaryl (wherein the aryl in -LAaryl is preferably phenyl, and wherein the aryl in -LAaryl is optionally substituted with one or more R 28 ), and more preferably each R 21 is independently selected from halo and phenyl (wherein said phenyl may be optionally substituted with one or more halo).
  • said R 16 is phenyl optionally substituted with one or more halo.
  • said R 16 is biphenyl, preferably 4-biphenyl.
  • R 3 is R 16 and R 16 is C3-7 cycloalkyl, preferably cyclopropyl or cyciobutyl, wherein said C3-7 cycloalkyl (or said cyclopropyl or said cyciobutyl) is optionally substituted with one or more R 21 .
  • each R 21 is independently selected from Ct-e alkyl (e.g. methyl), fr-s haloalkyl and halo.
  • said R 16 is cyclopropyl. .
  • R 3 is R 16 and R 16 is a saturated 4- to 7-membered heterocyclic group which contains one or two heteroatoms selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 21 .
  • each R 21 is independently selected from C1-6 alkyl, Ci « haloalkyl and halo.
  • said R 15 is selected from piperidinyl, pyrrolidinyl and morpholinyl, preferably from piperidin-1-yl, pyrrolidin-1-yl and morpholin-1-yi, wherein R 16 is optionally substituted with one or more R 21 , and wherein preferably each R 21 is independently selected from d-e alkyl, C1-6 haloalkyl and halo. It is particularly preferred that said R 16 is 1 -piperidinyl substituted with one or more fluoro, and more preferably 4,4-difluoropiperidin-1-yl.
  • R 3 is R 16 and R 13 is C1.5 alkyl, wherein said Ci e alkyl is optionally substituted with one or more R 20 .
  • each R 20 is independently selected from halo.
  • said alkyl is C2-6 alkyl, which is optionally substituted with one or more R 20 (preferably halo, more preferably fluoro).
  • said Ci.s alkyl (or C2-6 alkyl) is unsubstituted.
  • R 3 is R 16 and R 16 is heteroaryl, wherein said heteroaryl is optionally substituted with one or more R 21 .
  • said heteroaryl is pyrazolyl (preferably pyrazol-1-yl) optionally substituted with one or more R 21 .
  • the invention provides a compound of Formula (I), preferably of Formula (II), more preferably of Formula (la) or (lb), or a salt thereof, wherein:
  • R 1 is hydrogen, Ci. 6 alkyl or C1-3 haloalkyl, preferably hydrogen or C1.4 alkyl, more preferably hydrogen, methyl or ethyl, and still more preferably hydrogen;
  • each R 2 is hydrogen
  • each R 4 is independently selected from hydrogen and halo (preferably fluoro) and preferably each R 4 is hydrogen;
  • n and n are each independently selected from 0 and 1 ;
  • L 1 is (CH 2 ),.?;
  • L 2 is (CH 2 ) 1-6 , wherein said (CH 2 )i-6 is optionally substituted with one or more (preferably one or two) R 12 ,
  • the invention provides a compound of Formula (I), preferably of Formula (II), more preferably of Formula (la) or (lb), or a salt thereof, wherein:
  • R 1 is hydrogen
  • each R 2 and each R 4 is hydrogen
  • n and n are each independently selected from 0 and 1 ;
  • LJ is (CH 2 )i-2, wherein said (CH 2 )i. 2 is optionally substituted with one or more (preferably one or two) R 12 ;
  • L 2 is (CH 2 )i-6, wherein said (CH 2 )i-6 is optionally substituted with one or more (preferably one or two) R 12 ; with the proviso that when Y is -NR 10 - or -0- and R 3 is -NR 13 R 14 , -OR 15 or N-linked-R 16 , then n is 1 and L 2 is (CH 2 )2-6, wherein said (CH2)?.6 is optionally substituted with one or more (preferably one or two) R 12 .
  • the invention provides a compound of Formula (I), preferably of
  • R 1 is hydrogen
  • each R 2 and each R 4 is hydrogen;
  • n is selected from 0 and 1 ;
  • n 1 ;
  • L 1 is (CH2)i-2, wherein said (CH 2 )i-2 is optionally substituted with one or more (preferably one or two) R 12 ; and L 2 is (CH2)i-6, wherein said (CHJ)I.S is optionally substituted with one or more (preferably one or two) R 12 ; with the proviso that when Y is -NR 10 - or -0- and R 3 is -NR 13 R 14 -OR 15 or N-linked-R 16 , then n is 1 and L 2 is (CH 2 )?*, wherein said (CH2)2-6 is optionally substituted with one or more (preferably one or two) R 12 .
  • the invention provides a compound of Formula (I), preferably of Formula (II), more preferably of Formula (la) or (lb), or a salt thereof, wherein:
  • R 1 is hydrogen
  • each R 2 and each R 4 is hydrogen
  • n and n are each independently selected from 0 and 1 ;
  • L 1 is (CH 2 )i 2, wherein said (CH2)i-2 is optionally substituted with one or more (preferably one or two) R 12 ;
  • L 2 is (CH2)i-6, wherein said ((3 ⁇ 4) ⁇ . 6 is optionally substituted with one or more (preferably one or two) R 12 ; with the proviso that when Y is -NR 10 - or -0- and R 3 is -OR 15 or N-linked-R 15 , then n is 1 and L 2 is (CH 2 ) 2 -6, wherein said (CH2)2-6 is optionally substituted with one or more (preferably one or two) R 12 ; and
  • R 3 is selected from -OR 15 and R 16 .
  • R 3 is R 16 , wherein preferably R 16 is aryl, more preferably phenyl, wherein said aryl or said phenyl is optionally substituted with one or more R 21 .
  • the invention provides a compound of Formula (I), preferably of Formula
  • R 1 is hydrogen
  • each R 2 and each R 4 is hydrogen
  • n is selected from 0 and 1 ;
  • n 1 ;
  • L 1 is (CH2)i-2, wherein said (CH2)i ? is optionally substituted with one or more (preferably one or two) R 12 ;
  • L 2 is (CH2)i-6, wherein said (Chbji s is optionally substituted with one or more (preferably one or two) R 12 ; with the proviso that when Y is -NR 10 - or -0- and R 3 is -OR 15 or N-linked-R 16 , then n is 1 and L 2 is (CH 2 ) 2 -6, wherein said (CH2)?6 is optionally substituted with one or more (preferably one or two) R 12 ; and
  • R 3 is selected from -OR 15 and R 16 , In some embodiments, R 3 is R 16 , wherein preferably R 16 is aryl, more preferably phenyl, wherein said aryl or said phenyl is optionally substituted with one or more R 21 .
  • a preferred group of compounds of the invention corresponds to those compounds of Formula (I), preferably of Formula (II), more preferably of formula (la) or (lb), or a salt thereof, wherein:
  • R 1 is hydrogen, C1-3 alky! or Ci s haloalkyl, preferably hydrogen or CM alkyl, more preferably hydrogen, methyl or ethyl, and still more preferably hydrogen;
  • each R 2 is hydrogen
  • n and n are each independently selected from 0 and 1;
  • L 1 is CH 2 ;
  • R 3 is R 15 .
  • said R 16 is aryl, preferably phenyl, wherein said aryl or said phenyl is optionally substituted with one or more R 21 and wherein preferably, if present, said R 21 is/are independently selected from halo and phenyl, and more preferably independently selected from ha!o.
  • said R 16 is C3-7 cycloalkyl, preferably cyclopropyl, wherein said C3-7 cycloalky! or said cyclopropyl is optionally substituted with one or more R 21 , and preferably said R 16 is cyclopropyl.
  • said R 16 is a saturated 4- to 7-membered heterocyclic group which contains one or two heteroatoms selected from N, 0 and S, wherein R 15 is optionally substituted with one or more R 21 (preferably, each R 21 is independently selected from d-e alkyl, Ci e haloalkyl and halo), wherein preferaby said R 16 is selected from piperidinyl, pyrrolidinyi and morpholinyl, optionally substituted with one or more R 21 (preferably each independently selected from Cn alkyl, CM haloalkyl and halo), more preferably said R 16 is 1 -piperidinyl substituted with one or more fluoro, and still more preferably said R 16 is 4,4-difluoropiperidin-1-yl.
  • said R 16 is Cu alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R 2Q (wherein preferably, each R 2Q is independently selected from halo), and preferably said R 16 is C- 6 alkyl.
  • a more preferred group of compounds of the invention corresponds to those compounds of Formula (I), preferably of Formula (II), more preferably of formula (la) or (lb), or a salt thereof, wherein:
  • R 1 is hydrogen, Ct-e alkyl or C1.6 haloalkyl, preferably hydrogen or Cu alkyl, more preferably hydrogen, methyl or ethyl, and still more preferably hydrogen;
  • each R 2 is hydrogen
  • Y is selected from -NR 10 -, -0- and -CH2-;
  • n is selected from 0 and 1 , with the proviso that when m is 1 then Y is -0-;
  • n 1 ;
  • L 1 is CH 2 ;
  • L 2 is (CH 2 )u
  • R 3 is R 16 .
  • said R 16 is aryl, preferably phenyl, wherein said aryl or said phenyl is optionally substituted with one or more R 21 and wherein preferably, if present, said R 21 is/are independently selected from halo and phenyl, and more preferably independently selected from halo.
  • said R 16 is C3-7 cycloalkyl, preferably cyclopropyl, wherein said C3-7 cycloalkyl or said cyclopropyl is optionaliy substituted with one or more R 21 , and preferably said R 16 is cyciopropyl.
  • said R 16 is a saturated 4- to 7-membered heterocyclic group which contains one or two heteroatoms selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 21 (preferably, each R 21 is independently selected from Ci-6 alkyl, Cu haloalkyl and halo), wherein preferaby said R 16 is selected from piperidinyl, pyrrolidinyl and morpholinyl, optionally substituted with one or more R 21 (preferably each independently selected from C%6 alkyl, Ci-6 haloalkyl and halo), more preferably said R 1S is 1 -piperidinyl substituted with one or more fluoro and still more preferably said R 16 is 4,4-difluoropiperidin-1-yl.
  • R 21 preferably, each R 21 is independently selected from Ci-6 alkyl, Cu haloalkyl and halo
  • R 21 preferably each independently selected from Ci-6 alkyl, Cu haloalkyl and halo
  • said R 1S is C 1-6 alkyl, wherein said Ci-s alkyl is optionally substituted with one or more R 20 (wherein preferably, each R 20 is independently selected from halo), and preferably said R 16 is C1.5 alkyl.
  • R 1 is hydrogen, CM alkyl or C1-6 haloalkyl, preferably hydrogen or C1.4 alkyl, more preferably hydrogen, methyl or ethyl, and still more preferably hydrogen;
  • each R 2 and each R 4 is hydrogen
  • Y is selected from -NR 10 -, -0- and -CH2-;
  • n is selected from 0 and 1 , with the proviso that when m is 1 then Y is -0-;
  • n 1 ;
  • U is CH 2 ;
  • R 3 is R 16 ,
  • said R 16 is aryl, preferably phenyl, wherein said aryl or said phenyl is optionally substituted with one or more R 21 and wherein preferably, if present, said R 21 is/are independently selected from halo and phenyl, and more preferably independently selected from halo.
  • said R 16 is C3-7 cycloalkyl, preferably cyciopropyl, wherein said C3-7 cycloalkyl or said cyciopropyl is optionally substituted with one or more R 21 , and preferably said R 16 is cyciopropyl.
  • said R 16 is a saturated 4- to 7-membered heterocyclic group which contains one or two heteroatoms selected from N, 0 and S, wherein R 16 is optionally substituted with one or more R 21 (preferably, each R 21 is independently selected from CLS alkyl, Ci s haloalkyl and halo), wherein preferaby said R 15 is selected from piperidinyl, pyrrolidinyl and morpholinyl, optionally substituted with one or more R 21 (preferably each independently selected from C1 5 alkyl, Ci e haloalkyl and halo), more preferably said R 16 is 1 -piperidinyl substituted with one or more fluoro and still more preferably said R 16 is 4,4-difluoropiperidin-l-yl.
  • R 21 preferably, each R 21 is independently selected from CLS alkyl, Ci s haloalkyl and halo
  • R 15 is selected from piperidinyl, pyrrolidinyl and morpholin
  • said R 16 is Ci.g alkyl, wherein said C1.5 alkyl is optionally substituted with one or more R 20 (wherein preferably, each R 20 is independently selected from halo), and preferably said R 16 is Ct-e alkyl.
  • a particularly preferred group of compounds of Formula (I) corresponds to those compounds of Formula (II), preferably of formula (la) or (lb), more preferably of formula (la), or a salt thereof, wherein: R 1 is hydrogen; each R 2 is hydrogen: each R 4 is independently selected from hydrogen and halo (preferably fluoro) and preferably each R 4 is hydrogen; Y is -NR 10 -; m is 0; n is 1 ; L 2 is (CH2)i-4, preferably (CH 2 )?
  • R 3 is aryl or heteroaryl, preferably aryl, more preferably phenyl, wherein said aryl, said heteroaryl or said phenyl is optionally substituted with one or more R 21 , and wherein preferably, if present, said R 21 is/are independently selected from halo and phenyl, and more preferably independently selected from halo.
  • a preferred compound of Formula (I) within this group is 5'-((3-(4-chlorophenyl) propyl)amino)-[2,2'-bipyridine]-4-carboxylic acid, or a salt thereof.
  • a preferred compound of Formula (I) within this group is 5'-(benzyloxy)-[2,2'-bipyridine ⁇ -4-carboxyiic acid, or a salt thereof.
  • Another preferred compound of Formula (I) within this group is 5'-(phenethoxymethyl)-[2,2'-bipyridine]-4-carboxylic acid, or a salt thereof.
  • Another particularly preferred group of compounds of Formula (I) corresponds to those compounds of Formula (II), preferably of formula (la) or (lb), more preferably of formula (la), or a salt thereof, wherein: R 1 is hydrogen; each R 2 is hydrogen; each R 4 is independently selected from hydrogen and halo (preferably fluoro) and preferably each R 4 is hydrogen; Y is selected from -NR 13 -, -0- and -GH2-; m is selected from 0 and 1 , with the proviso that when m is 1 then Y is -0-; L 1 is CH 2 ; n is 1 ; L 2 is (CH 2 ) M , preferably (CH 2 ) 2 -3; and R 3 is 1- piperidinyl substituted with one or more fluoro, preferably 4,4-difluoropiperidin-1-yl.
  • -(L 1 ) m -Y- (L 2 ) n - is a group selected from -NR ⁇ -Ch CH 2 Ch -, -O-CH2CH2CH2-, -CH 2 CH 2 CH 2 CH and -CH2-O-CH2CH2-.
  • a preferred compound of Formula (I) within this group is 5'-(4-(4,4-difluoropiperidin-1-yl)butyl)-[2,2 ! -bipyridine]-4- carboxylic acid, or a salt thereof.
  • Another preferred compound of Formula (I) within this group is 5'-(3-(4,4- difiuoropiperidin-1-yl)propoxy) 2,2'-bipyridine]-4-carboxylic acid, or a salt thereof.
  • Another preferred compound of Formula (I) within this group is 5'-((3-(4 ) 4-difluoropiperidin-1-y!)propyl)(methyl)amino)-[2,2'-bipyridine]-4- carboxylic acid, or a salt thereof.
  • Another preferred compound of Formula (I) within this group is 5'-(butyl(3-(4,4- difluoropiperidin-1-yl)propyl)amino) 2,2'-bipyridine]-4-carboxylic acid, or a salt thereof.
  • Another preferred compound of Formula (I) within this group is 5'-((2-(4,4-difluoropiperidin-1-yl)ethoxy)methyl)-[2,2'-bipyridine]-4- carboxylic acid , or a salt thereof.
  • Still another particularly preferred group of compounds of Formula (I) corresponds to those compounds of Formula (II), preferably of formula (la) or (lb), more preferably of formula (la), or a salt thereof, wherein: R 1 is hydrogen; each R 2 is hydrogen; each R 4 is independently selected from hydrogen and halo (preferably fluoro) and preferably each R 4 is hydrogen; Y is selected from -NR 10 -, -0- and -CH2-; m is selected from 0 and 1 , with the proviso that when m is 1 then Y is -0-; L 1 is CH 2 ; n is 1 ; L 2 is (CH 2 )i ; and R 3 is cyclopropyl.
  • m is 0 and Y is -NR 10 - or m is 1 and Y is -0-.
  • a preferred compound of Formula (I) within this group is 5'-((cyclopropylmethoxy)methyl)-[2 l 2'-bipyridine]-4-carboxylic acid, or a salt thereof.
  • Another preferred compound of Formula (! within this group is 5'-((cyclopropylmethyl)(methyl)amino)-[2,2'- bipyridine]-4-carboxylic acid, or a salt thereof.
  • Another preferred compound of Formula (I) within this group is 5'-
  • Still another particularly preferred group of compounds of Formula (I) corresponds to those compounds of Formula (II), preferably of formula (la) or (lb), more preferably of formula (la), or a salt thereof, wherein; R 1 is hydrogen; each R 2 is hydrogen; each R 4 is independently selected from hydrogen and halo
  • each R 4 is hydrogen; Y is selected from -NR 10 -, -0- and -CHr and preferably is selected from -NR 10 - and -CH2-; m is 0; n is 1 ; U is (CH 2 )i-4; and R 3 is Ci S alkyl, wherein said Ci- 5 alkyl is optionally substituted with one or more halo.
  • a preferred compound of Formula (I) within this group is S'-pentyl-
  • [2,2'-bipyridine]-4-carboxylic acid or a salt thereof.
  • Another preferred compound of Formula (I) within this group is 5'-(butylamino)-[2,2'-bipyridine]-4-carboxylic acid, or a salt thereof.
  • the invention provides a compound of Formula (I) or a salt thereof, selected from:
  • the invention provides a compound of Formula (I), or a salt thereof, selected from the compounds in Table 4
  • the invention provides a compound of Formula (I), or a salt thereof, selected from the compounds in Table 5:
  • aryl, heteroaryi, 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- yi, pyridin-3-yl or pyridin-4-yl ring
  • piperidinyl may refer to a piperidin-1-yl, piperidin-2-yl, piperidin-3-yi or piperidin-4-y! 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 heteroaryi
  • 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 C1-4, C1.6, C2-6, C3.7 and the like.
  • C y . z alkyl refers to a saturated straight or branched acyclic hydrocarbon group having y to z carbon atoms.
  • a C1-6 alkyl is an alkyl having from one to six carbon atoms.
  • Examples of Cu alkyl include, but are not limited to, methyl, ethyl, n-propyi, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, or sec-hexyl.
  • a C1 3 alkyl is an alkyl having from one to three carbon atoms. Examples of C1.3 alkyl include methyl, ethyl, n-propyl and isopropyl.
  • C>, z alkoxy refers to an C fZ 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.
  • Cu 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.
  • Ci 3 alkoxy thus refers to an alkoxy group wherein the alkyl moiety has from 1 to 3 carbon atoms and includes methoxy, ethoxy, n-propoxy, and isopropoxy.
  • C y . z alkylene refers to a saturated straight or branched divalent acyclic hydrocarbon group having from y to z carbon atoms.
  • a 0.6 alkylene is an alkylene having from one to six carbon atoms
  • a C2-6 alkylene is an alkylene having from two to six carbon atoms
  • a 0-4 alkylene is an alkylene having from one to four 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 6, from 2 to 6 or from 1 to 4. 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 C2-6 alkenylene is an alkenylene having from two to six carbon atoms
  • a C24 alkenylene is an alkenylene having from two to four carbon atoms.
  • C y . z alkynylene refers to a saturated straight or branched divalent acyclic hydrocarbon group having from y to z carbon atoms and containing one or more triple bonds.
  • a C2-6 alkynyiene is an alkynylene having from two to six carbon atoms
  • a C2-4 alkynylene is an alkynylene having from two to four 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 multicyciic (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-1 H-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 cycloalkyl 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 examples include, but are not limited to, cyclopropyf, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, bicyc!o[2.2.1 jheptanyi, bicyclo[2.2.2]octanyl, decalinyl, and the like.
  • 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 y . z cycloalkyl refers to a monocyclic cycloalkyl having from y to z ring-forming carbon atoms.
  • a C3.7 cycloalkyl has 3 to 7 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a C3-6 cycloalkyl has from 3 to 6 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • 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 C1-6 haloalkyl is a .5 alkyl which is substituted one or more times with one or more halo, and a C1.3 haloalkyl is a C1-3 alkyl which is substituted one or more times with one or more halo.
  • Haloalkyl groups include perhaloalkyl groups, i.e. alky! groups where all hydrogen atoms are replaced by halo.
  • haloalkyl groups include, but are not limited to, fiuoromethyl, difluoromethyi, trifluoromethyi, 2,2,2-trifluoroethyl, 1-fluoro- 2-fluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, chloromethyl, dichloromethyl, trichloromethyl difluorochloromethyl, dichlorofluoromethyl, 1 ,2-dichloroethyl, 3,3-dichloropropyl and the like.
  • the haloalkyl is a fluoroaikyl, i.e. an alkyl group which is substituted one or more times with one or more fluoro.
  • 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 7 haloalkyl.
  • a Cu haloalkoxy group thus refers to a haloalkoxy group wherein the haioaikyl 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 imidazolyi, pyridyl, quinolyl, pyrido[2,3- djpyrimidinyl 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 group is fully aromatic.
  • Nonlimiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl, pyrrolyl, imidazolyi, pyrazolyl, oxazoiyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazine, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, phthalazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazoiyl, benzox
  • 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, carbazotyl or phthalimidyl.
  • the heterocycyi can be attached to the rest of the molecule through any C or N atom that results in a stable structure.
  • heterocyclyl groups include, but are not limited to, pyrrolkJinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyi, homopiperazinyl, azetidinyl, oxetanyi, homopiperidinyl, oxepanyl, thiepanyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrro!inyl, pyrazolinyt, pyrazolidinyl, imidazol,
  • C y - Z hydroxyalkyl refers to an alkyl group having from y to z carbon atoms as defined herein which is substituted one or more times (preferably one or two) with hydroxy groups. Accordingly, a Ci « hydroxyalkyl is a Cue alkyl which is substituted one or more times with one or more hydroxy and a CM hydroxyalkyl is a C1-3 alkyl which is substituted one or more times with one or more hydroxy.
  • hydroxy ⁇ or hydroxy refers to -OH.
  • optionally interrupted means that the respective alkylene, aikenylene, alkynylene or (CH2) X group is uninterrupted or is interrupted between adjacent carbon atoms by a heteroatom selected from 0 and S or a heterogroup NR 1C , i.e. an 0, S or NR 10 is placed between two adjacent carbon atoms in the alkylene, aikenylene, alkynylene or (CH 2 ) X group.
  • Optionally interrupted as used herein also includes alkylene, aikenylene, alkynylene or (CH 2 )x groups where the heteroatom or heterogroup (i.e.
  • an optionally interrupted C4 alkylene group includes groups such as - CH2OCH2CH2CH2-, -OCH2CH2CH2CH2- and -NR 10 CH 2 CH2CH 2 CHr.
  • substitution means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a monovalent substitutent, or, if applicable, two hydrogen atoms are replaced with a divalent substituent like a oxo group or with two R 13 groups linked together as provided herein. 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 unsatu ration, but is not intended to include aryl or heteroaryl groups, as herein defined.
  • N-linked in relation to R 16 (as in N-linked-R 16 ) means a R 15 group that is linked to the remainder of the molecule through a N atom.
  • a wavy line ⁇ in chemical drawings indicates a 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-eno! pairs and annular forms where a proton can occupy two or more positions of a heterocyclic system as for example in 1 H- and 3H-imidazole. Tautomeric forms can be in equilibrium or sterically 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 Cl, and 125 l.
  • 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 above and in the claims as well as the compounds described in the Examples), including all stereoisomers, tautomers and isotopically labeled forms 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, b (sulfates, 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,
  • 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 !igands 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 stoichiometric 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.
  • the first step involves a cross-coupling reaction of a heterocyclic organometallic species with a heterocyclic halide.
  • Oganometal!lic intermediates can be generated either on the heteroaryi bearing the COOR 1 substituent (i.e. a compound of Formula (ill)) or in the heteroaryi bearing the -(U)m-Y-(L 2 )n-R 3 substituent (i.e. a compound of Formula (VI) ).
  • 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 a 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 trialkylsiiyl 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 or Pd(PPI3 ⁇ 4)4, in the presence of a suitable Cu salt such as Cu(OAc)2 or Cul, in a suitable solvent such as toluene, DME, tetrahydrofuran or dimethy!formamide, using a suitable base such as potassium carbonate.
  • a suitable Pd/ligand combination such as XPhos and Pd2(dba)3 or Pd(PPI3 ⁇ 4)4
  • a suitable Cu salt such as Cu(OAc)2 or Cul
  • a suitable solvent such as toluene, DME, tetrahydrofuran or dimethy!formamide
  • a suitable base such as potassium carbonate.
  • the temperature of the reaction can go from room temperature to 120°C and the time of reaction from 1h to 48h.
  • boronic derivatives include diethyl, dimethyl, N-methyli
  • the reaction can be performed using a suitable Pd/iigand combination such as Pd(PPh 3 )4, Pd(PPh 3 )Ch 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 dimethyiformamide.
  • a suitable Cu salt such as Cul or CuO
  • CsF tetrahydrofuran, dioxane or dimethyiformamide
  • the temperature of the reaction can go from room temperature to 120°C and the time of reaction from 1 h to 48h.
  • the organotin employed can be trimethylstannyi derivative.
  • An intermolecuiar Stille Kelly reaction can also be used, in which both reagents are haloheteroaryls and are treated with (BuaSn)?, EUNI, and a Pd/ligand combination.
  • the reaction can be performed using a suitable Pd/iigand combination such as PPhj and Pd?(dba)3 , XPhos and Pd2(dba) 3 , RuPnos and Pd2(dba)3 or Pd(PPh 3 )4, in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • a suitable Pd/iigand combination such as PPhj and Pd?(dba)3 , XPhos and Pd2(dba) 3 , RuPnos and Pd2(dba)3 or Pd(PPh 3 )4, in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • the reaction can be performed using a suitable Pd/ligand combination such as PdCb(PPh3)? and PPhs or Pd(OAc)z 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 tetrabutylamonium fluoride, in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide.
  • a suitable Pd/ligand combination such as PdCb(PPh3)? and PPhs or Pd(OAc)z and di(1-adamantyl)-n-butylphosphine
  • a suitable Cu salt such as Cul or CuBr
  • tetrabutylamonium fluoride in a suitable solvent
  • the temperature of the reaction can go from room temperature to 120°C and the time of reaction from 1h to 48h.
  • Krohnke's ring assembly methodology can be used in the case that compounds of Formula (I) contain a pyridine, following standard conditions.
  • Reaction of (IV) with (VII) can be performed using a suitable Pd/ligand combination such as P'Bu3 and Pd(OAc)2 or PBU3-HBF4 and Pd(OAc)?, in the presence of a suitable base as potassium carbonate, in a suitable solvent such as toluene.
  • a suitable base as potassium carbonate
  • the temperature of the reaction can go from room temperature to 120°C and the time of reaction from 1 h to 48h.
  • the resulting N -oxide (VIII) can easily be reduced to compound of Formula (I) with hydrogen or sodium borohydride using palladium on charcoal as a catalyst or also using phosphorous trichloride.
  • the compounds of Formula (IV) can be obtained 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 (IVa), (IVb), (IVc), (IVd) and (IVe) or analogous synthetic procedures.
  • Z 4 , Z 5 , R 2 , R 3 , L 1 , L 2 , m and n have the meaning described above with respect to a compound of Formula (I);
  • X is triflate, CI, Br or l;and B is CI, Br, I, or alkyl or aryl sulphonate.
  • compounds of Formula (IVa) can be obtained by reaction of (IX) with (X) by means of activating agents.
  • activating agents are among others: dicyclohexyl carbodiimide (DCC), 1- hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 1-ethyl-3-(3 !
  • Reaction can be carried out in the presence of a base, such as, disopropylethylamine, pyridine, thriethylamine, or N-methylmorpholine , in a solvent, such as dimethoxyethane, MA/-dimethylformamide, tetrahydrofuran, dichloromethane or dioxane.
  • a base such as, disopropylethylamine, pyridine, thriethylamine, or N-methylmorpholine
  • a solvent such as dimethoxyethane, MA/-dimethylformamide, tetrahydrofuran, dichloromethane or dioxane.
  • carboxy!ic acids in (X) are activated as mixed anhydrides or acid chlorides and then coupled with (IX) in the presence of a suitable base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine or the like.
  • compounds of Formula (IVb) can be obtained by reaction of (IX) with (XI) by means of reductive amination in the presence of a reducing agent such as sodium cyanoborohydride or sodium thacetoxyborohydride in a suitable solvent such as dioxane, tetrahydrofuran, dichloromethane or diethyl ether.
  • a reducing agent such as sodium cyanoborohydride or sodium thacetoxyborohydride
  • a suitable solvent such as dioxane, tetrahydrofuran, dichloromethane or diethyl ether.
  • compounds of Formula (IVb) can be obtained by means of amine alkylation of compounds of Formula (IX) in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate or the like.
  • Other preferred solvents include dioxane, tetrahydorfurane and pyridine. Temperature can be varied from room temperature to 100°C
  • compounds of Formula (IVc) can be obtained by ether synthesis by reaction of (XII) with
  • compounds of Formula (IVd) can be obtained by reaction of compounds of Formula (IVd).
  • compounds of Formula (IVe) can be obtained by reaction of compounds of Formula (XV) with the corresponding pyrazole derivative, in the presence of a base such as potassium carbonate in a solvent such as DMSO at a temperature from room temperature to reflux of solvent for a time from 1h to 24h.
  • a base such as potassium carbonate
  • a solvent such as DMSO
  • the compounds of Formula (VI) can be obtained from compounds of Formula (IV) by transmetallation following standard procedures in the preparation of reagents for Suzuki, Stille Hiyama and Negishi couplings, well known to those skilled in the art of organic chemistry.
  • N-methyliminodiacetic acid boronate can be prepared by reaction of an haloheterocycle with nBuLi in the presence of B(OiPr)3 at -78°C followed by the addition of N-methyliminodiacetic acid
  • trimethyitin heterocycies can be prepared by reaction;of haloheterocycles with hexamethylditin and Pd (PPh 3 ).i in toluene at 110°C for 16h
  • organozinc derivatives can be prepared from haloheterocycles by treatment with Zn in THF at room temperature for 1to 6h
  • trimetilsily! heterocycies can be prepared by reaction of haoheterocycles with nBuL
  • some compounds of the present invention can also be obtained by cross-coupling reactions described in Scheme 1 and 2, where instead of (IV) and (VI), a corresponding intermediate carrying a partially elaborated (L 1 ) m -Y-(L 2 ) n -R 3 is used and after cross coupling step, the complete structure of ⁇ 1%-Y- (L 2 ) n -R 3 is built by the methodology described above in Scheme 3.
  • a compound of Formula (I) where R 1 is H can be prepared by hydrolysis of the corresponding ester by treatment with a suitable acid or a base.
  • bases which can be used include, without limitation, LiOH, NaOH, KOH or MeaSiOK in a mixture of water and a solvent miscible with water such as dioxane, tetrahydrofuran, MeOH, EtOH, between 0°C and room temperature for 1 to 3 days.
  • a suitable acid is aqueous HCI.
  • 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.
  • 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).
  • the compounds of the invention have been found to be potent inhibitors of a JmjC-KDM of the KDM5 and/or KDM4 subfamilies.
  • some compounds of the invention have been found to inhibit also 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 26 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 26.
  • 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 al. 2005, Mo! Cell 18(6): 623-35) and induction of senescence (Chicas A. ef 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. ef al. 2010, Cell 141 (1 ):69-80). Sensitisation to anticancer therapy after KDM5A inhibition has also been described in colon, breast, cancer and Non Small Cell Lung Cancer cell lines (Vinogradova M. ef 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. ef 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. ef al. 2013, Endocr Relat Cancer 21(1) 51-61), Head and Neck Squamous Carcinoma cell lines (Li H. ef 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, 2016, 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. et 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, et 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. ef 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. ef al. 2014, Cancer Ceil 25(6):762-77).
  • KDM5B inhibition is also relevant in basal-iike (Bamodu OA et al.
  • 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 celis-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. et 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 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. et al. 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) demethyiates 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.
  • KDM4A can also work as a transcriptional repressor: it directly interacts with the N-terminal region of the compressor N-CoR or histone deacetylases (Zhang D. ef 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. et al. 2011 , Proc Natl Acad Sci USA.
  • 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 NOTCH1 , and may be linked to the stem cell phenotypes (Liu G. et al. 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.
  • 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. ef al. 2013, Carcinogenesis 34(10):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 (Maiiette F.A. et 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 demethyiation 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. et 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. et 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. et al. 2007, Nat Cell Biol. 9(3):347-53).
  • KDM4A 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. et 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 medu!loblastomas (Knuutila, S. et al. 1998, Am. J. Pathol. 152:1107-1123).
  • 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-T1F2 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. ef al. 2007 Genes Dev. 21 : 2545-2557) and modulates regulation of adipogenesis by the nuclear receptor PPARy (Lizcano F. et al. 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 ef 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 et 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 demethyiate H3K27me2 and H3K27me3 (Xiang et al. 2017, Cell Res 17(10):850-7).
  • JMJD3 Jumonji domain-containing protein D3
  • UTX ubiquitously transcribed X-chromosome tetratricopeptide repeat protein
  • 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 et 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 et 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 RNA HOTA!R in renal cell carcinoma cells was associated to the upregulation of KDM6B (Xia et al. 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 ef 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 et 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 ef al. 2014, Nat Commun 5:5425).
  • KDM6B has also been shown to have a ro!e 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 et 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 et 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 chemotberapeutic drugs (Marthur et al. 2017, Haematologica 102(2):373-380).
  • KDM6A and KDM6B 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 et 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 or a KDM4 protein and/or a KDM6 protein.
  • a JmjC-KDM e.g. a KDM5 protein or a KDM4 protein and/or a KDM6 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), or pharmaceutically acceptable salt thereof, for use as a medicament.
  • the present invention further provides a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), or pharmaceutically acceptable salt thereof, for use in treating a disease associated with a JmjC-KDM, particularly a KDM5 and/or KDM4 and/or KDM6.
  • the present invention further provides the use of a compound of Formula (I), (la), (lb), (lc), (Id), (le),
  • 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 (II), more preferably of formula (la) or (lb), or pharmaceutically acceptable salt thereof, for treating a disease associated with a JmjC-KDM, particularly a KDM5 and/or KDM4 and/or KDM6.
  • the present invention further provides a method for treating a disease associated with a JmjC-KDM, particularly a KDM5 and/or KDM4 and/or KDM6, comprising administering a therapeutically effective amount of a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), or pharmaceutically acceptable salt thereof, sufficient to inhibit a KDM5 and/or KDM4 and/or KDM6 activity.
  • a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), or pharmaceutically acceptable salt thereof.
  • the present invention further provides the use of a compound of Formula (I), (la), (lb), (lc), (Id), (le),
  • 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), (!a), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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 (II), 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 (II), 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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 leukemialn
  • 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 leukemialn
  • the present invention further provides the use of a compound of Formula (I), (la), (lb), (lc), (Id), (le),
  • 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 ceil 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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, uterine cancer, melanoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, lymphoma and leukemia.
  • the present invention further provides a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (Id), (le), (if) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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.
  • 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 KDM6, and/or diseases or conditions the course of which can be influenced by modulating the methy!ation 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 KDM6, Modulation of the methylation status
  • Diseases associated with a KDM5 and/or a KDM4 and/or a KDM6 include, without limitation, the diseases and conditions as described herein.
  • 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, medul!oblastoma, neuroblastoma, mesothelioma, multiple myeloma, osteosarcoma, lymphoma and leukemia.
  • 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
  • said cancer is selected from breast cancer, bladder cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck carcinoma, squamous eel! carcinoma, liver cancer, lung cancer, prostate cancer, cervical cancer, ovarian cancer, uterine cancer, melanoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, lymphoma and leukemia.
  • said cancer is drug-resistant cancer.
  • 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.
  • 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, ceil 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) (or any of its subgenus of Formula (la), (lb), (lc), (Id), (le), (If) or (II)), 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.
  • Examples of pharmaceutically acceptable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, staches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrysta!line 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.
  • 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, com 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), dis
  • 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 cetylstearyi 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 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, epidophylbtoxins, 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, epidophylbtoxins, 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, epidophylbtoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazines,
  • Particularly useful members of those classes include, for example, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexafe, mitomycin C, porfiromycin, 5- fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo- phylbtoxin 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 inteiieukins.
  • 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, or trofosfamide), 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 (N.N'N'-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, fiudarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6- thioguanine), and pyrimidine analog antimetabolites (such as cytarabine, decitabine, azacytidine, 5-ffuorouracil (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, or sapacitabine).
  • an antimetabolite including folic acid analog antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltit
  • 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 docetaxe!, 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, epothiione C, epothilone D, epothilone E, or epothilone F) or an epothilone B analog (such as ixabepilone/azaepothilone B).
  • a taxane such as docetaxe!, larotaxel, ortataxel, paclitaxel/taxol, or tesetaxel
  • a Vinca alkaloid such
  • 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 (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 or trametinib.
  • a B-Raf inhibitor like vemurafenib (PLX4032), encorafenib or dabrafenib
  • MEK inhibitor like cobetinib, binimetinib, selumetinib or trametinib.
  • 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, or vandetanib.
  • 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, mbitecan, or lameliarin 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, mbitecan, or lameliarin 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, fiutamide, 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; 3J-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)-3J-dimethyl-2,4,6,8-non
  • 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-oxodecanoyi-1-methoxy-L-ti7ptophyl-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
  • 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, certo!izumab pego!, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizum
  • tefibazumab tefibazumab. tociiizumab, toralizumab, trastuzumab, tucotuzumab celmoieukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.
  • 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, RB, p53, WT1, BRCA1 , and BRCA2)
  • cancer vaccines e.g., tumor associated antigens such as gangliosides (GM2), prostate specific antigen (PSA), alpha-fetoprotein (AFP), carcinoembryonic anti
  • 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.
  • 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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. 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the antineoplastic agent.
  • the antineoplastic agent is selected from the list 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, medulloblastoma, neuroblastoma, osteosarcoma, lymphoma and leukemia.
  • the present invention in particular relates to the following:
  • Z 1 , Z 2 , and Z 3 are each independently selected from CR 4 and N, and Z 4 and Z 5 are each independently selected from CR 2 and N, with the proviso that only one of T , Z 2 , Z 3 , Z 4 and Z 5 can be N;
  • R 1 is selected from hydrogen, Ci. s alkyl, Ci- 6 haloalkyl, -(C,. 6 alkylene)-OR 5 , - ⁇ C-s alkylene)-NR 6 R 7 , -LA carbocyclyl, -L 3 -aryi,-L ? -heterocyc!yi and -L 3 -heteroaryl, wherein the carbocyclyl in -LAearbocyclyl, the aryl in - L 3 -aryl, the heterocyclyl in -LAheterocyc!yl and the heteroaryl in -L 3 -heteroaryl are each optionally substituted with one or more R 8 ,
  • each R 2 is independently selected from hydrogen, halo, Ci-s alkyl, Ci-s haloalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, - OH and -NH 2 ;
  • each R 4 is independently selected from hydrogen and halo
  • L 1 is Ci-4 alkylene, C2-4 alkenylene or C2-4 alkynylene, wherein said Cu alkylene, said C2-4 alkenylene and said C24 alkynylene are optionally interrupted by 0, S or NR 10 , and wherein said Cu alkylene, said C2-4 alkenylene and said C24 alkynylene are optionally substituted with one or more R 12 ;
  • L 2 is C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene, wherein said C1 6 alkylene, said C2-6 alkenylene and said C2-6 alkynylene are optionally interrupted by 0, S or NR 10 , and wherein said Cu, alkylene, said C2-6 alkenylene and said Cn alkynylene are optionally substituted with one or more R 12 ;
  • n and n are each independently selected from 0 and 1 ;
  • R 3 is selected from -NR 13 R 14 , -OR 15 and R ,s ;
  • R 6 and R 7 are each independently selected from hydrogen and Cu alkyl, or R 6 and R 7 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 substituents independently selected from halo, Ci.s alkyl, -OH, -NH 2 , -NH(C,. 6 alkyl), and -N(Ci S alkyl ⁇ 2 ;
  • each L 3 is independently selected from a bond and Cu alkylene;
  • R s and R 1c are each independently selected from hydrogen, C1-5 alkyl and Ci-s haloalkyl;
  • -R 11 - is a biradical of a 5-membered heteroaryi ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S with the proviso that at least one is a N atom, and wherein -R 11 - is linked to -(L 1 ) m - and - ⁇ L 2 ) justify- R 3 in a 1 ,3-disposition;
  • each R 12 is independently selected from Cn alkyl, halo, CI-B haloalkyl, -L 3 -carbocyclyl, -L 3 -aryl,-L 3 -heterocyclyl and -L 3 -heteroaryl, wherein the carbocyclyl in -L 3 -carbocyclyl, the aryl in -LAaryl, the heterocyclyl in -LA heterocyclyl and the heteroaryi in -LAheteroaryl are each optionally substituted with one or more R 17 , and wherein two groups R 12 attached to a same C atom of the alkylene, alkenylene or alkynylene group are optionally linked together to form with said C atom a C3-6 cycloalkyl group or a saturated 4- to 6-membered monocyclic heterocyclic ring containing 1 heteroatom selected from N, 0 and S, wherein said C3-3 cycloalkyl and 4- to 6-membered
  • R 13 , R 14 and R 15 are each independently selected from hydrogen, Cu alky!, C1 0 haloalkyl, -(Ci e alkylene)-OR 18 , -L 3 -carbocyclyl, -L 3 -aryl,-L 3 -heterocyclyl and -L 3 -heteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyl in -LAheterocyclyl and the heteroaryi in -LAheteroaryl are optionally substituted with one or more R 19 ;
  • R 16 is selected from C1-6 alkyl, carbocyclyl, aryl, heterocyclyl and heteroaryi, wherein said alkyi is optionally substituted with one or more R 20 and said carbocyclyl, said aryl, said heterocyclyl and said heteroaryi are each optionally substituted with one or more R 21 ;
  • each R 22 is independently selected from C1.6 alkyl
  • each R 5 , each R 18 , each R 23 , each R 24 , each R 26 , each R 26 and each R 27 is independently selected from hydrogen and Cm alkyl.
  • any alkyiene can be optionally substituted with one or more R 12 .
  • R 3 is R 16 and R 16 is selected from carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein said carbocyclyl, said aryl, said heterocyclyl and said heteroaryl are each optionally substituted with one or more R 21 , 12.
  • R 3 is R 16 and R 16 is phenyl, wherein said phenyl is optionally substituted with one or more R 21 .
  • a pharmaceutical composition which comprises a compound of any one of items 1 to 12 or a
  • BINAP 2,2'-bis(diphenylphosphine)- 1 ,1 '-binaphthyl
  • Pd(PPh3)4 tetrakis(thphenylphosphine) palladium (0)
  • Pd(PPh3)?Cl2 Bis(triphenylphosphine)palladium chloride
  • Pet ether petroleum ether
  • T3P Propylphosphonic Anhydride
  • Method 2 Column: KINETEX-1.7u XB-C18 100A (50mm x 2.1 mm, 1.7 ⁇ ); 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 3 Column: Gemini C18 (150mm x 4.6mm, 5 ⁇ ); Mobile Phase: A: 0.01 M Ammonium Acetate (aq), B: Acetonitrile; Gradient: Time/% B: 0/10, 1/10, 6/90, 8/98, 12/98, 12.01/10; Flow Rate: 1.0 mL/min;
  • Method 4 Column: Xbridge C18 (75mm x 4.6mm, 3.5 ,um); Mobile Phase: A: Acetonitrile, B: 5 mM Ammonium Bicarbonate in Aq; Gradient: Time/% B: 0/95, 1/95, 5/5, 7.8/5, 8/95, 10/95; Flow Rate: 1.0 mL/min; Diluent: Acetonitrile:Water (1 :1);
  • Method 5 Column: Xbridge C18 (75mm x 4.6mm, 3.5 ⁇ ); Mobile Phase: A: 10 mM Ammonium Bicarbonate 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 6 Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 ⁇ ); Mobile Phase: A: 0.05% Formic Acid in Acetonitrile, B: 0.05% Formic Acid in Water; Gradient: Time/% B: 0/97, 0.3/97, 3.2/2, 3.8/2, 4.3/97, 4.5/97; 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. 0.05% Formic Acid in Water, B: 0.05% Formic Acid in Acetonitrile; Gradient: Time/% A: 0/97, 0.3/97, 3.5/2, 4.8/2, 5/97, 5.01/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min; Method 8: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ⁇ ); 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, 4.5/2, 4.51/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min;
  • Method 9 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 10 Column: Xbridge C18 (75mm x 4.6mm, 3.5 urn); Mobile Phase: A: 0.01 M Ammonium Acetate (aq), B: Acetonitrile; Gradient: Time/% B: 0/10, 1/10, 6/90, 7/98, 10/98, 10.01/10; Flow Rate: 1.0 mL/min; Method 11 : Column: KINETEX 5u XB-C18 (100mm x 4.6mm); Mobile Phase: B: 0.01 M Ammonium Acetate (aq), A: Acetonitrile; Gradient: Time/% B: 0/95, 0.5/95, 2.0/85, 4.0/45, 6.5/5, 9.0/5, 9.10/95, 10.10/95; Column Temp: 35°C; Flow Rate: 1.0 mL/min;
  • Method 12 Column: Xbridge C18 (75mm x 4.6mm, 3.5 pm); Mobile Phase: A: Acetonitrile, B: 5 mM Ammonium Bicarbonate in Aq; Gradient: Time/% A: 0/2, 2/2, 4/15, 7/55, 8/95, 10/95, 14/95, 14.1/2; Flow Rate: 1.0 mL/min; Diluent: TFA:Water (1 :1);
  • Method 13 Column: L-Column2(150mm x 4.6mm, 5 ⁇ ); Mobile Phase: A: Acetonitrile, B: 0.01 M Ammonium Acetate in Aq; Gradient: Time/% A: 0/5, 1/5, 15/80, 20/90, 25/90, 25.01/5; Column Temp: 35°C; Flow Rate: 1.0 mL/min; Diluent: Acetonitrile:Water (1 :1);
  • Method 14 Column: Xbridge C18 (75mm x 4.6mm, 3.5 ⁇ ); 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 15 Column: Gemini C18 (150mm x 4.6mm, 5 ⁇ ); Mobile Phase: A: 0.01 M Ammonium Bicarbonate (aq), B: Acetonitrile; Gradient: Time/% B: 0/10, 1/10, 6/90, 7/98, 10/98, 10.01/10; Flow Rate: 1.0 mL/min; Method 16: Column: Xbridge C18 (75mm x 4.6mm, 3.5 ⁇ ); Mobile Phase: A: Acetonitrile, B: 10 mM Ammonium Acetate in Aq; Gradient: Time/% A: 0/2, 2/2, 4/15, 7/55, 8/95, 10/95, 14/95, 14.1/2; Flow Rate: 1.0 mL/min; Diluent: ACN:Water (1 :1);
  • Method 17 Column: Xbridge C18 (75mm x 4.6mm, 3.5 ⁇ ); 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 18 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ⁇ ); 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, 3.8/2, 4.2/97, 4.5/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min;
  • Method 19 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ⁇ ); Mobile Phase: B: 0.1% Formic Acid in Water, A: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B: 0/2, 0.3/2, 2.3/98, 2.8/98, 2.8/2, 3.0/2; Column Temp: 60°C; Flow Rate: 0.8 mL/min.
  • Method 21 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ⁇ ); 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 22 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/% A: 0/97, 2.6/0, 3.3/0, 3.6/97, 4.0/97; Column Temp: 35°C; Flow Rate: 0.55 mL/min; Diluent: Acetonitrile:Water (1 :1).
  • Method 23 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 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 24 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ,um); Mobile Phase: B: 0.1% Formic Acid in Acetonitrile, A: 0.1% Formic Acid in water; Gradient: Time/% B: 0/10, 1.8/100, 3.8/100, 4.0/10, 5/10, Column Temp: 50°C; Flow Rate: 0.7 mL/min;
  • Method 25 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ⁇ ); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A: 0/95,0.3/95,2.0/5,3.5/5,3.6/95,4.2/95; Column Temp: 40°C; Flow Rate: 0.6 mL/min;
  • Method 26 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 pm); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A: 0/90,1/10,2.2/10,2.3/90,2.6/90; Column Temp: 50°C; Flow Rate: 0.8 mL/min;
  • Method 27 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 urn); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A: 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 28 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ⁇ ); 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 29 Column - AQUITY UPLC BEH C18 (50mm x 2.1 mm, 1.7 ⁇ ); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A: 0/98 0.2/98,1.8/2,2.4/2,2.60/98; Column Temp: 50°C; Flow Rate: 0.8 mL/min;
  • Method 30 Column - AQUITY UPLC BEH C18 (50mm x 2.1 mm, 1.7 ⁇ ); Mobile Phase: A: 0.1% Formic Acid in Water, B: Acetonitrile; Gradient: Time/% A: 0/98 0.5/98,3.4/2,4.2/2,4.5/98, 5.0/98; Column Temp: 35°C; Method 31 : Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ⁇ ); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A: 0/97, 0.3/97, 3.0/2, 4.0/2, 4.2/97, 4.50/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min; Method 32: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ,um); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% For
  • Method 33 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 Acetonitriie; Gradient: Time/% B: 0/5, 0.3/95, 2.0/95, 3.7/95, 4.2/5, 5.7/5; Column Temp: 40°C; Flow Rate: 0.5 mL/min;
  • Method 34 Column: XBridge BEH C18 (50mm x 3.0mm, 2.5 ⁇ ); Mobile Phase: A: 0.01 M Ammonium Formate in water.ACN (95:5), B: 0.01 M Ammonium Formate in water.ACN (5:95); Gradient: Time/% B: 0/2, 4/98, 4.5/98, 5/2, 5.5/2, 6.5/2; Flow Rate: 1.0 mL/min;
  • Method 35 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ⁇ ); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitriie; Gradient: Time/% A: 0/98, 0.2/98, 1.8/2, 2.4/2, 2.60/98, 3.0/98 Column Temp: 50°C; Flow Rate: 0.8 mL/min;
  • Method 36 Column: Xbridge C18 (75mm x 4.6mm, 3.5 pm); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitriie; Gradient: Time/% B: 0/10, 6/100, 9/100, 9.50/10,12/10.Flow Rate: 1.0 mL/min; Method 37: Column: Atlantis T3 (150mm x 4.6mm, 3.5 ⁇ ); Mobile Phase: A: 0.1% Formic Acid in Water, B: Acetonitriie; Gradient: Time/% B: 0/10, 8/100, 12/100, 12.5/10, 15/10. Flow Rate: 1.0 mL/min;
  • Method 38 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ⁇ ); Mobile Phase: A: 0.01 M Ammonium Bicarbonate in Water, B: Acetonitriie; Gradient: Time/% B: 0/3; 1.0/3; 7.0/100; 7.5/100: 9.0/3; 10.0/3.Column Temp: 35°C; Flow Rate: 0.5 mL/min;
  • Method 39 Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ⁇ ); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitriie; Gradient: Time/% A: 0/97; 1.0/97; 7.0/0; 7.5/0; 9.0/97; 10.0/97.Column Temp: 35°C; Flow Rate: 0.5 mL/min;
  • the reaction mixture was diluted with DCM (100 mL), washed with water (50 mL), aq.NaHCOs solution (50 ml). The organic layer was dried over anhydrous Na?SCvnch filtered and the filtrate was concentrated under reduced pressure. The residue was suspended in DCM, the precipitated solid was filtered, washed with DCM and dried in vacuum to afford the title compound (2 g, 41%) as a brown gummy liquid.
  • step a To a stirred solution of the compound obtained in the previous section, step a, (11.0 g, 0.041 mol) in DMSO (30 mL) was added NaCN (3.0 g, 0.062 mol) at rt. The reaction mixture was stirred at RT for 6h. The progress of the reaction was monitored by TLC. The reaction mixture was poured into ice water and extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with brine solution (200 mL) and dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to get the title compound (7.0 g, 86%) as a brown liquid.
  • step b (7.0 g, 0.035 mol) and B0C2O (16 mL, 0.071 mol) in methanol (30 mL) was added NiCI 2 .6H 2 0 (1.6 g, 0.007 mol), followed by the addition of NaBhU (5.4 g, 0.14 mol).
  • the resulting reaction mixture was allowed to stir at RT for 4h. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated; the residue was partitioned between EtOAc (100 mL) and water (50 mL).
  • step c To a stirred solution of the compound obtained in the previous section, step c, (2.4 g, 0.008 mol) in 1 ,4-dioxane (15 mL) was added 4M HCI in 1 ,4-dioxane (2.0 mL) and the resulting reaction mixture was stirred at room temperature for 4h. Solvent was removed under reduced pressure, and the residue was triturated with diethyl ether (2 mL) and dried under vacuum to afford the title compound (2.0 g) as a hydrochloride salt.
  • step d To a stirred solution of the compound obtained in the previous section, step d, (2.0 g, 0.01 mol) and 1- (ferf-butoxycarbonyl)piperidine-3-carboxylic acid (2.7 g, 0.012 mol) in DCM (10 mL) was added TEA (7.0 mL, 0.05 mol) followed by the addition of T3P(50% in EtOAc) (9.5 mL, 0.03 mol). The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with DCM, washed with water and brine. The organic layer was dried over anhydrous ! ⁇ SCM, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel and eluted with 2% MeOH/DCM to afford the title compound (600 mg, 15%) as a light yellow semisolid.
  • step a (3.5 g, 0.016 mol) in 1,4-dioxane
  • Step c Tert-butyl 5-(6-bromopyridin-3-yl)-1,3,4-oxadiazol-2-ylcarbamate
  • DIPEA 4.81 g, 0.037 mol
  • Boc 2 0 3 5.4 g, 0.025 mol
  • DMAP 0.45 g, 0.0037 mol
  • the reaction mixture was cooled to RT, diluted with water (50 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layers were dried over anhydrous Na2SO/. and concentrated under reduced pressure.
  • the crude compound was purified by flash column chromatography and eluted with 20% EtOAc/ pet ether to obtain the title compound (0.6 g, 14%) as a brown color solid.
  • Step a N-Benzyl-6-bromopyridin-3-amine
  • 6-bromo-3-amino pyridine (1 g, 0.005 mol) and benzaldehyde (0.61 g, 0.005 mol) in DCE (20 mL)
  • a catalytic amount of acetic acid and 4 ⁇ molecular sieves (0.1 g) at 10°C.
  • the reaction mixture was stirred for 10 min, then sodium triacetoxy borohydride (2.46 g, 0.011 mol) was added at the same temperature.
  • the resulting reaction mixture was allowed to stir at RT for 16h.
  • the reaction was diluted with DCM (100 mL) and poured in satiurated NaHCOa aq. solution (50 mL). The organic layer was dried over anhydrous Na2S04, filtered and the filtrate was concentrated. The crude compound was purified by column chromatography using silica gel and eluted with EtOAc: pet ether (3:7) to afford the title compound (800 mg, 52%) as a light brown solid.
  • Step b rerf-butyi benzyl(6-bromopyridin-3-yl)carbamate
  • step a (0.6 g, 0.0023 mol) in THF (5 mL) was added DMAP (0.33 g, 0.0027 mol) and Boc 2 0 (0.0025 mol) at RT.
  • the resulting solution was heated at 75 °C for 16h.
  • the reaction mixture was cooled to RT, diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na?SO heap, filtered and concentrated under reduced pressure.
  • the crude compound was purified by flash column chromatography and eluted with 15-17% EtOAc/ pet ether to obtain the title compound (0.6 g, 73%) as a white color solid.
  • step a (3.0 g, 10.48 mmol) in DCM (40 mL) was added DMAP (0.639 g, 5.24 mmol), TEA (2.116 g, 20.96 mmol) and Boc?0 (3.426 g, 15.72 mmol) at 0°C and allowed to stir at RT for 16 h.
  • the reaction mixture was diluted with DCM (200 mL) and water (100 mL) and the separated organic layer was dried over anhydrous NajSCv, filtered and concentrated under reduced pressure.
  • the crude compound was purified by silica gel flash column chromatography and eluted at 5% MeOH/DCM to afford the title compound (1.5 g, 37%) as a gummy
  • step a To a stirred solution of the compound obtained in the previous section, step a, (4.4 g, 16.79 mmol) in DMF (30 mL) was added TEA (3.391 g, 33.58 mmol) and 2-phenylethanamine (4.063 g, 33.58 mmol) at 0°C and allowed to stir at RT for 16h.
  • the reaction mixture was diluted with EtOAc (200 mL) and washed with water (100 mL) and brine solution (2 x 100 mL).
  • the separated organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure.
  • the crude compound was purified by silica gel column chromatography and eluted at 3% MeOH/DCM to afford the title compound (4.2 g, 72%) as a colorless gummy solid.
  • Step c Tert-butyl (3-((6-bromopyridin-3-yl)amino)-3-oxopropyl)(phenethyl)carbamate
  • step b To a stirred solution of the compound obtained in the previous section, step b, (4.0 g, 11.52 mmol) in 1 ,4- dioxane/water (1 :1 , 40 mL) was added NaOH (0.922 g, 23.054 mmol) and Boc?0 (7.5 g, 34.58 mmol) at 0°C and allowed to stir at RT for 16 h.
  • the reaction mixture was diluted with EtOAc (200 mL) and washed with water (100 mL) and brine solution (100 mL).
  • the separated organic layer was dried over anhydrous Na2SC1 ⁇ 4, filtered and concentrated under reduced pressure.
  • the crude compound was purified by silica gel flash column chromatography and eluted at 25% EtOAc/Pet ether to afford the title compound (4.0 g, 77%) as a colorless gummy solid.
  • Step b Tert-butyl (5-bromopyrazin-2-yl)(2-(diethylamino)ethyl)carbamate
  • step a To a stirred suspension of 60% NaH (0.420 g, 17.58 mmol) in DMF (20 mL) the compound obtained in the previous section, step a, (1.6 g, 5.86 mmol) was added followed by the addition of Boc-anhydride (1.9 g, 8.79 mmol) at 0°C and the reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO ⁇ and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 0-5% MeOH in
  • step a To a stirred solution of the compound obtained in the previous section, step a, (2.0 g, 11.17 mmol) in EtOAc, (10 mL) was added ethyl trifluoromethane sulfonate (2.58 g, 14.52 mmol) and a solution of NaHCOs (3.51 g, 33.51 mmol) in water (10 mL). The resulting solution was stirred at RT for 16h. The reaction mixture was diluted with water (50 mL), and extracted with EtOAc (2 x 70 mL), the combined organic layer were dried over Na2S04 and concentrated to obtain the title compound (1.7 g, crude) as a liquid compound. The crude compound was used for next step without further purification.
  • step b To a stirred solution of the compound obtained in the previous section, step b, (1.7 g, 8.17 mmol) in ACN (20 mL) was added TEA (1.66 g, 16.42 mmol) and Boc?0 (2.7 g, 12.31 mmol) at RT. The resulting solution was stirred at RT for 16h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layer was dried over is ⁇ SO* and concentrated. The crude compound was purified by silica gel (100-200 mesh) flash column chromatography eluted with 30% EtOAc/ pet ether to obtain the title compound (0.9 g, 26%) as a colorless liquid.
  • step c To a stirred solution of the compound obtained in the previous section, step c, (1.5 g, 4.88 mmol) in THF-MeOH (10 mL, 1 :1) was added a solution of LiOH.H 2 0 (0.61 g, 14.65 mmol) in water (2 mL) at 0°C. The resulting solution was stirred at RT for 3h. The reaction mixture was evaporated under reduced pressure, the residue was dissolved in water (20 mL), acidified (pH ⁇ 4) with saturated citric acid solution and extracted with EtOAc (2 x 70 mL), The combined organic layer was dried over Na2Si3 ⁇ 4 and concentrated to obtain the title compound (1.2 g, 84%) as a colorless liquid.
  • step d To a stirred solution of the compound obtained in the previous section, step d, (0.9 g, 3.07 mmol) and 6- bromopyridin-3-amine (0.58 g, 3.37 mmol) in DCM (10 mL) and TEA was added (0.93 g, 9.21 mmol) was added followed by T 3 P (50% solution in EtOAc) (2.93 g, 9.21 mmol) at 0°C and the reaction mixture was allowed to stir at RT for 16h. The reaction mixture was diluted with water (50 m) and extracted with DCM (2 x 70 mL). The combined organic layers dried over NazSO,, filtered and the filtrate was concentrated under reduced pressure. The obtained crude compound was purified by silica gel flash column chromatography and eluted at 35% EtOAc/ pet ether to afford the title compound (0.6 g, 44%) as an off white solid.
  • Step b 3-(1H-Pyrazol-1-yl)propan-1 -amine hydrochloride
  • step a To a stirred solution of of the compound obtained in the previous section, step a, (5 g, 41.27 mmol) in methanol (15 mL) was added a suspension of Raney-Nickel (1 g, wet) in methanol (15 mL) and then 25% NH4OH solution (5 mL) was added.
  • the reaction mixture was hydrogenated at 75 psi for 8h.
  • the reaction mixture was then filtered through the Celite, the filtrate was evaporated to remove methanol.
  • Step c W-(3-(1 H-Pyrazol-1 -yi)propyl)-5-bromopyrazin-2-arnine
  • step c (1.5 g, 5.319 mmol) in ACN (15 mL), TEA (2.2 mL, 15.95 mmol), Boc 2 0 (1.73 g, 7.97 mmol) and DMAP (0.12 g, 1.06 mmol) were added at 0 °C.
  • the reaction mixture was allowed to stir at RT for 16h.
  • the reaction mixture was concentrated; the residue was partitioned between EtOAc (100 mL) and water (100 mL).
  • the organic layer was washed with brine (30 mL), dried over anhydrous NazSO ⁇ filtered and the filtrate was concentrated.
  • the crude compound was purified by column chromatography using silica gel and the product was eluted with 20% EtOAc/pet ether to afford the title compound (1.2 g, 54%) as a pale yellow liquid.
  • Step b 3-((6-Bromopyridin-3-yl)methoxy)-N,W-diethylpropan-1 -amine
  • Step b W,Af-Diethyl-2-(1W-pyrazol-4-yl)ethan-1 -amine hydrochloride
  • step a To a solution of the compound obtained in the previous section, step a, (2.3 g, 17.69 mmol) in water (10 mL) was added diethyl amine (12.91 g, 176.9 mmol) and heated to 60°C for 16h. The reaction mixture was cooled to RT and concentrated under reduced pressure to the title compound (2.8 g, 94%) as a gummy.
  • step b To a solution of the compound obtained in the previous section, step b (2.8 g, 17.96 mmol) in DMSO (20 mL) was added 2-bromo-5-fluoropyridine (6.286 g, 35.92 mmol) and K2CO3 (7.435 g, 53.88 mmol), heated to 90°C for 16h The reaction mixture was cooled to rt, diluted with EtOAc (100 mL) and water (100 mL); the separated organic layer was washed with water (100 mL) and brine solution (100 mL) and dried the organic layer over anhydrous Na2S0 , filtered and concentrated.
  • 2-bromo-5-fluoropyridine 6.286 g, 35.92 mmol
  • K2CO3 7.435 g, 53.88 mmol
  • step a To a stirred solution of the compound obtained in the previous section, step a, (1.3 g, 4.54 mmol) in DCM (5 mL) was added TFA (3 mL) at 0°C and allowed to stir at RT for 3 h. The reaction mixture was concentrated and the residue was washed with n-pentane and diethyl ether. The obtained compound was dissolved in water and basified to pH-8 using saturated NaHC03 solution and the precipitated solid was filtered, washed with water and dried to afford the title compound (0.9 g, 66%) as a free base.
  • Step c Tert-butyl (3-((6-bromopyridin-3-yl)(methyl)amino)-3-oxopropyl)carbamate
  • step b To a stirred solution of the compound obtained in the previous section, step b, (450 mg, 2.41 mmol) and 3-(tert- butoxycarbonylamino) propanoic acid (457 mg, 2.41 mmol) in DCM (10 mL) was added Eh (1.7 mL, 12.09 mmol) and T3P (2.3 g, 7.25 mmol) at RT. The reaction mixture was stirred at RT for 16h. The reaction mixture was diluted with DCM (20 mL) and water (20 mL). Separated the organic layer, washed with water (20 mL), brine solution (10 mL) and dried over anhydrous Na?SC>4 and concentrated. The crude compound was purified by flash column chromatography and eluted at 50% EtOAc/Pet Ether to afford the title compound (0.3 g, 35%) as a white solid.
  • Step b N-(6-Bromopyridin-3-yl)-3-(ethyl (phenethyl) amino) propanamide
  • step a (2.0 g, 5.763 mmol, HCI salt) in MeOH (30 mL) was added acetaldehyde (2.5 g, 57.636 mmol), 4 ⁇ molecular sieves (2.0 g) and acetic acid (2 mL) at 0°C and stirred for 30 minutes at the same temperature.
  • NaCNBH 3 (0.905 g, 14.409 mmol) was added to the above reaction mixture and allowed to stir at rt for 16h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, basified to pH ⁇ 8 using saturated NaHCCb solution and filtered through Celite pad.
  • Step b N-(3-(1 H-Pyrazo!-1 -yl)propyl)-6-bromo-N-methylpyridin-3-amine
  • step a 750 mg, 1.0 equiv) in MeOH was added paraformaldehyde (10 equiv), molecular sieves and catalytic acetic acid at 0°C and stirred for 30 minutes at the same temperature, followed by added NaCNBH?..(2.5 equiv) and allowed to stir at rt fr 16h and the progress of the reaction was monitored by LCMS.
  • the reaction mixture was concentrated under reduced pressure and the residue was dissolved in water and basified to pH ⁇ 8 using saturated NaHCOj solution, filtered through Celite pad.
  • the separated aqueous layer was extracted with EtOAc (2 x 100 mL) and the combined organic layer was dried over anhydrous feSO ⁇ filtered and concentrated under reduced pressure to afford 700 mg of the title compound (89.5 % yield).
  • LCMS indicates that 50 % of desired product formation.
  • the reaction mixture was diluted with cold water and extracted with EtOAc (2 x 100 mL) and washed with water and brine solution. The separated organic layer was dried over anhydrous Na 2 S04, filtered and filtrate was concentrated under reduced pressure to afford 16 g of crude.
  • the crude was purified by column chromatography using 10 % EtOAc/ pet-ether on 100-200 silica to afford 9 g (63.7 % yield) of the title compound, as a light brown gummy liquid.
  • Step b 4-(6-Methoxypyridin-3-yl)butan-1-ol
  • step a (9 g, 1 equiv) and 10% Pd/C (30% w/w) in MeOH (10 ml) was under 80 psi pressure in par hydrogenated for 10 h.
  • the reaction mixture was filtered through Celite pad and washed with MeOH (5 mL).
  • the filtrate was concentrated under reduced pressure to afford 8 g (86.9 % yield) of the title compound, as a light brown gummy liquid.
  • step c (2 g, 1.0 equiv) in THF (1 mL), diethyl amine (5,0 equiv) was added and allowed to stir at RT. The reaction was concentrated under reduced pressure to get 2.3 g the crude compound 8, as a gummy solid. Purified by column chromatography using, 230-400 silica with 8% MeOH/DCM to afford 1.7 g (87.3 % yield) of the title compound .
  • Step b 2-([1 ,1 '-Biphenyl]-4-yl)-N-(6-bromopyridin-3-yl)-A/-butylacetamide
  • step a (2 g, 8.72 mmol) and 2-(biphenyl-4- yl)acetic acid (2.2 g, 10.47 mmol) in DCM (20 mL), T 3 P (8.3 mL, 26.18 mmol) and TEA (6 mL, 43.64 mmol) were added at 0°C and allowed to stir at RT for 16h.
  • the reaction mixture was poured into cold water (30 mL), extracted with EtOAc (2 x 50 mL) and washed with brine solution (30 mL). The separated organic layers were dried over anhydrous Na?SO,, filtered and concentrated under reduced pressure to get crude compound that was purified by column chromatography with 15 % EtOAc/ pet-ether to afford 1.9 g (51 %) of of the title compound.
  • terf-butyl (6-bromopyridin-3-yl)(3-(4,4-difiuoropiperidin-1-yi)propyl)carbamate
  • Tert-butyl (6-bromopyridin-3-yl)(3-chloropropyl)carbamate
  • 60%NaH 0.529 g, 22.05 mmol
  • Step b N-(6-Bromopyridin-3-yl)-W-(3-(4,4-difluoropiperidin-1-yl)propyl)butyramide
  • step a (1.1g,3.303mmol) in DCM(15ml), TEA (2.3ml,13.21 mmol) and butyryl chloride (0.65ml,6.606mmol) were added at OX and allowed to stir at RT for 16h.
  • the reaction mixture was diluted with DCM, washed with water, and the separated organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure.
  • the crude compound was purified by silica gel column chromatography and eluted at 15% EtOAc in pet ether to afford the title compound (1.00g, 81.8%) as a yellow gummy.
  • Step c 6-Bromo-W-butyl-W-(3-(4,4-difluoropiperidin-1 -yj)propyl)pyridin-3-amine
  • step b (0.990g, 2.23mmol) in THF(15ml)
  • BH3.DMS (3.34ml,6.69mmol) was added at 0°C and heated at 75°C for 16h.
  • the reaction mixture was concentrated under reduced pressure. MeOH was added to the reaction mixture and stirred at 65°C for 2h and evaporated to dryness.
  • the crude compound was purified by silica gel column chromatography and eluted at 10% EtOAc in pet ether to afford the title compound as a green gummy.

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Abstract

The invention relates to heteroaryl-carboxylic acids 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

HETEROARYL-CARBOXYLIC ACIDS AS HISTONE DEMETHYLASE INHIBITORS
TECHNICAL FIELD
The invention relates to compounds, particularly heteroaryl-carboxyiic acids and derivatives thereof as described herein, 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 histories 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(ll)-dependent 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.
WO2010/043866 discloses 4-carboxy-2,2'-bipyridine derivatives as histone demethylase inhibitors of the JMJD2 (also known as KDM4) subfamily, in particular JMJD2E (KDM4E). These compounds all have an amido or ester subsb'tuent (on the second pyridine ring) linked to the bipyridine moiety via the carbonyl group. This amido or ester substituent is always placed at position 4' of the bipyridine, i.e. at para position relative to the N atom of the second pyridine ring.
US2016/0068507 discloses inhibitors of histone demethylases of the JMJD2 and JARID1 families based on disubstituted pyridine compounds bearing at the 4-position a carboxy group and at the 2-position a substituted 1-pyrazolyl group. The pyrazolyl group is always attached via its N1 ring atom to the pyridine ring.
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 imgf000003_0001
(I)
wherein
Z\ Z2, and Z3 are each independently selected from CR4 and N, and Z4 and Z5 are each independently selected from CR2 and N, with the proviso that only one of Z1, Z2, Z3, Z4 and Z5 can be N;
R1 is selected from hydrogen, Cu, alkyl, Cu haloalkyl, -(Ci.6 alkylene)-OR-\ -(Ci.6 alky!ene)-NR6R7, -LA carbocyclyl, -L3-aryl -LAheterocyclyl and -LAheteroaryl, wherein the carbocyclyl in -lAcarbocyclyl, the aryl in - lAaryl, the heterocyclyl in -L3-heterocyclyl and the heteroaryl in -L3-heteroaryi are each optionally substituted with one or more R8,
each R2 is independently selected from hydrogen, halo, Ci-e alkyl, C1-6 haloalkyl, Ci e alkoxy, Ci-s hydroxyalkyi, - OH and -NH2;
each R4 is independently selected from hydrogen and halo;
Y is selected from -NR9C(=0)-, -NR1S -0-, -R11- and -CH2-, wherein said -NR9C(=0)- is linked to -(L%- via the NR9 group and to -(L2)n-R3 via the C(=0) group;
L' is Ci 4 alkylene, C2-4 alkenylene or C2-4 alkynylene, wherein said C1-4 alkylene, said C? 4 alkenylene and said C24 alkynylene are optionally interrupted by 0, S or NR10, and wherein said Cu alkylene, said C2.4 alkenylene and said C24 alkynylene are optionally substituted with one or more R12;
L2 is C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene, wherein said C1-6 alkylene, said C2-6 alkenylene and said C2.6 alkynylene are optionally interrupted by 0, S or NR10, and wherein said C%6 alkylene, said Cn alkenylene and said C2-6 alkynylene are optionally substituted with one or more R12;
m and n are each independently selected from 0 and 1 ;
R3 is selected from -NR13R14 , -OR15 and R16;
R6 and R7 are each independently selected from hydrogen and C1-6 alkyl, or R6 and R7 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 substituents independently selected from halo, 0-6 alkyl, -OH, -NH?, -NH(C,.6 alkyl), and -N(0 6 alkyl)2;
each L3 is independently selected from a bond and 0.4 alkyiene;
Rs and R,0are each independently selected from hydrogen, 0.6 alkyl and Ο ε haloalkyl;
-R11- is a biradical of a 5-membered heteroaryl ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S with the proviso that at least one is a N atom, and wherein -R'1- is linked to -(L1)m- and -(L2)n- R3 in a 1,3-disposition;
each R12 is independently selected from 0.6 alkyl, halo, 0-6 haloalkyl, -L3-carbocyclyl, - LAary i ,-L3-heierocyclyl and -LAheteroaryl, wherein the carbocyclyl in -L3-carbocyclyl, the aryl in -L3-aryl, the heterocyclyl in -LA heterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R1?, and wherein two groups R12 attached to a same C atom of the alkyiene, alkenylene or alkynylene group are optionally linked together to form with said C atom a C3-6 cycioalkyl group or a saturated 4- to 6-membered monocyclic heterocyclic ring containing 1 heteroatom selected from N, 0 and S, wherein said C3-6 cycioalkyl and 4- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from halo and 0.5 alkyl;
R13, R14and R15 are each independently selected from hydrogen, 0.6 alkyl, 0-6 haloalkyl, -(0-6 alkylene)-OR18, -LAcarbocyclyl, -L3-aryl,-L3-heterocycly! and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocycly!, the aryl in -LAaryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are optionally substituted with one or more R1S;
R15 is selected from O s alkyl, carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein said alkyl is optionally substituted with one or more R20 and said carbocyclyl, said aryl, said heterocyclyl and said heteroaryl are each optionally substituted with one or more R21;
each R20 is independently selected from halo, 0_6 alkoxy, 0_6 haloalkoxy, -OH, -NH2, -NH(d 6 alkyl), -N(0.s alkyl)2, -CN, -C(=0)R22, -C(=0)NR23R24, -NR23C(=0)R22, -NR23C(=0)NR23R24, -NR23S02R22, -S02NR?3R24 and - S02R22;
each R21 is independently selected from Ο.δ alkyl, 0.6 haloalkyl, halo, O s alkoxy, 0-6 haloalkoxy, -OH, -NH¾ - NH(C1-6 alkyl), -N(C, e- alkyl)2, -CN, -C(=0)R22, -C(=0)NR23R24 -NR23C(=0)R22, -NR23C(=0)NR23R24, - NR23SO?R22, -S02NR23R24, -SO2R22, -(0.6 aikylene)-OR25, -(0.s alkylene)-NR¾R2?, -LAcarbocyclyl, -LAaryl,- LAheterocyclyl and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are optionally substituted with one or more R28;
each R8, each R1', each R19 and each R28 is independently selected from 0 $ alkyl, 0-6 haloalkyl, halo, 0-s alkoxy, O e haloalkoxy, -OH, -NH¾ -NH(0.5 alkyl), -N(O s alkyl)2, -CN, -C(=0)R22, -C(=0)NR23R24, - NR23C(=0)R22, -NR23C(=0)NR23R24, -NR23S02R22, -S02NR23R24 and -S02R22;
each R22 is independently selected from Cn alkyl; and each R5, each R18, each R23, each R24, each R25, each R25 and each R27 is independently selected from hydrogen and C1-5 alky I.
The compounds of Formula (I) as described herein are inhibitors of JmjC-KDMs, e.g. KDM5 or KDM4 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 and/or KDM4-mediated disease. For example, the disease may be 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.
The 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 imgf000006_0001
(I)
wherein
Z\ 72, and Z3 are each independently selected from CR4 and N, and Z4 and Z5 are each independently selected from CR2 and N, with the proviso that only one of Z1 , Z2, Z3, Z4 and Z5 can be N;
R1 is selected from hydrogen, d-s alkyl, Cu haloalkyl, -(Ci-6 alkylene)-OR5, -(C« alkylene)-NR3R7, -LA carbocyclyl, -LAaryl -LAheterocyclyl and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in - LAaryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -L3-heteroaryl are each optionally substituted with one or more R8,
each R2 is independently selected from hydrogen, halo, Cu a!kyl, Ci-e haloalkyl, Ci-e alkoxy, Ci e hydroxyalkyl, - OH and -NH2;
each R4 is independently selected from hydrogen and halo; Y is selected from -NR9C(=0)-, -NR10-, -0-, -R11- and -CH2-, wherein said -NR9C(=0)- is linked to -(L%- via the NR9 group and to -{L2)N-R3 via the C(=0) group;
L1 is Ci-4 alkylene, C2-4 alkenylene or CM alkynylene, wherein said Cu alkylene, said C24 alkenylene and said C2-4 alkynylene are optionally interrupted by 0, S or NR10, and wherein said Cu alkylene, said C24 alkenylene and said C24 alkynylene are optionally substituted with one or more R12;
L2 is C1-6 alkylene, C2-6 alkenylene or C? e alkynylene, wherein said Cu alkylene, said C?.e a!kenyiene and said C2-6 alkynylene are optionally interrupted by 0, S or NR10, and wherein said Cu alkylene, said C2.5 alkenylene and said C2-6 alkynylene are optionally substituted with one or more R12;
m and n are each independently selected from 0 and 1 ;
R3 is selected from -NR,3RU , -OR15 and R16;
R6 and R7 are each independently selected from hydrogen and Cvs alkyl, or R6 and R7 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 substituents independently selected from halo, Ci-s alkyl, -OH, -NH2, -NH(Ci 6 alkyl), and -N(d.$ alkyi)2;
each L3 is independently selected from a bond and Cu alkylene;
R9 and R10 are each independently selected from hydrogen, C1-6 alkyl and Ci s haloalky!;
-R11- is a biradical of a 5-membered heteroaryl ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S with the proviso that at least one is a N atom, and wherein -Rn- is linked to -(L1}m- and -(L2)n- R3 in a 1 ,3-disposition;
each R12 is independently selected from C1-5 alkyl, halo, Ci-¾ haloalkyl, -L3-carbocyclyl, -L3-aryl,-L3-heterocyclyi and -L3-heteroaryl, wherein the carbocyclyl in -L3-carbocyclyl, the aryl in -LAaryl, the heterocyclyl in -L3- heterocyclyl and the heteroaryl in -lAheteroaryl are each optionally substituted with one or more R17, and wherein two groups R12 attached to a same C atom of the alkylene, alkenylene or alkynylene group are optionally linked together to form with said C atom a C3-6 cycloalkyl group or a saturated 4- to 6-membered monocyclic heterocyclic ring containing 1 heteroatom selected from N, 0 and S, wherein said C3-6 cycloalkyl and 4- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from halo and Cu alkyl;
R13, R14and R15 are each independently selected from hydrogen, Cu alkyl, C-, 6 haloalkyl, -(d.e alkylene)-OR18, -LAcarbocyclyl, -LAaryl -LAheterocyclyi and -lAheteroary!, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyl in -LAheterocyc!yl and the heteroaryl in -LAheteroaryl are optionally substituted with one or more R1S;
R16 is selected from d-6 alkyl, carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein said alkyl is optionally substituted with one or more R20 and said carbocyclyl, said aryl, said heterocyclyl and said heteroaryl are each optionally substituted with one or more R21; each R20 is independently selected from halo, C1.5 alkoxy, Cu haloalkoxy, -OH, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 alkyl)?, -CN, -C(=0)R22, -C(=0)NR23R24, -NR23C(=0)R22, -NR23C(=0)NR23R24, -NR23S02R22, -S02NR23R24 and - S02R22;
each R21 is independently selected from Ci-6 alkyl, Ci-s haloalkyl, halo, Ci-e alkoxy, C1-6 haloalkoxy, -OH, -NH2, - NH(C,-6 alkyl), -N(0.6 alkyl)2, -CN, -C(=0)R22, -C(=0)NR23R24, -NR23C(=0)R22, -NR23C(=0)NR23R24, - NR23S02R22, ~S02NR23R24, -S02R22, -(Ci.6 alkylene)-OR25, -<C1 6 alkylene)-NR26R27, -L3-carbocyclyl, -L3-aryl - L3-heterocycly! and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -LAaryl. the heterocyclyl in -lAheterocyclyl and the heteroaryl in -L3-heteroaryl are optionally substituted with one or more each R8, each R17, each R19 and each R28 is independently selected from Ci-e alkyl, Ci-6 haloalkyl, halo, Ci-e alkoxy, C-.6 haloalkoxy, -OH, -NH2, -NH(Ci 6 alkyl), -N(Ci 3 alkyl)2, -CN, -C(=0)R22, -C(=0)NR«R¾, -
NR23C(=0)R22 -NR23C(=0)NR23R24, -NR23S02R22, -S02NR23R24 and -S02R22;
each R22 is independently selected from Ci ε alkyl; and
each R5, each R18, each R23, each R24, each R25, each R26 and each R27 is independently selected from hydrogen and Ci-6 alkyl.
Compounds of this invention include those described above, and are further illustrated by the classes, subclasses, and species disclosed herein.
Embodiments of the present invention are outlined in the following paragraphs. It should be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination with any other embodiments described herein in a single embodiment.
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), Z1, Z2, and Z3 are each independently selected from CR4 and N, and Z4 and Z5 are each independently selected from CR2 and N, with the proviso that only one of Z1, Z2, Z3, Z4 and Z5 can be N. Thus, in a compound of Formula (I) either all of Z1, Z2, Z3, Z4 and Z5 are carbon atoms (CR4 in the case of Z\ Z2 and Z3, and CR2 in the case of Z4 and Z5) or one of Z1, Z2, Z3, Z4 and Z5 is a nitrogen atom and the remaining of Z1, Z2, Z3, Z4 and Z5 are carbon atoms (CR4 in the case of Z\ Z? and Z3, and CR2 in the case
Figure imgf000009_0001
One subset of the compounds of Formula (I) includes those of Formula (II):
Figure imgf000010_0001
(II)
A compound of Formula (II) corresponds to compounds of Formula (la), (lb) and (lc) as previously defined.
The present invention relates to a compound of any of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II) as defined herein, or any salt thereof.
Preferably, the compound of Formula (I) is a compound of Formula (II), or a salt thereof.
In some embodiments, the compound of Formula (II) is a compound of Formula (la), or a salt thereof.
In some embodiments, the compound of Formula (II) is a compound of Formula (lb), or a salt thereof.
In some embodiments, the compound of Formula (II) is a compound of Formula (lc), or a salt thereof.
More preferably, the compound of Formula (I) or (II) is a compound of Formula (la) or (lb), or a salt thereof. Still more preferably, the compound of Formula (I) or (II) is a compound of Formula (la). Accordingly, while various embodiments described herein below relate to a compound of Formula (I), (la), (lb), (lc), (Id), (le), (!f) or (II), it is particularly preferred that the compound specified in each one of these embodiments is a compound of Formula (la) or (lb), or a salt thereof, and it is even more preferred that the respective compound is a compound of Formula (la) or a salt thereof.
The compounds of the invention include carboxylic acids, when in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II) R1 is hydrogen, and esters thereof, when in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (if) or (II) R1 is selected from Ci_6 alkyl, Cu haloalkyl, -(Ci.6 alkylene)-OR5, -(C,.6 alkylene)-NR5R7, -LAcarbocyclyl, -LAaryl -LAheterocyclyl and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R8. Said esters can be used as prodrugs of the corresponding carboxylic acids (i.e. a compound wherein Rf is hydrogen). In addition, certain esters exhibit JmjC-KDM inhibitory activity perse.
Preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), R1 is hydrogen, Ci e alkyl or Ci.6 haloalkyl.
More preferably, in a compound of Formula (I) (la), (lb), (lc), (Id), (le), (If) or (II), R1 is hydrogen or C1.4 alkyl, still more preferably hydrogen, methyl or ethyl.
Even more preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), R1 is hydrogen. In some embodiments, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), each R2 is independently selected from hydrogen, halo, Ci 3 alkyl, C1.3 haloalkyl and C1-3 hydroxya!kyl.
In some embodiments, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), one of the groups R2 is selected from hydrogen, halo, C1.3 alkyl, C1.3 haloalkyl and C1-3 hydroxyalkyl, and the remaining groups R2 are hydrogen.
In some embodiments, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), one of the groups R2 is selected from hydrogen, fluoro, methyl, trifluoromethyl and -CH2OH, and the remaining groups R2 are hydrogen.
Preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), each R2 is hydrogen. More preferably, in a compound of Formula (!), (la), (lb), (Ic), (Id), (le), (If) or (II):
R1 is hydrogen, d-e alkyl or C1-6 haloalkyl, preferably hydrogen or C1-4 alkyl, more preferably hydrogen, methyl or ethyl, and still more preferably hydrogen; and
each R2 is hydrogen
In some embodiments, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), one of the groups R4 is selected from hydrogen and fluoro, and the remaining groups R4 are hydrogen.
Preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), each R4 is hydrogen. More preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), each R2 and each R4 is hydrogen.
In some embodiments, in a compound of Formula (I), (la), (lb), (Ic), (id), (le), (If) or (II), L1 is CM alkylene, wherein said C1.4 alkylene is optionally interrupted by 0, S or NR10, and wherein said Cu alkylene is optionally substituted with one or more R'2.
In some embodiments, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), L1 is (CH2)i-4, wherein said (CH2)i-4 is optionally substituted with one or more (preferably one or two) R12.
Preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), L1 is (CH2)i.?, wherein said (CH2>i 2 is optionally substituted with one or more (preferably one or two) R12.
More preferably, in a compound of Formula (I), (la), (lb), (Ic), (id), (le), (If) or (II), U is (CH2)i-2, and still more preferably SJ is CH2.
In some embodiments, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), L2 is Cu alkylene, wherein said C1 6 alkylene is optionally interrupted by 0, S or NR10, and wherein said C1-6 alkylene is optionally substituted with one or more R12.
In some embodiments, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), L2 is (CH2)i s, wherein said (CH2)i-s is optionally substituted with one or more (preferably one or two) R12.
Preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), L2 is (CH2)i-4, wherein said (CH2)i-4 is optionally substituted with one or more (preferably one or two) R12. More preferably, L2 is (CH2)i-4.
Preferably, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), m is selected from 0 and 1, and n is 1. In some preferred embodiments, m is 0 and n is 1. More preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (Ie), (If) or (II), m is selected from 0 and 1 ; L1 is (CH2)i-2, preferably CH2; n is 1 ; and L2 is (CH2)i_4 wherein said (CH2)i 4 is optionally substituted with one or more (preferably one or two) R12, and preferably L2 is (CH2)i 4.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), when Y is - NR10- or -0- and R3 is -NR13R14, -OR15 or N-linked-R16, n is 1 and L2 is C2 6 alkylene (preferably (CH2)2-6), wherein said C2 s alkylene (or said (CH2)2-6) is optionally interrupted by 0, S or NR10, and wherein said C2-6 alkylene (or said (CH2)2-6) is optionally substituted with one or more R12.
In some embodiments, in a compound of Formula (I), (ia), (lb), (lc), (Id), (le), (If) or (II), when Y is - NR10- or -0- and R3 is -NR13R14, -OR15 or N-iinked-R16, n is 1 and L2 is (CH2)2.S (preferably (CH2)2-4), wherein said (CH2)2-5 (or said (CH2)2.4) is optionally substituted with one or more R12.
In a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), the C1.4 alkylene, C2.4 alkenylene and C2-4 alkynylene in L1 and the Cu alkylene, Cn alkenylene and C2-6 alkynylene in L2 can be optionally substituted with one or more R12, As defined above, each R12 is independently selected from d-e aikyi, halo, Ci. s haloalkyl, -lAcarbocyclyl, -L3-aryl, -L3-heterocyclyl and -L3-heteroaryl, wherein the carbocyclyl in -LA carbocyclyl, the aryl in -IAaryl, the heterocyclyl in -L3-heterocyclyl and the heteroaryl in -L3-heteroaryl are each optionally substituted with one or more R17. Moreover, two groups R12 attached to a same C atom of the alkylene, alkenylene or alkynylene group can be optionally linked together to form with said C atom a C3-6 cycloalkyi group or a saturated 4- to 6-membered monocyclic heterocyclic ring containing 1 heteroatom selected from N, 0 and S, wherein said Cu cycloalkyi and 4- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from halo and C1-6 alkyl. Examples of said C3-6 cycloalkyi or 4- to 6-membered heterocyclic ring formed by said two R12 groups attached to a same C atom together with said C atom, are shown below:
Figure imgf000012_0001
wherein each ring depicted above can be optionally substituted with one or more substituents independently selected from halo and C1 6 alkyl. In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), each R12 is independently selected from Ci .3 alkyl and -LAaryl, wherein the aryi in -LAaryl is optionally substituted with one or more R17. Preferably, said aryi is phenyl optionally substituted with one or more R17.
In a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), -R11- is a bi radical of a 5-membered heteroaryl ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S with the proviso that at least one is a N atom, and wherein -R11- is linked to the -(L1)m- and -(L2)n-R3 group in a 1 , 3-d is position. Examples of such -R11- groups are shown in Table 1 , below.
Table 1:
Figure imgf000013_0001
wherein unless specified otherwise, these groups can be read in each of the two possible orientations, i.e. they can be linked to L1 through the point of attachment shown on the left side in the above drawings and to L2 through the point of attachment shown on the right side in the above drawings, or the other way around.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (if) or (II), -R11- is a group selected from Table 1. In some embodiments, -R11- is
Figure imgf000013_0002
Preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is selected from -NR9C(=0)-, -NR10-, -0- and -CH2-.
More preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is selected from -NR10-, -0- and -CH2-.
In some preferred embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is
-0-.
In other preferred embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is
-CH2-.
In other preferred embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is -NR10-.
In some other embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is -NR9C(=0)-. In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is selected from -NR9C(=0)-, -NR10-, -0-, -R11- and -CH2-, wherein said -NR9C(=0)- is linked to -(L1)m- via the NR9 group and to -(L2)n-R3 via the C(=0) group; m and n are each independently selected from 0 and 1 ; L1 is (CH2)i-4, wherein said (CH2)i /. is optionally substituted with one or more (preferably one or two) R12; and L2 is (CH2)i-6, wherein said (CH2)i s is optionally substituted with one or more (preferably one or two) R12; with the proviso that when Y is -NR10- or -0- and R3 is -NR13R14, -OR15 or N-linked-R15, then n is 1 and L2 is (CH2)2-6, wherein said (CH2)2.6 is optionally substituted with one or more (preferably one or two) R12.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is selected from -NR9C(=0)-, -NR10-, -0-, -R11- and -CH2-, wherein said -NR9C(=0)- is linked to -(L1)m- via the NR9 group and to -(L2)n-R3 via the C(=0) group; m and n are each independently selected from 0 and 1 ; U is (CH 2)1-2; and L2 is (CH2)1-,6 wherein said (CH2)i e is optionally substituted with one or more (preferably one or two) R12; with the proviso that when Y is -NR10- or -0- and R3 is -NR13R14, -OR15 or N-linked-R16, then n is 1 and L2 is (CH2)2.5, wherein said (CH2)2-6 is optionally substituted with one or more (preferably one or two) R12.
Preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is selected from -
NRsC(=0)-, -NR10-, -0-, -R11- and -CH2-, wherein said -NR9C(=0)- is linked to -(L1)m- via the NR9 group and to -(L2)„-R3 via the C(=0) group; m is selected from 0 and 1 ; n is 1 ; L1 is (CH2)i 2; and L2 is (CH2)i-6, wherein said (CHj)i 5 is optionally substituted with one or more (preferably one or two) R12; with the proviso that when Y is - NR10- or -0- and R3 is -NR13R14, -OR15 or N-linked-R15, then L2 is (CH2)2-S, wherein said (CH2)2.6 is optionally substituted with one or more (preferably one or two) R12,
More preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is selected from - NR10-, -0- and -CH2-; m is selected from 0 and 1 ; n is 1 ; L1 is (CH2)i-4, wherein said (CH2)i-4 is optionally substituted with one or more (preferably one or two) R1?; and L2 is (CH2)i-6, wherein said (CH2)i-6 is optionally substituted with one or more (preferably one or two) R12, with the proviso that when Y is -NR10- or -0- and R3 is -NR13R14, -OR15 or N-linked-R16, then L2 is (CH2)2.6, wherein said (CH2)2 6 is optionally substituted with one or more (preferably one or two) R12. Still more preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), Y is selected from -NR10-, -0- and -CH2-; m is selected from 0 and 1 ; n is 1 ; U is (CH2)i-¾ and L2 is (CH2)i-6, wherein said (Ch½)i-6 is optionally substituted with one or more (preferably one or two) R12, with the proviso that when Y is - NR10- or -0- and R3 is -NR13R14, -OR15 or N-!inked-R16, then L2 is (CH2)2.6, wherein said (CH2)2 6 is optionally substituted with one or more (preferably one or two) R12.
A particularly preferred group of compounds of Formula (I) are those compounds of Formula (II), and preferably of Formula (la) or (lb), wherein: Y is selected from -NR10-, -0- and -CH2-; m is selected from 0 and 1 ; n is 1 ; U is (CH2)i 2, preferably CH2; and L2 is (CH2)i , wherein said (CH2)i-4 is optionally substituted with one or more (preferably one or two) R12, and preferably L2 is (CH2)i 4. In some preferred embodiments, m is 0.
Even more preferred compounds of Formula (I) are those compounds of Formula (II), preferably of Formula (la) or (lb), wherein: Y is selected from -NR10-, -0- and -CH2-; m is selected from 0 and 1 with the proviso that when m is 1 then Y is -0-; n is 1 ; L1 is CH2; and L2 is (CH2)i 4, wherein said (CH2)I.H is optionally substituted with one or more (preferably one or two) R12, and preferably L2 is (CH2)u. In some preferred embodiments, m is 0.
While each of SJ, L2, Y, m and n have the meanings, including the preferred meanings defined for each of these groups, as described herein, exemplary illustrative values for the group -(L1)m-Y-(L2)n- in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II) are provided in Table 2, below:
Table 2:
Figure imgf000016_0001
wherein any aikylene depicted in the above groups can be optionally substituted with one or more (preferably one or two) R12 as defined above. Examples of groups in table 2 wherein such aikylene groups are substituted with one or more R12 are provided in Table 3 below:
Figure imgf000017_0001
In some embodiments, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), -(L1)m-Y-(L2)n- is selected from the groups listed in Table 2 or Table 3.
In some embodiments, in the groups listed in Table 2 or Table 3, R9 is hydrogen and R,A is hydrogen. In some embodiments, in the groups listed in Table 2 and Table 3, R9 is C-,s alkyl. In some embodiments, in the groups listed in Table 2 and Table 3, R10 is CLS alkyl.
The specific divalent groups -(L1)m-Y-(L2)n- shown in Tables 2 and 3 and in the embodiments below are to be read in same orientation as shown in the chemical drawings, i.e. they are linked via the left end to the bis-heteroaryl core and via the right end to R3.
In a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), R3 is selected from -NR13R14 , -OR15 and R16.
In some embodiments, in a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If) or (II), R3 is -NR1SRU. Preferably, R13 and R14 are each independently selected from hydrogen, Ci-s alkyl, C1-6 haloalkyl, -LA C3-7 cyc!oalkyl, -L3-aryl and -LAheteroaryl, wherein the C3-7 cycloalkyl in -L3-C3-7 cycloalkyi, the ary! in -L3-aryl, and the heteroaryl in -L3-heteroaryl are optionally substituted with one or more R19; and more preferably R13 and R14 are each independently selected from hydrogen, C« alky! and -LApheny!, wherein the phenyl in -LA phenyl is optionally substituted with one or more R19.
Preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (Ie), (If) or (II), R3 is selected from -OR15 and R16,
More preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), R3 is R16.
Still more preferably, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), R3 is R16 and R15 is selected from C1.5 alkyl, C3-7 cycloalkyl, aryl (preferably phenyl), heterocyclyl and heteroaryl, wherein said Cn alkyl is optionally substituted with one or more R20 and wherein said C3-7 cycloalkyl, said aryl, said phenyl, said heterocyclyl and said heteroaryl are each optionally substituted with one or more R21.
In some preferred embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (li), R3 is R16 and R16 is selected from C3.7 cycloalkyl, phenyl, heterocyclyl and heteroaryl, wherein said C3-7 cycloalkyl, said phenyl, said heterocyclyl and said heteroaryl are each optionally substituted with one or more R21.
in some particularly preferred embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), R3 is R16 and R16 is aryl, preferably phenyl, wherein said aryl or said phenyl is optionally substituted with one or more R21. Preferably, if present, each R21 is independently selected from halo, alkyl, C1.6 haloalkyl and -LAaryl (wherein the aryl in -LAaryl is preferably phenyl, and wherein the aryl in -LAaryl is optionally substituted with one or more R28), and more preferably each R21 is independently selected from halo and phenyl (wherein said phenyl may be optionally substituted with one or more halo). In some preferred embodiments, said R16 is phenyl optionally substituted with one or more halo. In some other preferred embodiments, said R16 is biphenyl, preferably 4-biphenyl.
In some other particularly preferred embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), R3 is R16 and R16 is C3-7 cycloalkyl, preferably cyclopropyl or cyciobutyl, wherein said C3-7 cycloalkyl (or said cyclopropyl or said cyciobutyl) is optionally substituted with one or more R21. Preferably, each R21 is independently selected from Ct-e alkyl (e.g. methyl), fr-s haloalkyl and halo. In some preferred embodiments, said R16 is cyclopropyl. .
In some other particularly preferred embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), R3 is R16 and R16 is a saturated 4- to 7-membered heterocyclic group which contains one or two heteroatoms selected from N, 0 and S, wherein R16 is optionally substituted with one or more R21. Preferably, each R21 is independently selected from C1-6 alkyl, Ci « haloalkyl and halo. More preferaby, said R15 is selected from piperidinyl, pyrrolidinyl and morpholinyl, preferably from piperidin-1-yl, pyrrolidin-1-yl and morpholin-1-yi, wherein R16 is optionally substituted with one or more R21, and wherein preferably each R21 is independently selected from d-e alkyl, C1-6 haloalkyl and halo. It is particularly preferred that said R16 is 1 -piperidinyl substituted with one or more fluoro, and more preferably 4,4-difluoropiperidin-1-yl. In some other particularly preferred embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), R3 is R16 and R13 is C1.5 alkyl, wherein said Ci e alkyl is optionally substituted with one or more R20. Preferably, each R20 is independently selected from halo. In some embodiments, said alkyl is C2-6 alkyl, which is optionally substituted with one or more R20 (preferably halo, more preferably fluoro). In some preferred embodiments, said Ci.s alkyl (or C2-6 alkyl) is unsubstituted.
In some embodiments, in a compound of Formula (I), (la), (lb), (lc), (Id), (le), (if) or (II), R3 is R16 and R16 is heteroaryl, wherein said heteroaryl is optionally substituted with one or more R21. In some embodiments, said heteroaryl is pyrazolyl (preferably pyrazol-1-yl) optionally substituted with one or more R21.
In a preferred embodiment, the invention provides a compound of Formula (I), preferably of Formula (II), more preferably of Formula (la) or (lb), or a salt thereof, wherein:
R1 is hydrogen, Ci.6 alkyl or C1-3 haloalkyl, preferably hydrogen or C1.4 alkyl, more preferably hydrogen, methyl or ethyl, and still more preferably hydrogen;
each R2 is hydrogen;
each R4 is independently selected from hydrogen and halo (preferably fluoro) and preferably each R4 is hydrogen;
Y is selected from -NR9C(=0)-, -NR10-, -0-, -R11- and -CH2-, wherein said -NR9C(=0)- is linked to -(L%- via the NR9 group and to -(L2)„-R3 via the C(=0) group;
m and n are each independently selected from 0 and 1 ;
L1 is (CH2),.?; and
L2 is (CH2)1-6, wherein said (CH2)i-6 is optionally substituted with one or more (preferably one or two) R12,
In some preferred embodiments, the invention provides a compound of Formula (I), preferably of Formula (II), more preferably of Formula (la) or (lb), or a salt thereof, wherein:
R1 is hydrogen;
each R2 and each R4 is hydrogen;
Y is selected from -NR9C(=0)-, -NR10-, -0-, -R11- and -CH2-, wherein said -NRsC(=0)- is linked to -(L%- via the NR3 group and to -(L2)n-R3 via the C(=0) group;
m and n are each independently selected from 0 and 1 ;
LJ is (CH2)i-2, wherein said (CH2)i.2 is optionally substituted with one or more (preferably one or two) R12; and
L2 is (CH2)i-6, wherein said (CH2)i-6 is optionally substituted with one or more (preferably one or two) R12; with the proviso that when Y is -NR10- or -0- and R3 is -NR13R14, -OR15 or N-linked-R16, then n is 1 and L2 is (CH2)2-6, wherein said (CH2)?.6 is optionally substituted with one or more (preferably one or two) R12.
In some preferred embodiments, the invention provides a compound of Formula (I), preferably of
Formula (II), more preferably of Formula (la) or (lb), or a salt thereof, wherein:
R1 is hydrogen;
each R2 and each R4 is hydrogen; Y is selected from -NR9C(=0)-, -NR10-, -0-, -R11- and -CHr, wherein said -NR9C(=0)- is linked to -(!_%- via the NR9 group and to -(L2)n-R3 via the C(=0) group;
m is selected from 0 and 1 ;
n is 1 ;
L1 is (CH2)i-2, wherein said (CH2)i-2 is optionally substituted with one or more (preferably one or two) R12 ; and L2 is (CH2)i-6, wherein said (CHJ)I.S is optionally substituted with one or more (preferably one or two) R12; with the proviso that when Y is -NR10- or -0- and R3 is -NR13R14 -OR15 or N-linked-R16, then n is 1 and L2 is (CH2)?*, wherein said (CH2)2-6 is optionally substituted with one or more (preferably one or two) R12.
In some other preferred embodiments, the invention provides a compound of Formula (I), preferably of Formula (II), more preferably of Formula (la) or (lb), or a salt thereof, wherein:
R1 is hydrogen;
each R2 and each R4 is hydrogen;
Y is selected from -NR9C(=0)-, -NR10-, -0-, -R11- and -CH2-, wherein said -NR9C(=0)- is linked to -(L1)m- via the NR9 group and to -(L2)n-R3 via the C(=0) group;
m and n are each independently selected from 0 and 1 ;
L1 is (CH2)i 2, wherein said (CH2)i-2 is optionally substituted with one or more (preferably one or two) R12 ;
L2 is (CH2)i-6, wherein said ((¾)ι.6 is optionally substituted with one or more (preferably one or two) R12; with the proviso that when Y is -NR10- or -0- and R3 is -OR15 or N-linked-R15, then n is 1 and L2 is (CH2)2-6, wherein said (CH2)2-6 is optionally substituted with one or more (preferably one or two) R12; and
R3 is selected from -OR15 and R16. In some embodiments, R3 is R16, wherein preferably R16 is aryl, more preferably phenyl, wherein said aryl or said phenyl is optionally substituted with one or more R21.
In some other embodiments, the invention provides a compound of Formula (I), preferably of Formula
(II), more preferably of Formula (la) or (lb) , or a salt thereof, wherein:
R1 is hydrogen;
each R2 and each R4 is hydrogen;
Y is selected from -NR9C(=0)-, -NR10-, -0-, -R11- and -CHr, wherein said -NR9C(=0)- is linked to -{!_%- via the NR9 group and to -(L2)n-R3 via the C(=0) group;
m is selected from 0 and 1 ;
n is 1 ;
L1 is (CH2)i-2, wherein said (CH2)i ? is optionally substituted with one or more (preferably one or two) R12 ; and
L2 is (CH2)i-6, wherein said (Chbji s is optionally substituted with one or more (preferably one or two) R12; with the proviso that when Y is -NR10- or -0- and R3 is -OR15 or N-linked-R16, then n is 1 and L2 is (CH2)2-6, wherein said (CH2)?6 is optionally substituted with one or more (preferably one or two) R12; and
R3 is selected from -OR15 and R16, In some embodiments, R3 is R16, wherein preferably R16 is aryl, more preferably phenyl, wherein said aryl or said phenyl is optionally substituted with one or more R21. A preferred group of compounds of the invention corresponds to those compounds of Formula (I), preferably of Formula (II), more preferably of formula (la) or (lb), or a salt thereof, wherein:
R1 is hydrogen, C1-3 alky! or Ci s haloalkyl, preferably hydrogen or CM alkyl, more preferably hydrogen, methyl or ethyl, and still more preferably hydrogen;
each R2 is hydrogen;
Y is selected from -NR10-, -0-, -CH2- and -NR9C(=0)-;
m and n are each independently selected from 0 and 1;
L1 is CH2;
Figure imgf000021_0001
R3 is R15. In one preferred embodiment, said R16 is aryl, preferably phenyl, wherein said aryl or said phenyl is optionally substituted with one or more R21 and wherein preferably, if present, said R21 is/are independently selected from halo and phenyl, and more preferably independently selected from ha!o. In another preferred embodiment, said R16 is C3-7 cycloalkyl, preferably cyclopropyl, wherein said C3-7 cycloalky! or said cyclopropyl is optionally substituted with one or more R21, and preferably said R16 is cyclopropyl. In another preferred embodiment, said R16 is a saturated 4- to 7-membered heterocyclic group which contains one or two heteroatoms selected from N, 0 and S, wherein R15 is optionally substituted with one or more R21 (preferably, each R21 is independently selected from d-e alkyl, Ci e haloalkyl and halo), wherein preferaby said R16 is selected from piperidinyl, pyrrolidinyi and morpholinyl, optionally substituted with one or more R21 (preferably each independently selected from Cn alkyl, CM haloalkyl and halo), more preferably said R16 is 1 -piperidinyl substituted with one or more fluoro, and still more preferably said R16 is 4,4-difluoropiperidin-1-yl. In still another preferred embodiment, said R16 is Cu alkyl, wherein said C1-6 alkyl is optionally substituted with one or more R2Q (wherein preferably, each R2Q is independently selected from halo), and preferably said R16 is C- 6 alkyl.
A more preferred group of compounds of the invention corresponds to those compounds of Formula (I), preferably of Formula (II), more preferably of formula (la) or (lb), or a salt thereof, wherein:
R1 is hydrogen, Ct-e alkyl or C1.6 haloalkyl, preferably hydrogen or Cu alkyl, more preferably hydrogen, methyl or ethyl, and still more preferably hydrogen;
each R2 is hydrogen;
Y is selected from -NR10-, -0- and -CH2-;
m is selected from 0 and 1 , with the proviso that when m is 1 then Y is -0-;
n is 1 ;
L1 is CH2;
L2 is (CH2)u; and
R3 is R16. In one preferred embodiment, said R16 is aryl, preferably phenyl, wherein said aryl or said phenyl is optionally substituted with one or more R21 and wherein preferably, if present, said R21 is/are independently selected from halo and phenyl, and more preferably independently selected from halo. In another preferred embodiment, said R16 is C3-7 cycloalkyl, preferably cyclopropyl, wherein said C3-7 cycloalkyl or said cyclopropyl is optionaliy substituted with one or more R21, and preferably said R16 is cyciopropyl. In another preferred embodiment, said R16 is a saturated 4- to 7-membered heterocyclic group which contains one or two heteroatoms selected from N, 0 and S, wherein R16 is optionally substituted with one or more R21 (preferably, each R21 is independently selected from Ci-6 alkyl, Cu haloalkyl and halo), wherein preferaby said R16 is selected from piperidinyl, pyrrolidinyl and morpholinyl, optionally substituted with one or more R21 (preferably each independently selected from C%6 alkyl, Ci-6 haloalkyl and halo), more preferably said R1S is 1 -piperidinyl substituted with one or more fluoro and still more preferably said R16 is 4,4-difluoropiperidin-1-yl. In still another preferred embodiment, said R1S is C1-6 alkyl, wherein said Ci-s alkyl is optionally substituted with one or more R20 (wherein preferably, each R20 is independently selected from halo), and preferably said R16 is C1.5 alkyl.
An even more preferred group of compounds of the invention corresponds to those compounds of
Formula (I), preferably of Formula (II), more preferably of formula (la) or (lb), or a salt thereof, wherein:
R1 is hydrogen, CM alkyl or C1-6 haloalkyl, preferably hydrogen or C1.4 alkyl, more preferably hydrogen, methyl or ethyl, and still more preferably hydrogen;
each R2 and each R4 is hydrogen;
Y is selected from -NR10-, -0- and -CH2-;
m is selected from 0 and 1 , with the proviso that when m is 1 then Y is -0-;
n is 1 ;
U is CH2;
Figure imgf000022_0001
R3 is R16, In one preferred embodiment, said R16 is aryl, preferably phenyl, wherein said aryl or said phenyl is optionally substituted with one or more R21 and wherein preferably, if present, said R21 is/are independently selected from halo and phenyl, and more preferably independently selected from halo. In another preferred embodiment, said R16 is C3-7 cycloalkyl, preferably cyciopropyl, wherein said C3-7 cycloalkyl or said cyciopropyl is optionally substituted with one or more R21, and preferably said R16 is cyciopropyl. In another preferred embodiment, said R16 is a saturated 4- to 7-membered heterocyclic group which contains one or two heteroatoms selected from N, 0 and S, wherein R16 is optionally substituted with one or more R21 (preferably, each R21 is independently selected from CLS alkyl, Ci s haloalkyl and halo), wherein preferaby said R15 is selected from piperidinyl, pyrrolidinyl and morpholinyl, optionally substituted with one or more R21 (preferably each independently selected from C1 5 alkyl, Ci e haloalkyl and halo), more preferably said R16 is 1 -piperidinyl substituted with one or more fluoro and still more preferably said R16 is 4,4-difluoropiperidin-l-yl. In still another preferred embodiment, said R16 is Ci.g alkyl, wherein said C1.5 alkyl is optionally substituted with one or more R20 (wherein preferably, each R20 is independently selected from halo), and preferably said R16 is Ct-e alkyl.
A particularly preferred group of compounds of Formula (I) corresponds to those compounds of Formula (II), preferably of formula (la) or (lb), more preferably of formula (la), or a salt thereof, wherein: R1 is hydrogen; each R2 is hydrogen: each R4 is independently selected from hydrogen and halo (preferably fluoro) and preferably each R4 is hydrogen; Y is -NR10-; m is 0; n is 1 ; L2 is (CH2)i-4, preferably (CH2)? 3; and R3 is aryl or heteroaryl, preferably aryl, more preferably phenyl, wherein said aryl, said heteroaryl or said phenyl is optionally substituted with one or more R21, and wherein preferably, if present, said R21 is/are independently selected from halo and phenyl, and more preferably independently selected from halo. A preferred compound of Formula (I) within this group is 5'-((3-(4-chlorophenyl) propyl)amino)-[2,2'-bipyridine]-4-carboxylic acid, or a salt thereof.
Another particularly preferred group of compounds of Formula (I) corresponds to those compounds of Formula (II), preferably of formula (la) or (lb), more preferably of formula (la), or a salt thereof, wherein: R1 is hydrogen; each R2 is hydrogen; each R4 is independently selected from hydrogen and halo (preferably fluoro) and preferably each R4 is hydrogen; Y is -0-; m is 0 or 1 ; L1 is Chb; n is 1 ; L2 is (CFb)^; and R3 is aryl or heteroaryl, preferably aryl, more preferably phenyl, wherein said aryl, said heteroaryl or said phenyl is optionally substituted with one or more R21, and wherein preferably, if present, said R21 is/are independently selected from halo and phenyl, and more preferably independently selected from halo. A preferred compound of Formula (I) within this group is 5'-(benzyloxy)-[2,2'-bipyridine}-4-carboxyiic acid, or a salt thereof. Another preferred compound of Formula (I) within this group is 5'-(phenethoxymethyl)-[2,2'-bipyridine]-4-carboxylic acid, or a salt thereof.
Another particularly preferred group of compounds of Formula (I) corresponds to those compounds of Formula (II), preferably of formula (la) or (lb), more preferably of formula (la), or a salt thereof, wherein: R1 is hydrogen; each R2 is hydrogen; each R4 is independently selected from hydrogen and halo (preferably fluoro) and preferably each R4 is hydrogen; Y is selected from -NR13-, -0- and -GH2-; m is selected from 0 and 1 , with the proviso that when m is 1 then Y is -0-; L1 is CH2; n is 1 ; L2 is (CH2)M, preferably (CH2)2-3; and R3 is 1- piperidinyl substituted with one or more fluoro, preferably 4,4-difluoropiperidin-1-yl. More preferably, -(L1)m-Y- (L2)n- is a group selected from -NR^-Ch CH2Ch -, -O-CH2CH2CH2-, -CH2CH2CH2CH and -CH2-O-CH2CH2-. A preferred compound of Formula (I) within this group is 5'-(4-(4,4-difluoropiperidin-1-yl)butyl)-[2,2!-bipyridine]-4- carboxylic acid, or a salt thereof. Another preferred compound of Formula (I) within this group is 5'-(3-(4,4- difiuoropiperidin-1-yl)propoxy) 2,2'-bipyridine]-4-carboxylic acid, or a salt thereof. Another preferred compound of Formula (I) within this group is 5'-((3-(4)4-difluoropiperidin-1-y!)propyl)(methyl)amino)-[2,2'-bipyridine]-4- carboxylic acid, or a salt thereof. Another preferred compound of Formula (I) within this group is 5'-(butyl(3-(4,4- difluoropiperidin-1-yl)propyl)amino) 2,2'-bipyridine]-4-carboxylic acid, or a salt thereof. Another preferred compound of Formula (I) within this group is 5'-((2-(4,4-difluoropiperidin-1-yl)ethoxy)methyl)-[2,2'-bipyridine]-4- carboxylic acid , or a salt thereof.
Still another particularly preferred group of compounds of Formula (I) corresponds to those compounds of Formula (II), preferably of formula (la) or (lb), more preferably of formula (la), or a salt thereof, wherein: R1 is hydrogen; each R2 is hydrogen; each R4 is independently selected from hydrogen and halo (preferably fluoro) and preferably each R4 is hydrogen; Y is selected from -NR10-, -0- and -CH2-; m is selected from 0 and 1 , with the proviso that when m is 1 then Y is -0-; L1 is CH2; n is 1 ; L2 is (CH2)i ; and R3 is cyclopropyl. More preferably, m is 0 and Y is -NR10- or m is 1 and Y is -0-. A preferred compound of Formula (I) within this group is 5'-((cyclopropylmethoxy)methyl)-[2l2'-bipyridine]-4-carboxylic acid, or a salt thereof.
Another preferred compound of Formula (!) within this group is 5'-((cyclopropylmethyl)(methyl)amino)-[2,2'- bipyridine]-4-carboxylic acid, or a salt thereof. Another preferred compound of Formula (I) within this group is 5'-
((2-cyclopropylethy!)(methyl)amino)-[2,2'-bipyridine]-4-carboxylic acid, or a salt thereof.
Still another particularly preferred group of compounds of Formula (I) corresponds to those compounds of Formula (II), preferably of formula (la) or (lb), more preferably of formula (la), or a salt thereof, wherein; R1 is hydrogen; each R2 is hydrogen; each R4 is independently selected from hydrogen and halo
(preferably fiuoro) and preferably each R4 is hydrogen; Y is selected from -NR10-, -0- and -CHr and preferably is selected from -NR10- and -CH2-; m is 0; n is 1 ; U is (CH2)i-4; and R3 is Ci S alkyl, wherein said Ci-5 alkyl is optionally substituted with one or more halo. A preferred compound of Formula (I) within this group is S'-pentyl-
[2,2'-bipyridine]-4-carboxylic acid, or a salt thereof. Another preferred compound of Formula (I) within this group is 5'-(butylamino)-[2,2'-bipyridine]-4-carboxylic acid, or a salt thereof.
In another particularly preferred embodiment, the invention provides a compound of Formula (I) or a salt thereof, selected from:
5'-((3-(4-chlorophenyl) propyl)amino)-[2,2'-bipyridine]4-carboxy!ic acid,
5'-{benzyloxy)-[2 ,2-bi pyrid ine]-4-carboxy!ic acid;
5'-(phenethoxymethyl)-[2,2'-bipyridine]-4-carboxy!ic acid;
5'-(4-(4,4-difluoropiperidin-1-yi)butyl)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-(4,4-difluoropiperidin-1-yl)propoxy)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((3-(4,4-difluoropiperidin-1-yl)propyl)(methyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(butyl(3-(4,4-difluoropiperidin-1-yl)propyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((cyclopropyimethoxy)methyl)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((cyclopropylmethyl)(methyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((2-cyclopropylethyl)(methyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-pentyl-[2,2'-bipyridine]-4-carboxyiic acid;
5'-(butylamino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(N-Butyl-1 -methylcyclobutane-1 -carboxamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((3-(1 H-Pyrazol-1-yl)propyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5X4-(2-(Diethylamino)ethyl)-1H-pyrazol-1-yl)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(2-([1 , 1 !-Biphenyl]-4-yl)-N-butylacetamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(2-([1 , 1 '-Biphenyl]-4-yl)acetamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((2-(4,4-difluoropiperidin-1-yl)ethoxy)methyl)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-(Ethyl(phenethyl)amino)propoxy)-[2,2'-bipyridine]4-carboxylic acid;
5'-(3-(Ethyl(phenethyl)amino)propanamido)-(2,2'-bipyridine]-4-carboxylic acid;
5'-(3-(Diethylamino)propoxy)-[2,2'-bipyridine]-4-carboxylic acid ;
or a salt thereof. In some embodiments, the invention provides a compound of Formula (I), or a salt thereof, selected from the compounds in Table 4
Table 4:
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Among the compounds listed in Table 4, those containing a COOH group (i.e. corresponding to R1=hydrogen) are preferred.
In some embodiments, the invention provides a compound of Formula (I), or a salt thereof, selected from the compounds in Table 5:
Table 5:
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
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, heteroaryi, 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- yi, pyridin-3-yl or pyridin-4-yl ring, and the term "piperidinyl" may refer to a piperidin-1-yl, piperidin-2-yl, piperidin-3-yi or piperidin-4-y! 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 heteroaryi, 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 C1-4, C1.6, C2-6, 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 C1-6 alkyl is an alkyl having from one to six carbon atoms. Examples of Cu alkyl include, but are not limited to, methyl, ethyl, n-propyi, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, or sec-hexyl. A C1 3 alkyl is an alkyl having from one to three carbon atoms. Examples of C1.3 alkyl include methyl, ethyl, n-propyl and isopropyl.
The term " C>,z alkoxy" refers to an CfZ 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 Cu 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 Ci 3 alkoxy thus refers to an alkoxy group wherein the alkyl moiety has from 1 to 3 carbon atoms and includes methoxy, ethoxy, n-propoxy, and isopropoxy.
The term " Cy.z alkylene" refers to a saturated straight or branched divalent acyclic hydrocarbon group having from y to z carbon atoms. Thus, a 0.6 alkylene is an alkylene having from one to six carbon atoms, a C2-6 alkylene is an alkylene having from two to six carbon atoms, and a 0-4 alkylene is an alkylene having from one to four 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 6, from 2 to 6 or from 1 to 4. 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 C2-6 alkenylene is an alkenylene having from two to six carbon atoms, and a C24 alkenylene is an alkenylene having from two to four carbon atoms.
The term " Cy.z alkynylene" refers to a saturated straight or branched divalent acyclic hydrocarbon group having from y to z carbon atoms and containing one or more triple bonds. Thus, a C2-6 alkynyiene is an alkynylene having from two to six carbon atoms, and a C2-4 alkynylene is an alkynylene having from two to four 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 multicyciic (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-1 H-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. In some embodiments, 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 cycloalkyl 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, cyclopropyf, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, bicyc!o[2.2.1 jheptanyi, bicyclo[2.2.2]octanyl, decalinyl, and the like. 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 "Cy.z cycloalkyl" refers to a monocyclic cycloalkyl having from y to z ring-forming carbon atoms. A C3.7 cycloalkyl has 3 to 7 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A C3-6 cycloalkyl has from 3 to 6 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 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 C1-6 haloalkyl is a .5 alkyl which is substituted one or more times with one or more halo, and a C1.3 haloalkyl is a C1-3 alkyl which is substituted one or more times with one or more halo. Haloalkyl groups include perhaloalkyl groups, i.e. alky! groups where all hydrogen atoms are replaced by halo. Examples of haloalkyl groups include, but are not limited to, fiuoromethyl, difluoromethyi, trifluoromethyi, 2,2,2-trifluoroethyl, 1-fluoro- 2-fluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, chloromethyl, dichloromethyl, trichloromethyl difluorochloromethyl, dichlorofluoromethyl, 1 ,2-dichloroethyl, 3,3-dichloropropyl and the like. Preferably, the haloalkyl is a fluoroaikyl, i.e. an alkyl group which is substituted one or more times with one or more fluoro.
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 7 haloalkyl. A Cu haloalkoxy group thus refers to a haloalkoxy group wherein the haioaikyl 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 imidazolyi, pyridyl, quinolyl, pyrido[2,3- djpyrimidinyl 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 group is fully aromatic. Nonlimiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl, pyrrolyl, imidazolyi, pyrazolyl, oxazoiyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, triazine, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, phthalazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazoiyl, benzoxazolyi, cinnoliny!, 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)r) 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, carbazotyl or phthalimidyl. The heterocycyi can be attached to the rest of the molecule through any C or N atom that results in a stable structure. Examples of heterocyclyl groups include, but are not limited to, pyrrolkJinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyi, homopiperazinyl, azetidinyl, oxetanyi, homopiperidinyl, oxepanyl, thiepanyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrro!inyl, pyrazolinyt, pyrazolidinyl, imidazolinyl, imidazoltdinyl, oxazo!idinyl, 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, phthalimidyi, tetrah yd roth iopyrany I 1 ,1 -dioxide, 2-azaspiro[4.5]decanyl, 2,3- dihydrospiro[indene-1 ,4'-piperidinyl], and 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 "Cy-Z hydroxyalkyl" refers to an alkyl group having from y to z carbon atoms as defined herein which is substituted one or more times (preferably one or two) with hydroxy groups. Accordingly, a Ci « hydroxyalkyl is a Cue alkyl which is substituted one or more times with one or more hydroxy and a CM hydroxyalkyl is a C1-3 alkyl which is substituted one or more times with one or more hydroxy.
As used herein, the term " hydroxy Γ or "hydroxy" refers to -OH.
The term "optionally interrupted" means that the respective alkylene, aikenylene, alkynylene or (CH2)X group is uninterrupted or is interrupted between adjacent carbon atoms by a heteroatom selected from 0 and S or a heterogroup NR1C, i.e. an 0, S or NR10 is placed between two adjacent carbon atoms in the alkylene, aikenylene, alkynylene or (CH2)X group. Optionally interrupted as used herein also includes alkylene, aikenylene, alkynylene or (CH2)x groups where the heteroatom or heterogroup (i.e. 0, S or NR10) is placed at either end of the alkylene, aikenylene, alkynylene or (CH2)X group instead of between two adjacent carbon atoms in said group. For example, an optionally interrupted C4 alkylene group includes groups such as - CH2OCH2CH2CH2-, -OCH2CH2CH2CH2- and -NR10CH2CH2CH2CHr.
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, or, if applicable, two hydrogen atoms are replaced with a divalent substituent like a oxo group or with two R13 groups linked together as provided herein. 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 "1 ,3-disposition" in relation to -R11- means that the two points of attachment of the heteroaryl ring R11 to the remainder of the molecule are placed on ring atoms that are separated by a ring atom between them.
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 unsatu ration, but is not intended to include aryl or heteroaryl groups, as herein defined.
The term "N-linked" in relation to R16 (as in N-linked-R16) means a R15 group that is linked to the remainder of the molecule through a N atom. A wavy line ^ in chemical drawings indicates a 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-eno! pairs and annular forms where a proton can occupy two or more positions of a heterocyclic system as for example in 1 H- and 3H-imidazole. Tautomeric forms can be in equilibrium or sterically 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, 36Cl, and 125l. 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 above and in the claims as well as the compounds described in the Examples), including all stereoisomers, tautomers and isotopically labeled forms 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, b (sulfates, 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, hydroxy benzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, pheny!butyrates, citrates, lactates, gamma-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, ethane-sulfonates, propanesulfonates, benzenesulfonates, toluenesuifonates, trifluoromethansulfonates, naphthalene-1 -sulfonates, naphtha!ene-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 !igands 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 stoichiometric 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 de protection 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 in two steps following the procedure shown in Scheme 1 below.
Figure imgf000042_0001
wherein Z\ Z2, Z3, Z4, Z5, R1, R2, R3, L1, L2, Y, m and n have the same meaning described for compound of Formula (I) and M and X have the meaning defined below.
The first step involves a cross-coupling reaction of a heterocyclic organometallic species with a heterocyclic halide. Oganometal!lic intermediates can be generated either on the heteroaryi bearing the COOR1 substituent (i.e. a compound of Formula (ill)) or in the heteroaryi bearing the -(U)m-Y-(L2)n-R3 substituent (i.e. a compound of Formula (VI) ).
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 a 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 trialkylsiiyl 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 or Pd(PPI¾)4, in the presence of a suitable Cu salt such as Cu(OAc)2 or Cul, in a suitable solvent such as toluene, DME, tetrahydrofuran or dimethy!formamide, using a suitable base such as potassium carbonate. The temperature of the reaction can go from room temperature to 120°C and the time of reaction from 1h to 48h. Examples of boronic derivatives include diethyl, dimethyl, N-methyliminodiacetic acid (MIDA) derivative and 2,2'-(pfienylazanediyl)bis(ethan-1 -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/iigand combination such as Pd(PPh3)4, Pd(PPh3)Ch 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 dimethyiformamide. The temperature of the reaction can go from room temperature to 120°C and the time of reaction from 1 h to 48h. The organotin employed can be trimethylstannyi derivative. An intermolecuiar Stille Kelly reaction can also be used, in which both reagents are haloheteroaryls and are treated with (BuaSn)?, 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/iigand combination such as PPhj and Pd?(dba)3 , XPhos and Pd2(dba)3 , RuPnos and Pd2(dba)3 or Pd(PPh3)4, in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide. The temperature of the reaction can go from room temperature to 120°C and the time of reaction from 1 h 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 PdCb(PPh3)? and PPhs or Pd(OAc)z 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 tetrabutylamonium fluoride, in a suitable solvent such as tetrahydrofuran, dioxane or dimethylformamide. The temperature of the reaction can go from room temperature to 120°C and the time of reaction from 1h to 48h.
Alternatively Krohnke's ring assembly methodology can be used in the case that compounds of Formula (I) contain a pyridine, following standard conditions.
Compounds of Formula (I) can also be prepared in two steps through a direct arylation of a compound of Formula (VII) with halo derivative of Formula (IV) followed by reduction of the resulting N-oxide of Formula (VIII) as outlined in Scheme 2.
Figure imgf000043_0001
wherein 2\ Z2 Z3, Z4, Is, R\ R2, R3, L1, L2, Y, m and n have the meaning described above with respect to a compound of Formula (I) and X is CI, Br or I.
Reaction of (IV) with (VII) can be performed using a suitable Pd/ligand combination such as P'Bu3 and Pd(OAc)2 or PBU3-HBF4 and Pd(OAc)?, in the presence of a suitable base as potassium carbonate, in a suitable solvent such as toluene. The temperature of the reaction can go from room temperature to 120°C and the time of reaction from 1 h to 48h.The resulting N -oxide (VIII) can easily be reduced to compound of Formula (I) with hydrogen or sodium borohydride using palladium on charcoal as a catalyst or also using phosphorous trichloride.
The compounds of Formula (IV) can be obtained 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 (IVa), (IVb), (IVc), (IVd) and (IVe) or analogous synthetic procedures.
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000045_0002
(XV)
(IVe)
Scheme 3
wherein Z4, Z5, R2, R3, L1, L2, m and n have the meaning described above with respect to a compound of Formula (I); X is triflate, CI, Br or l;and B is CI, Br, I, or alkyl or aryl sulphonate.
For example, compounds of Formula (IVa) can be obtained by reaction of (IX) with (X) by means of activating agents. Examples of said 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 (GDI), Benzotriazol-l-yl-oxytris-(dimethylamino)- phosphonium hexafluorophosphate (BOP), Benzotriazol-1-yl-oxytris-pyrrolidinophosphonium hexafluorophosphate (PyBop), 0-(1 Hbenzotriazol-1-y!)-N,N,N',N'-tetramethyluronium hexafluorophosphate(HBTU), 1 -[Bis(dimethylamino)methylene]-1 H-1 , 2 , 3-triazolo [4 , 5-b]py rid ini urn 3-oxid hexafluorophosphate (HATU). Reaction can be carried out in the presence of a base, such as, disopropylethylamine, pyridine, thriethylamine, or N-methylmorpholine , in a solvent, such as dimethoxyethane, MA/-dimethylformamide, tetrahydrofuran, dichloromethane or dioxane. Alternatively, carboxy!ic acids in (X) are activated as mixed anhydrides or acid chlorides and then coupled with (IX) in the presence of a suitable base such as sodium hydride, triethylamine, diisopropylethylamine, pyridine or the like.
For example, compounds of Formula (IVb) can be obtained by reaction of (IX) with (XI) by means of reductive amination in the presence of a reducing agent such as sodium cyanoborohydride or sodium thacetoxyborohydride in a suitable solvent such as dioxane, tetrahydrofuran, dichloromethane or diethyl ether. Alternatively, compounds of Formula (IVb) can be obtained by means of amine alkylation of compounds of Formula (IX) in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate or the like. Other preferred solvents include dioxane, tetrahydorfurane and pyridine. Temperature can be varied from room temperature to 100°C.
For example, compounds of Formula (IVc) can be obtained by ether synthesis by reaction of (XII) with
(XIII) in the presence of a base such us sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide.
For example, compounds of Formula (IVd) can be obtained by reaction of compounds of Formula
(XIV) with the corresponding isothiocyante in the presence of a coupling agent such as 1-ethyl-3-(3'- dimethylamino)carbodiimide (EDC), in the presence of a base such as triethylamine in a solvent such as tetrahydrofurane, dioxane or dimethylformamide at a temperature from 0°C to 80°C for a time from 1h to 24h.
For example, compounds of Formula (IVe) can be obtained by reaction of compounds of Formula (XV) with the corresponding pyrazole derivative, in the presence of a base such as potassium carbonate in a solvent such as DMSO at a temperature from room temperature to reflux of solvent for a time from 1h to 24h.
The compounds of Formula (VI) can be obtained from compounds of Formula (IV) by transmetallation following standard procedures in the preparation of reagents for Suzuki, Stille Hiyama and Negishi couplings, well known to those skilled in the art of organic chemistry. For example, N-methyliminodiacetic acid boronate can be prepared by reaction of an haloheterocycle with nBuLi in the presence of B(OiPr)3 at -78°C followed by the addition of N-methyliminodiacetic acid; trimethyitin heterocycies can be prepared by reaction;of haloheterocycles with hexamethylditin and Pd (PPh3).i in toluene at 110°C for 16h; organozinc derivatives can be prepared from haloheterocycles by treatment with Zn in THF at room temperature for 1to 6h; and trimetilsily! heterocycies can be prepared by reaction of haoheterocycles with nBuLi in the presence of trimethylsylchloride at -78°C in THF.
The compounds of Formula (III), (V), (VII), (IX), (X). (XI), (XII), (XIII) and (XIV) are commercially available or may be easily obtained from commercial compounds using standard procedures.
Furthermore, some compounds of the present invention can also be obtained by cross-coupling reactions described in Scheme 1 and 2, where instead of (IV) and (VI), a corresponding intermediate carrying a partially elaborated (L1)m-Y-(L2)n-R3 is used and after cross coupling step, the complete structure of {1%-Y- (L2)n-R3 is built by the methodology described above in Scheme 3.
In general, a compound of Formula (I) where R1 is H can be prepared by hydrolysis of the corresponding ester by treatment with a suitable acid or a base. Examples of bases which can be used include, without limitation, LiOH, NaOH, KOH or MeaSiOK in a mixture of water and a solvent miscible with water such as dioxane, tetrahydrofuran, MeOH, EtOH, between 0°C and room temperature for 1 to 3 days. A suitable acid is aqueous HCI.
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 reduction of a ketone by treatment with a reducing agent such as sodium borohydride; the oxidation of a thioeter to a sulfoxide or sulfone under standard conditions; the conversion of an alcohol into a halogen by reaction with SOCI?, PBrs, tetrabutylammonium bromide in the presence of P2O5, or PCI¾ 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) 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 a JmjC-KDM of the KDM5 and/or KDM4 subfamilies. In addition, some compounds of the invention have been found to inhibit also 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 26 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 26. Compounds of the invention have also been shown to inhibit JmjC-KDM activity in cells, as shown by the results described in Example 27. The latter 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 in vitro biochemical KDM inhibitory activity into cellular KDM inhibitory activity, particularly for compounds containing carboxylic acid groups.
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 al. 2005, Mo! Cell 18(6): 623-35) and induction of senescence (Chicas A. ef 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. ef al. 2010, Cell 141 (1 ):69-80). Sensitisation to anticancer therapy after KDM5A inhibition has also been described in colon, breast, cancer and Non Small Cell Lung Cancer cell lines (Vinogradova M. ef 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. ef 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. ef al. 2013, Endocr Relat Cancer 21(1) 51-61), Head and Neck Squamous Carcinoma cell lines (Li H. ef 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, 2016, 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. et 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, et 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. ef 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. ef al. 2014, Cancer Ceil 25(6):762-77). At the same time, KDM5B inhibition is also relevant in basal-iike (Bamodu OA et al. 2016, BMC Cancer 16(1 ):160) and advanced- stage breast cancers (Yamane K. et al. 2007, Mo! Cell 25(6):801-12), and in multiple myeloma (Tumber A. ef al. 2017, Cell Chem Biol. 24(3) :371-380). Depletion of KDM5B was also shown to inhibit cell proliferation of hepatocellular carcinoma (Wang D. ef 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. et 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 ceils, characterized by increased clonogenic potential and resistance to several anticancer drugs. KDM5B inhibition sensitizes melanoma cells to chemotherapy (Roesch A. et 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 celis-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. et 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. et al. 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. et al. 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) demethyiates 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 deiocalization 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 compressor N-CoR or histone deacetylases (Zhang D. ef 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 KDM4A, 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. et 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 NOTCH1 , and may be linked to the stem cell phenotypes (Liu G. et al. 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. et 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. ef al. 2013, Carcinogenesis 34(10):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 (Maiiette F.A. et 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 demethyiation 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. et 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. et 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. et al. 2007, Nat Cell Biol. 9(3):347-53).
KDM4A 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. et 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 medu!loblastomas (Knuutila, S. et al. 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. ef 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-T1F2 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. ef al. 2007 Genes Dev. 21 : 2545-2557) and modulates regulation of adipogenesis by the nuclear receptor PPARy (Lizcano F. et al. 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 ef 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 et 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 demethyiate H3K27me2 and H3K27me3 (Xiang et al. 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 et 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 (McLaughlin-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 et 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 RNA HOTA!R in renal cell carcinoma cells was associated to the upregulation of KDM6B (Xia et al. 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 ef 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 et al. 2014, Nat Med 20(12):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 et 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 et 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 ef al. 2014, Nat Commun 5:5425).
KDM6B has also been shown to have a ro!e 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 et 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 et 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 chemotberapeutic drugs (Marthur et 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 ef al. 2012, PLoS Pathog. 8(5):e1002680). KDM6B was found to enhance the expression of the transcription efficiency of HBV enhancer I l/core promoter (En II) in a C/EB Ρα-dependent manner (Chen et 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 et 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 or a KDM4 protein and/or a KDM6 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), or pharmaceutically acceptable salt thereof, for use as a medicament.
The present invention further provides a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), or pharmaceutically acceptable salt thereof, for use in treating a disease associated with a JmjC-KDM, particularly a KDM5 and/or KDM4 and/or KDM6.
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 (II), more preferably of formula (la) or (lb), 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 KDM4 and/or KDM6.
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 (II), more preferably of formula (la) or (lb), or pharmaceutically acceptable salt thereof, for treating a disease associated with a JmjC-KDM, particularly a KDM5 and/or KDM4 and/or KDM6.
The present invention further provides a method for treating a disease associated with a JmjC-KDM, particularly a KDM5 and/or KDM4 and/or KDM6, comprising administering a therapeutically effective amount of a compound of Formula (I), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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 (II), 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), (!a), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), 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 (II), 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 (II), 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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 leukemialn 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), (la), (lb), (lc), (Id), (le),
(If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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 ceil 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (Id), (le), (if) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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.
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 KDM6, and/or diseases or conditions the course of which can be influenced by modulating the methy!ation 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 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, medul!oblastoma, 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 eel! 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, ceil 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) (or any of its subgenus of Formula (la), (lb), (lc), (Id), (le), (If) or (II)), 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, microcrysta!line 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, com 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 cetylstearyi 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 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, epidophylbtoxins, 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, dichloromethotrexafe, mitomycin C, porfiromycin, 5- fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo- phylbtoxin 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 inteiieukins.
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' aM 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, or trofosfamide), 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 (N.N'N'-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, fiudarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6- thioguanine), and pyrimidine analog antimetabolites (such as cytarabine, decitabine, azacytidine, 5-ffuorouracil (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, or sapacitabine).
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 docetaxe!, 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, epothiione 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 or trametinib.
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, or vandetanib.
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, mbitecan, or lameliarin 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, fiutamide, 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, selkxlib, aminolevulinic acid, methyl aminolevulinate, efaproxiral, porfimer sodium, talaporfin, temoporfin, verteporfin, anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur, celecoxib, demecolcine, elesclomol, elsamitrucin, etog lucid, lonidamine, lucanthone, masoprocol, mitobronitol, mitoguazone, mitotane, oblimersen, omacetaxine, sifjmagene, ceradenovec, tegafur, testolactone, tiazofurine, tipifamib, 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; 3J-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- 5,6J,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)-3J-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester; Tegison), Acitretin ((all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3J-dimethyl-2,4,6,8-nonatetraenoic acid; Ro 10-1670; Soriatane; Neotigason), Tazarotene (ethyl 6-[2-(4,4-dimethy!thiochroman-6-yl)-ethynyl] nicotinate; Tazorac; Avage; Zorac), Tocoretinate (9-cis-tretinoin; Tocoferil), Adapalene (6-[3-(1-adamantyi)-4- methoxyphenyl]-2-naphthoic acid: Differin), Motretinide (trimethylmethoxyphenyl-N-ethyl retinamide; Trasmaderm), retinaldehyde (Retinal), CD437 (6-[3-( 1 -adamantyi)-4-hydroxyphenyl)-2-naphthalene carboxyiic 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), LG 100268 (LG268), LG 100324, SR11203 ([2-(4-carboxyphenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)-1 ,3-dithiane), SR11217 (4-(2-methyl-1 -(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)propenyl)benzoic acid), SR11234, SR11236 (2-(4-carboxyphenyl)-2-(5,6J,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthalenyl)-1 ,3-dioxane), SR11246, AGN194204, derivatives of 9-cis-RA such as LGD1069 (3- methyi TTNEB; Bexarotene; Targretin®; 4-[1-(5,6J,8-tetrahydro-3,5,5:8,8-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-oxodecanoyi-1-methoxy-L-ti7ptophyl-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, certo!izumab pego!, 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, taiizumab. tefibazumab. tociiizumab, toralizumab, trastuzumab, tucotuzumab celmoieukin, 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, RB, 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 (MART-I, gap 100, MAGE 1 ,3 tyrosinase), papillomavirus E6 and E7 fragments, whole cells or portions/Iysates 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (lc), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), 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), (la), (lb), (Ic), (Id), (le), (If) or (II), preferably a compound of Formula (II), more preferably of formula (la) or (lb), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the antineoplastic agent.
In some embodiments of any of the above methods, the antineoplastic agent is selected from the list 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, medulloblastoma, neuroblastoma, osteosarcoma, lymphoma and leukemia. In accordance with the above, the present invention in particular relates to the following:
1.A compound of Formula (I) or a salt thereof:
Figure imgf000067_0001
(I)
wherein
Z1, Z2, and Z3 are each independently selected from CR4 and N, and Z4 and Z5 are each independently selected from CR2 and N, with the proviso that only one of T , Z2, Z3, Z4 and Z5 can be N;
R1 is selected from hydrogen, Ci.s alkyl, Ci-6 haloalkyl, -(C,.6 alkylene)-OR5, -{C-s alkylene)-NR6R7, -LA carbocyclyl, -L3-aryi,-L?-heterocyc!yi and -L3-heteroaryl, wherein the carbocyclyl in -LAearbocyclyl, the aryl in - L3-aryl, the heterocyclyl in -LAheterocyc!yl and the heteroaryl in -L3-heteroaryl are each optionally substituted with one or more R8,
each R2 is independently selected from hydrogen, halo, Ci-s alkyl, Ci-s haloalkyl, Ci-6 alkoxy, Ci-e hydroxyalkyl, - OH and -NH2;
each R4 is independently selected from hydrogen and halo;
Y is selected from -NR10-, -0-, -CH2-, -NR3C(=0)- and -R11-, wherein said -NR3C(=0)- is linked to -(L%- via the NR9 group and to -(L2)n-R3 via the C(=0) group;
L1 is Ci-4 alkylene, C2-4 alkenylene or C2-4 alkynylene, wherein said Cu alkylene, said C2-4 alkenylene and said C24 alkynylene are optionally interrupted by 0, S or NR10, and wherein said Cu alkylene, said C2-4 alkenylene and said C24 alkynylene are optionally substituted with one or more R12;
L2 is C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene, wherein said C1 6 alkylene, said C2-6 alkenylene and said C2-6 alkynylene are optionally interrupted by 0, S or NR10, and wherein said Cu, alkylene, said C2-6 alkenylene and said Cn alkynylene are optionally substituted with one or more R12;
m and n are each independently selected from 0 and 1 ;
R3 is selected from -NR13R14 , -OR15 and R,s;
R6 and R7 are each independently selected from hydrogen and Cu alkyl, or R6 and R7 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 substituents independently selected from halo, Ci.s alkyl, -OH, -NH2, -NH(C,.6 alkyl), and -N(Ci S alkyl}2;
each L3 is independently selected from a bond and Cu alkylene; Rs and R1c are each independently selected from hydrogen, C1-5 alkyl and Ci-s haloalkyl;
-R11- is a biradical of a 5-membered heteroaryi ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S with the proviso that at least one is a N atom, and wherein -R11- is linked to -(L1)m- and -{L2)„- R3 in a 1 ,3-disposition;
each R12 is independently selected from Cn alkyl, halo, CI-B haloalkyl, -L3-carbocyclyl, -L3-aryl,-L3-heterocyclyl and -L3-heteroaryl, wherein the carbocyclyl in -L3-carbocyclyl, the aryl in -LAaryl, the heterocyclyl in -LA heterocyclyl and the heteroaryi in -LAheteroaryl are each optionally substituted with one or more R17, and wherein two groups R12 attached to a same C atom of the alkylene, alkenylene or alkynylene group are optionally linked together to form with said C atom a C3-6 cycloalkyl group or a saturated 4- to 6-membered monocyclic heterocyclic ring containing 1 heteroatom selected from N, 0 and S, wherein said C3-3 cycloalkyl and 4- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from halo and d e alkyl;
R13, R14and R15 are each independently selected from hydrogen, Cu alky!, C1 0 haloalkyl, -(Ci e alkylene)-OR18, -L3-carbocyclyl, -L3-aryl,-L3-heterocyclyl and -L3-heteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyl in -LAheterocyclyl and the heteroaryi in -LAheteroaryl are optionally substituted with one or more R19;
R16 is selected from C1-6 alkyl, carbocyclyl, aryl, heterocyclyl and heteroaryi, wherein said alkyi is optionally substituted with one or more R20 and said carbocyclyl, said aryl, said heterocyclyl and said heteroaryi are each optionally substituted with one or more R21;
each R20 is independently selected from halo, Ci e alkoxy, Ci 6 haloalkoxy, -OH, -NH2, -NH(Ci-6 alky!), -N(Ci s alkyl)2 ,-CN, -C(=0)R22, -C{=0)NR23R24, -NR23C(=0)R22, -NR23C(=0)NR23R24, -NR23S02R22, -S02NR23R24 and - S02R22;
each R21 is independently selected from C1 6 alkyl, C1-6 haloalkyl, halo, C1-6 alkoxy, C1-6 haloalkoxy, -OH, -NH2, - NH(Ci-6 alkyl), -N(C, s alkyl)?, -CN, -C(=0)R22, -C(=0)NR23R24, -NR23C(=0)R22, -NR23C(=0)NR23R24 - NR23S02R22, -S02NR23R24, -S02R22, -(Ci-6 alkylene)-0R25, -(Ci.6 alkylene)-NR2(5R27, -LAcarbocyclyl, -LAaryl,- L3-heterocyclyl and -LAheteroaryl, wherein the carbocyclyl in -LAcarbocyclyl, the aryl in -LAaryl, the heterocyclyl in -LAheterocyclyl and the heteroaryi in -LAheteroarylare optionally substituted with one or more R28;
each R8, each R17, each R1S and each R28 is independently selected from Cu alkyl, Ci e haloalkyl, halo, C%s alkoxy, Ci s haloalkoxy, -OH, -NH2, -NH(Ci.6 alkyl), -N(Ci 6 alkyl)? ,-CN, -C(=0)R2∑, -C(=0)NR23R24, - NR23C(=0)R22, -NR23C(=0)NR23R24, -NR23S02R22, -S02NR23R24 and -S02R22;
each R22 is independently selected from C1.6 alkyl; and
each R5, each R18, each R23, each R24, each R26, each R26 and each R27 is independently selected from hydrogen and Cm alkyl.
2. The compound of item 1 , which is a compound of Formula (II):
Figure imgf000069_0001
(II)
or a salt thereof.
3. The compound of item 1 or 2, wherein R1 is hydrogen
4,The compound of any one of items 1 to 3, wherein each R2 and each R4 is hydrogen.
5.The compound of any one of items 1 to 4, wherein L1 is
Figure imgf000069_0002
wherein said (CH2)i ? is optionally substituted with one or more R12.
6 Jhe compound of any one of items 1 to 5, wherein L2 is (CH2)i-s, wherein said {CH2)n is optionally substituted with one or more R12.
7.The compound of any one of items 1 to 6, wherein Y is selected from -NR10-, -0- and -CH2-.
8. The compound of any one of items 1 to 7, wherein n is 1.
9. The compound of any one of items 1 to 4, wherein -{L1)m-Y-(L2)n- is selected from the following list 1
Figure imgf000070_0001
Figure imgf000070_0002
wherein any alkyiene can be optionally substituted with one or more R12.
lO.The compound of any one of items 1 to 9, wherein R3 is selected from -OR15 and R16.
11 The compound of any one of items 1 to 9, wherein R3 is R16 and R16 is selected from carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein said carbocyclyl, said aryl, said heterocyclyl and said heteroaryl are each optionally substituted with one or more R21, 12. The compound of any one of items 1 to 9, wherein R3 is R16 and R16 is phenyl, wherein said phenyl is optionally substituted with one or more R21.
13. A pharmaceutical composition which comprises a compound of any one of items 1 to 12 or a
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14.A compound as described in any one of items 1 to 12, or a pharmaceutically acceptable salt thereof, for use as a medicament.
15.A compound as described in any one of items 1 to 12, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer 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: tert-buiyioxycarbonyl
(Boc)jO: di-tert-butyl dicarbonate,
n-BuOH: n-butanol
DCE: 1 ,2-dichloroethane
DCM: Dichloromethane
DIEA: A/,A/-diisopropylethylamine
D!PEA: Α/,Ν-Diisopropylethylamine,
DMAP: 4-(dimethylamino)pyridine
DME: 1 ,2-dimethoxyethane
DMF: Λ/,Λ/'-dimethylformamide
DMSO: dimethylsulfoxide,
EDC.DCI: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
Et20. Diethyl ether
EtOAc: ethyl acetate
EtOH: ethanol
FA: Formic acid
HPLC: high performance liquid chromatography
LC-MS: liquid chromatography-mass spectroscopy
Mel: lodomethane
fvfeOH: methanol
Me3SiOK: potassium trimethy!silanolate, Pd2(dba)3 : ths(dibenzylidenacetone)dipalladium(0)
Pd(PPh3)4 : tetrakis(thphenylphosphine) palladium (0)
Pd(PPh3)?Cl2 : Bis(triphenylphosphine)palladium chloride
Pet ether: petroleum ether,
RT: room temperature
Rt: retention time,
sat.: saturated,
TEA: triethylamine
TFA: Trifluoroacetic acid
THF: tetrahydrofurane
TLC: thin layer chromatography
T3P: Propylphosphonic Anhydride
UPLC: Ultra Performance Liquid Chromatography
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 Dm); 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: KINETEX-1.7u XB-C18 100A (50mm x 2.1 mm, 1.7 μπι); 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 3: Column: Gemini C18 (150mm x 4.6mm, 5 μηη); Mobile Phase: A: 0.01 M Ammonium Acetate (aq), B: Acetonitrile; Gradient: Time/% B: 0/10, 1/10, 6/90, 8/98, 12/98, 12.01/10; Flow Rate: 1.0 mL/min;
Method 4: Column: Xbridge C18 (75mm x 4.6mm, 3.5 ,um); Mobile Phase: A: Acetonitrile, B: 5 mM Ammonium Bicarbonate in Aq; Gradient: Time/% B: 0/95, 1/95, 5/5, 7.8/5, 8/95, 10/95; Flow Rate: 1.0 mL/min; Diluent: Acetonitrile:Water (1 :1);
Method 5: Column: Xbridge C18 (75mm x 4.6mm, 3.5 μηι); Mobile Phase: A: 10 mM Ammonium Bicarbonate 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 6: Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 μίτι); Mobile Phase: A: 0.05% Formic Acid in Acetonitrile, B: 0.05% Formic Acid in Water; Gradient: Time/% B: 0/97, 0.3/97, 3.2/2, 3.8/2, 4.3/97, 4.5/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min;
Method 7: Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 μηη); Mobile Phase: A. 0.05% Formic Acid in Water, B: 0.05% Formic Acid in Acetonitrile; Gradient: Time/% A: 0/97, 0.3/97, 3.5/2, 4.8/2, 5/97, 5.01/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min; Method 8: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μιη); 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, 4.5/2, 4.51/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min;
Method 9: Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 μπι); 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 10: Column: Xbridge C18 (75mm x 4.6mm, 3.5 urn); Mobile Phase: A: 0.01 M Ammonium Acetate (aq), B: Acetonitrile; Gradient: Time/% B: 0/10, 1/10, 6/90, 7/98, 10/98, 10.01/10; Flow Rate: 1.0 mL/min; Method 11 : Column: KINETEX 5u XB-C18 (100mm x 4.6mm); Mobile Phase: B: 0.01 M Ammonium Acetate (aq), A: Acetonitrile; Gradient: Time/% B: 0/95, 0.5/95, 2.0/85, 4.0/45, 6.5/5, 9.0/5, 9.10/95, 10.10/95; Column Temp: 35°C; Flow Rate: 1.0 mL/min;
Method 12: Column: Xbridge C18 (75mm x 4.6mm, 3.5 pm); Mobile Phase: A: Acetonitrile, B: 5 mM Ammonium Bicarbonate in Aq; Gradient: Time/% A: 0/2, 2/2, 4/15, 7/55, 8/95, 10/95, 14/95, 14.1/2; Flow Rate: 1.0 mL/min; Diluent: TFA:Water (1 :1);
Method 13: Column: L-Column2(150mm x 4.6mm, 5μηη); Mobile Phase: A: Acetonitrile, B: 0.01 M Ammonium Acetate in Aq; Gradient: Time/% A: 0/5, 1/5, 15/80, 20/90, 25/90, 25.01/5; Column Temp: 35°C; Flow Rate: 1.0 mL/min; Diluent: Acetonitrile:Water (1 :1);
Method 14: Column: Xbridge C18 (75mm x 4.6mm, 3.5 μηι); 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 15: Column: Gemini C18 (150mm x 4.6mm, 5 μηι); Mobile Phase: A: 0.01 M Ammonium Bicarbonate (aq), B: Acetonitrile; Gradient: Time/% B: 0/10, 1/10, 6/90, 7/98, 10/98, 10.01/10; Flow Rate: 1.0 mL/min; Method 16: Column: Xbridge C18 (75mm x 4.6mm, 3.5 μπι); Mobile Phase: A: Acetonitrile, B: 10 mM Ammonium Acetate in Aq; Gradient: Time/% A: 0/2, 2/2, 4/15, 7/55, 8/95, 10/95, 14/95, 14.1/2; Flow Rate: 1.0 mL/min; Diluent: ACN:Water (1 :1);
Method 17: Column: Xbridge C18 (75mm x 4.6mm, 3.5 μηι); 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 18: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μπΊ); 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, 3.8/2, 4.2/97, 4.5/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min;
Method 19: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μΐϊΐ); Mobile Phase: B: 0.1% Formic Acid in Water, A: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B: 0/2, 0.3/2, 2.3/98, 2.8/98, 2.8/2, 3.0/2; Column Temp: 60°C; Flow Rate: 0.8 mL/min. Method 20: Column: YMC TRAIT C18; Mobile Phase: A: Acetonitrile, B: 0.01 M Ammonium Bicarbonate in Aq; Gradient: A=40 %, B=60 %. Flow Rate: 25.0 mL/min.
Method 21 : Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μτη); 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 22: Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 μπι); Mobile Phase: A: 0.1% Formic Acid in Acetonitrile, B: 0.1% Formic Acid in Water; Gradient: Time/% A: 0/97, 2.6/0, 3.3/0, 3.6/97, 4.0/97; Column Temp: 35°C; Flow Rate: 0.55 mL/min; Diluent: Acetonitrile:Water (1 :1).
Method 23: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μπι); 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 24: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ,um); Mobile Phase: B: 0.1% Formic Acid in Acetonitrile, A: 0.1% Formic Acid in water; Gradient: Time/% B: 0/10, 1.8/100, 3.8/100, 4.0/10, 5/10, Column Temp: 50°C; Flow Rate: 0.7 mL/min;
Method 25: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μπη); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A: 0/95,0.3/95,2.0/5,3.5/5,3.6/95,4.2/95; Column Temp: 40°C; Flow Rate: 0.6 mL/min;
Method 26: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 pm); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A: 0/90,1/10,2.2/10,2.3/90,2.6/90; Column Temp: 50°C; Flow Rate: 0.8 mL/min;
Method 27: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 urn); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A: 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 28: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μπι); 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 29: Column - AQUITY UPLC BEH C18 (50mm x 2.1 mm, 1.7 μτη); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A: 0/98 0.2/98,1.8/2,2.4/2,2.60/98; Column Temp: 50°C; Flow Rate: 0.8 mL/min;
Method 30: Column - AQUITY UPLC BEH C18 (50mm x 2.1 mm, 1.7 μπι); Mobile Phase: A: 0.1% Formic Acid in Water, B: Acetonitrile; Gradient: Time/% A: 0/98 0.5/98,3.4/2,4.2/2,4.5/98, 5.0/98; Column Temp: 35°C; Method 31 : Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μηι); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% A: 0/97, 0.3/97, 3.0/2, 4.0/2, 4.2/97, 4.50/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min; Method 32: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 ,um); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitriie; Gradient: Time/% A: 0/97, 0.3/97, 3.0/2, 4.0/2, 4.3/97, 4.50/97; Column Temp: 35°C; Flow Rate: 0.6 mL/min;
Method 33: Column: Aquity UPLC BEH C18 (50mm x 2.1mm, 1.7 μιτι); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitriie; Gradient: Time/% B: 0/5, 0.3/95, 2.0/95, 3.7/95, 4.2/5, 5.7/5; Column Temp: 40°C; Flow Rate: 0.5 mL/min;
Method 34: Column: XBridge BEH C18 (50mm x 3.0mm, 2.5 μιπ); Mobile Phase: A: 0.01 M Ammonium Formate in water.ACN (95:5), B: 0.01 M Ammonium Formate in water.ACN (5:95); Gradient: Time/% B: 0/2, 4/98, 4.5/98, 5/2, 5.5/2, 6.5/2; Flow Rate: 1.0 mL/min;
Method 35: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μηι); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitriie; Gradient: Time/% A: 0/98, 0.2/98, 1.8/2, 2.4/2, 2.60/98, 3.0/98 Column Temp: 50°C; Flow Rate: 0.8 mL/min;
Method 36: Column: Xbridge C18 (75mm x 4.6mm, 3.5 pm); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitriie; Gradient: Time/% B: 0/10, 6/100, 9/100, 9.50/10,12/10.Flow Rate: 1.0 mL/min; Method 37: Column: Atlantis T3 (150mm x 4.6mm, 3.5 μηι); Mobile Phase: A: 0.1% Formic Acid in Water, B: Acetonitriie; Gradient: Time/% B: 0/10, 8/100, 12/100, 12.5/10, 15/10. Flow Rate: 1.0 mL/min;
Method 38: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μιτι); Mobile Phase: A: 0.01 M Ammonium Bicarbonate in Water, B: Acetonitriie; Gradient: Time/% B: 0/3; 1.0/3; 7.0/100; 7.5/100: 9.0/3; 10.0/3.Column Temp: 35°C; Flow Rate: 0.5 mL/min;
Method 39: Column: Aquity UPLC BEH C18 (50mm x 2.1 mm, 1.7 μιτι); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitriie; Gradient: Time/% A: 0/97; 1.0/97; 7.0/0; 7.5/0; 9.0/97; 10.0/97.Column Temp: 35°C; Flow Rate: 0.5 mL/min;
REFERENCE EXAMPLE 1
Methyl 2-(trimethylstannyl)isonicotinate
To a stirred solution of methyl 2-chloro isonicotinate (2 g, 0.012 mol) in toluene (20 mL) was added hexamethylditin (4.5 g, 0.014 mol), the mixture was degassed with argon for 10 minutes, then Pd(PPha)4 (1.35 g, 0.001 mol) was added, the mixture 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 Ce!ite pad, washed with EtOAc and the filtrate was concentrated to get a crude compound. 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 ): Rt = 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: Reference Starting HPLC Rt
Compound name m/z example material method (mln)
Ethyl 2-chloro 316.1
1a Ethyl 2-(trimethy Istan ny I) iso n icotinate 2 1.75
isonicotinate (M+H~)
REFERENCE EXAMPLE 2
Methyl 5'-{fert-butoxycarbonylamino)-2,2'-bipyridine-4-carboxylate
In a pressure tube, to a stirred solution of ferf-butyl 6-bromopyridin-3-ylcarbamate (2 g, 0.007 mol) in 1 ,4 dioxane (40 mL) was added reference example 1 (2,6 g, 0.009 mol), Cul (278 mg, 0.0015 mol) and CsF(2,2 g, 0.015 mol) and the resulting solution was degassed using nitrogen. Pd(PPfi3). (846 mg, 0.0007 mol) was added, degassed again and heated at 110°C for 16h. The reaction mixture was cooled to RT, diluted with EtOAc and filtered through Celite pad. The filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography and eluted with 20 % EtOAc/Pet-ether to afford 1.8 g (74%) of the title compound.
LC-MS (method 1 ): R, = 2.26 min; m/z = 330.08 (M+H*).
REFERENCE EXAMPLE 3
Methyl 5'-amino-[2,2'-bipyridine]-4-carboxylate hydrochloride To a stirred solution of reference example 2 (1.5 g, 0.0045 mol) in MeOH (10 mL) was added 4M HCI in dioxane (15 mL) at 0°C. The reaction mixture was stirred at room temperature for 24h. The reaction mixture was concentrated and washed with diethyl ether (2 X 10 mL) to give 1.4 g of reference example 3 as hydrochloride salt. The crude compound was used for the next step without any further purification.
LC-MS (method 1): Rt = 1.08 min; m/z = 230.06 (M+H*),
REFERENCE EXAMPLE 4
Ferf-butyl 3-((6-bromopyridin-3-yl)amino}-3-oxo-1-phenylpropylcarbamate TEA (5.83g, 0.058 mol) followed by T3P [50% solution in EtOAc, 11.02g, 0.035 mol) were added to a stirred solution of 6-bromo-3-amino pyridine (2g, 0.012 mol) and 3-{Boc amino)-3-phenyl propionic acid (3.67 g, 0.011 mol) in DCM (20 mL) 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 DCM (100 mL), washed with water (50 mL), aq.NaHCOs solution (50 ml). The organic layer was dried over anhydrous Na?SCv„ filtered and the filtrate was concentrated under reduced pressure. The residue was suspended in DCM, the precipitated solid was filtered, washed with DCM and dried in vacuum to afford the title compound (2 g, 41%) as a brown gummy liquid.
LC-MS (method 1): R, = 2.26 min; m/z = 421.85 (M+H*+2)
Following a similar procedure to that described in reference example 4, but using in each case the corresponding starting materials, the following compounds were obtained:
Reference HPLC Rt
Compound name Starting material m/z example method (min) Terf-butyl (3-((6-bromopyridin- 3-{Tert-
346.19a 3-yl)amino)-3- butoxycarbonyl)amino 2.31
7 (M+H-+2) oxopropyl)carbamate )propanoic acid
Tert-butyl 3-((6-bromopyridirv HTert-
386.18
3-yl)carbamoyl)piperidine-1 - butoxycarbonyl}piperi 2
b 2.71 (M+H*+2) carboxylate dine-3-carboxy!ic acid
N-(6-Bromopyridin-3-yi)-3- 3-Methoxypropanoic 259.19c 1.83
methoxypropanamide acid 2
(Μ+Η')
2-([1 ,1'-Bipheny!]-4-yl)-N-(6- 2-([1 ,1'-Biphenyl]-4- 367.15d 2.90
bromopyridin-3-yl)acetamide yi)acetic acid 2 (M+H+).
N-(6-Bromopyridin-3-yl)-3- 3-Phenylpropanoic 304.98e 2.09
phenylpropanamide acid 6 (Μ+Η')
3-((7erf- butoxycarbonyl)amin
Te/f-butyl (3-((5-bromopyrazin- o)propanoic acid and
347.20f 2-yl)amino)-3- 5-bromopyrazin-2- 2.42
2
(M+H++2) oxopropyl)carbamate amine instead of 6- bromo-3-amino
pyridine
Phenyl acetic acid
and
N-(5-Bromopyrazin-2-yl)-2- 5-bromopyrazin-2- 294.21g 2.38
phenylacetamide amine instead of 6- 2 (M+H-+2) bromo-3-amino
pyridine
N-(6-Bromopyridin-3-yl)-2- 2-Cyclobutyiacetic 269.08h 2.53
cyclobutylacetamide acid 2 (M+H-)
N-(6-Bromopyridin-3-yl)-4- 4-Phenylbutanoic 319.17i 2.73
phenylbutanamide acid 2 (M+H+)
N-(6-Bromopyridin-3-yl)-2- 291.08j 2-Phenylacetic acid 2.46
phenylacetamide 2 (Μ+Η')
W-(6-Bromopyridin-3-yl)-1 -
1-Methylpiperidine-4- 300.15k methylpiperidine-4- carboxyiic acid 1 1.04 (M+H*+2) carboxamide
1 W-(6-Bromopyridin-3-y!)-1- 1 -Methylpiperidine-3- 1.41 300.21
8
Figure imgf000078_0001
Te/t- butyl 3-((2-(6-bromopyridin-3-yl)ethyl)carbamoyl)plperidine-1-carboxylate
Step a. (6-Bromopyridin-3-yl)methyl methanesulfonate
At 5°C, to a stirred solution of (6-bromopyridin-3-yl)methanol (15 g, 0.079 mol) and TEA (22 mL, 0.159 mol) in DCM (75 mL) was added methanesulfonylchloride (6.7 mL, 0.087 mol). The resulting reaction mixture was stirred at 5°C for 2h. The progress of the reaction was monitored by TLC, The reaction mixture was quenched with aq. NH4CI and diluted with DCM. The organic layer was washed with aq.NaHCC^ solution and water. The organic layer was dried over anhydrous Na2S04, filtered and the filtrate was concentrated to afford the title compound (11.1 g, 53%) as a brown solid. The compound was used for the next step without any further purification.
LC-MS (method 1): R, = 1.56 min; m/z = 267.75 (M+H++2).
Step b. 2-(6-Bromopyrldin-3-y!) acetonitrile
To a stirred solution of the compound obtained in the previous section, step a, (11.0 g, 0.041 mol) in DMSO (30 mL) was added NaCN (3.0 g, 0.062 mol) at rt. The reaction mixture was stirred at RT for 6h. The progress of the reaction was monitored by TLC. The reaction mixture was poured into ice water and extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with brine solution (200 mL) and dried over anhydrous Na2SC>4, filtered and the filtrate was concentrated under reduced pressure to get the title compound (7.0 g, 86%) as a brown liquid.
LC-MS (method 1): Rt = 1.44 min; m/z = 198.79 (M+H*+2).
Step c. Tert-butyl (2-(6-bromopyridin-3-yl) ethyl)carbamate
At 0°C, to a stirred solution of the compound obtained in the previous section, step b, (7.0 g, 0.035 mol) and B0C2O (16 mL, 0.071 mol) in methanol (30 mL) was added NiCI2.6H20 (1.6 g, 0.007 mol), followed by the addition of NaBhU (5.4 g, 0.14 mol). The resulting reaction mixture was allowed to stir at RT for 4h. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated; the residue was partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na;>S04, filtered and the filtrate was concentrated. The crude compound was purified by column chromatography using silica gel and eluted with 30% EtOAc/pet ether to afford the title compound (2.5 g, 32%) as a light yellow liquid.
LC-MS (method 1): Rt = 2.02 min; m/z = 300.85 (M+H*). Step d. 2-(6-Bromopyridin-3-yl) ethan-1 -amine hydrochloride
To a stirred solution of the compound obtained in the previous section, step c, (2.4 g, 0.008 mol) in 1 ,4-dioxane (15 mL) was added 4M HCI in 1 ,4-dioxane (2.0 mL) and the resulting reaction mixture was stirred at room temperature for 4h. Solvent was removed under reduced pressure, and the residue was triturated with diethyl ether (2 mL) and dried under vacuum to afford the title compound (2.0 g) as a hydrochloride salt.
LC-MS (method 3): Rt = 4.80 min; m/z = 201.10 (Μ+Η').
Step e. 7ert-butyl 3-((2-(6-bromopyridin-3-yl)ethyl)carbamoyl)piperidine-1-carboxyiate
At 0 °C, to a stirred solution of the compound obtained in the previous section, step d, (2.0 g, 0.01 mol) and 1- (ferf-butoxycarbonyl)piperidine-3-carboxylic acid (2.7 g, 0.012 mol) in DCM (10 mL) was added TEA (7.0 mL, 0.05 mol) followed by the addition of T3P(50% in EtOAc) (9.5 mL, 0.03 mol). The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with DCM, washed with water and brine. The organic layer was dried over anhydrous !^SCM, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel and eluted with 2% MeOH/DCM to afford the title compound (600 mg, 15%) as a light yellow semisolid.
LC-MS (method 1): F¾ = 2.03 min; m/z = 413.88 (M+H-+2).
REFERENCE EXAMPLE 6
3-((7erf-butoxycarbonyi){phenyl)amino)propanoic acid
To a stirred solution 3-(phenyiamino)propanoic acid (1g, 0.006 mol) and NaHCOs (0.509 g, 0.006 moi) in dioxaneihbO (10:5 mL) was added Boc-anhydride (1.32 g, 0.006 mol) at 0°C. The reaction mixture was allowed to RT and stirred for 18 h (the reaction was monitored by TLC). The reaction mixture was diluted with water (10mL) and washed with ethyl acetate (2x20 mL). The aqueous layer pH was adjusted to 3.0 using 1 N HCI aq. solution and extracted with ethyl acetate (3x25 mL). The combined organic layers were washed with brine solution (1x20mL). The separated organic layer was dried over anhydrous !^SCM, filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (0.9 g, 56%).
LC-MS (method 1): F¾ = 1.97 min; m/z = 263.72 (M-H*).
Following a similar procedure to that described in reference example 6, but using the corresponding starting material, the following compound was obtained:
Figure imgf000079_0001
3-(1-Methyl-1H-pyrazol-4-yl)propanal
To a stirred solution of 3-(1 -methyl-1 H-pyrazol-4-yl) propan-1-ol (500 mg, 0.0036 mol) in DCM (10 mL) was added Dess-Martin periodinane (2.271 g, 0.005mol) at 0°C and allowed to stir at rt for 2 h. The reaction mixture was diluted with DCM (100 mL), washed with saturated NaHCC<3 aq. solution (50 mL) and brine solution (50 mL). The separated organic layer was dried over anhydrous Na2SO_, filtered and the filtrate was concentrated under reduced pressure to afford the title compound (350 mg, 71%) as a clear liquid.
LC-MS (method 5): R, = 1.05 min; m/z = 139.3 (M+H*).
REFERENCE EXAMPLE 8
3-(4-Chlorophenyl)propanal
A solution of 3-(4-chlorophenyl)propan-1 -ol (2.0 g, 0.012 mol) in dry CH2Cb (25 mL) was added DMSO (6 mL) and EtaN (3.56 g, 0.0358 mmol). The reaction mixture was cooled to 0°C and added a solution of pyridine sulfur trioxide (2.8 g, 0.018 mol) in DMSO (6 mL). The reaction mixture was stirred at 0°C for 0.5 h and then at RT for 6 h. The reaction mixture was concentrated in vacuum and the residue was diluted with Et?0 (100 mL) and H2O (100 mL). The organic layer was separated and the aqueous layer was extracted with Et?0 (3 * 50 mL). The combined organic layers were dried over anhydrous Na2SCM, filtered and concentrated under reduced pressure. The obtained crude compound was purified by silica gei (60-120) column chromatography and eluted at 10% EtOAc/pet ether the title compound (1.0 g, 50%) as a colourless oil.
REFERENCE EXAMPLE 9
3-(4-Fluorophenyl)propanal
To a solution of the 3-(4-fluorophenyl)propan-1 -ol (1.0 g, 0.006 mol) in DCM (20 mL) was added Celite (1.5 g) and Pyridinium chlorochromate (3.48 g, 0.016 mol) and the mixture was stirred at RT for 3 h. The reaction mixture was concentrated and purified by silica gel flash column chromatography and eluted with 100% DCM to afford the title compound (0.750 g, 76%) as a colourless oil.
REFERENCE EXAMPLE 10.
lert-butyl (5-(6-bromopyridin-3-yl)-1,3.4-oxadiazol-2-yl)carbamate Step a. 6-Bromonicotinohydrazide
To a stirred solution of methyl 6-bromonicotinate (5.0 g, 0.023 mol) in MeOH (50 mL) was added hydrazine hydrate (2.31 g, 0.046 mol) at RT, the resulting solution was stirred at RT for 16h. The reaction mixture was cooled to 0 °C, filtered and the separated solid was dried to obtain the title compound (3.5 g, 70%) as a white color solid.
LC-MS (method 7): R, = 0.92 min; m/z = 215.94 (M+H*).
Step b. 5-(6-Bromopyridin-3-yl)-1 ,3,4-oxadiazo!»2-amine
To a stirred solution of the compound obtained in the previous section, step a, (3.5 g, 0.016 mol) in 1,4-dioxane
(20 mL) and water (20 mL) was added NaHCOa (3.4 g, 0.032 mol), cyanogen bromide (2.56 g, 0.024 mol) at 0
°C. The resulting solution was at RT for 5h. The reaction mixture was diluted with water (30 mL), and filtered to obtain the title compound (3.0 g, 77%) as an off white solid.
LC-MS (method 2): R, = 1.78 min; m/z = 239.09 (M+H*).
Step c. Tert-butyl 5-(6-bromopyridin-3-yl)-1,3,4-oxadiazol-2-ylcarbamate To a stirred solution of the compound obtained in the previous section, step b, (3.0 g, 0.012 mol) in DMF (30 mL) was added DIPEA (4.81 g, 0.037 mol), Boc20 3 (5.4 g, 0.025 mol), DMAP (0.45 g, 0.0037 mol) and the resulting solution was heated at 50°C for 16h. The reaction mixture was cooled to RT, diluted with water (50 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layers were dried over anhydrous Na2SO/. and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 20% EtOAc/ pet ether to obtain the title compound (0.6 g, 14%) as a brown color solid.
LC-MS (method 2): R, = 2.40 min; m/z = 343.04 (M+H*+2).
REFERENCE EXAMPLE 11.
N-Benzyl-5-(6-bromopyridin-3-yl)-1 ,3,4-oxadiazol-2-amine
To a stirred solution of 6-bromonicotinohydrazide (1.5 g, 0.0079 mol) in THF (20 mL) was added benzyl isothiocyanate (1.13 g, 0.0076 mol) at RT and the resulting solution was stirred for 16h at RT. EDC.HCI (1.98 g, 0.010 mol), and TEA (2.1 g, 0.021 mol) was added to the above reaction mixture and stirred at RT for 16h. The reaction mixture was diluted with water (50 mL) and filtered the separated solid and dried to obtain the title compound (1.5 g, 66%) as a white color solid.
LC-MS (method 1): R, = 1.95 min; m/z = 330.76 (M+H+).
Following a similar procedure to that described in reference example 11 , but using the corresponding starting material, the following compound was obtained:
Figure imgf000081_0001
REFERENCE EXAMPLE 12
6-Bromo-N-phenylpyrldin-3-amlne
To a stirred solution of 2-bromo-5-iodopyridine (2.0 g, 0.007 mol) in toluene (20 mL) was added aniline (0.98 g, 0.001 mmol), Cs2C03 (4.5 g, 0.014 mol) and BINAP (0.0009 mol). The resulting solution was degassed using nitrogen gas and then Pd?(dba)3 (0.64 g, 0.0007 mol) was added. The resulting reaction mixture was heated at 100°C for 16h. The reaction mixture was cooled to RT, diluted with water (50 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layers were dried over anhydrous Na?SO, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 10% EtOAc/ pet ether to obtain the title compound (0.5 g, crude) as a gummy liquid. The crude compound was used as such for next step without any further purification.
LC-MS (method 2): R, = 2.72 min; m/z = 250.97 (M+H-+2).
REFERENCE EXAMPLE 13
Tert-butyl benzyl(6-bromopyridin-3-yl)carbamate
Step a. N-Benzyl-6-bromopyridin-3-amine To a stirred solution of 6-bromo-3-amino pyridine (1 g, 0.005 mol) and benzaldehyde (0.61 g, 0.005 mol) in DCE (20 mL) was added a catalytic amount of acetic acid and 4Λ molecular sieves (0.1 g) at 10°C. The reaction mixture was stirred for 10 min, then sodium triacetoxy borohydride (2.46 g, 0.011 mol) was added at the same temperature. The resulting reaction mixture was allowed to stir at RT for 16h. The reaction was diluted with DCM (100 mL) and poured in satiurated NaHCOa aq. solution (50 mL). The organic layer was dried over anhydrous Na2S04, filtered and the filtrate was concentrated. The crude compound was purified by column chromatography using silica gel and eluted with EtOAc: pet ether (3:7) to afford the title compound (800 mg, 52%) as a light brown solid.
LC-MS (method 2): R, = 2.76 min; m/z = 263.10 (M+H+).
Step b. rerf-butyi benzyl(6-bromopyridin-3-yl)carbamate
To a stirred solution of the compound obtained in the previous section, step a, (0.6 g, 0.0023 mol) in THF (5 mL) was added DMAP (0.33 g, 0.0027 mol) and Boc20 (0.0025 mol) at RT. The resulting solution was heated at 75 °C for 16h. The reaction mixture was cooled to RT, diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na?SO„, filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 15-17% EtOAc/ pet ether to obtain the title compound (0.6 g, 73%) as a white color solid.
LC-MS (method 2): R, = 3.16 min; m/z = 365.07 (M+H++2).
Following a similar procedure to that described in reference example 13, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000082_0001
REFERENCE EXAMPLE 14
Tert-butyl (3-((6-bromopyridin-3-yl)oxy)propyl)carbamate
To a stirred solution of 6-bromopyridin-3-ol (1.5 g, 0.0086 mol), fert-butyl (2-bromoethyl)carbamate (2.46 g, 0.0103 mol) in DMF (25 mL) was added Nal (1.92 g, 0.0129 mol) followed by the addition of K2C03 (3.50 g, 0.0259 mol) at 0°C and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 25 mL) and the organic layer was dried over anhydrous Na?S04, filtered and the filtrate was concentrated under reduced pressure. The obtained crude compound was purified by flash column chromatography using 25% EtOAc in petroleum ether as eluent to afford the title compound (1.30 g, 46%) as an off-white solid.
LC-MS (method 2): Rt = 2.68 min; m/z = 331.18 (M+H+). REFERENCE EXAMPLE 15
2-Bromo-5-(3-phenylpropoxy)pyridine)
To a stirred suspension of 60% NaH (0.689 g, 17.24 mmol) in D F (20 mL) was added a solution of 6- bromopyridin-3-ol (1 g, 5.74 mmol) at 0°C, followed by the addition of (3-bromopropyl)benzene (1.14 g, 5.74 mmol) at 0°C and the reaction mixture was stirred at RT for 16 h. The mixture was quenched in cold ice water and extracted with EtOAc (3 x 40 mL) and the organic layer was dried over anhydrous Na?SO<j, filtered; the filtrate was concentrated under reduced pressure. The crude compound was purified by Grace column chromatography eluted with 20% ethyl acetate in pet ether to afford the title compound (760 mg, 45%).
LC-MS (method 2): Rt = 3.10 min; m/z = 292.34 ( +H*).
REFERENCE EXAMPLE 16
5-Bromo-N-(3-phenylpropyl)pyrazin-2-amine
To a stirred suspension of 60% NaH (0.27 g, 11.49 mmol) in DMF (10 mL) was added a solution of 5- bromopyrazin-2-amine (1 g, 5.75 mmol) in DMF (5 mL) at 0°C. The resulting solution was stirred for 15 min, then 3-phenyl 1-bromo propane (1.37 g, 6.89 mmol) was added at 0°C. The reaction mixture was allowed to RT and stirred for 16 h. The reaction mixture was quenched with water and extracted with EtOAc (3 X 30 mL). The separated organic layer was dried over anhydrous NajSO/,, filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 8% EtOAc in petroleum ether as an eluent to afford the title compound (0.8 g, 48%).
LC-MS (method 2): Rt = 2.95 min; m/z = 292.45 (M+H 'j.
Following a similar procedure to that described in reference example 16, but using the corresponding starting material, the following compound was obtained:
Figure imgf000083_0001
Terf-butyl (5-bromopyrazin-2-yl)(3-(diethylamino)propyl)carbamate Step a. N'-(5-Bromopyrazin-2-yl)-AP,W3-diethylpropane-1 ,3-diamine
In a microwave, to a stirred solution of 2,5-dibromopyrazine (3.0 g, 12.71 mmol) in n-BuOH (10 mL) was added W!,A/'-diethylpropane-1 , 3-diamine (1.652 g, 12.71 mmol), DIPEA (1.639 g, 12.71 mmol) and it was heated to 160°C for 30 minutes. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL) and brine solution (50 mL). The separated organic layer was dried over anhydrous a2S04, filtered and filtrate was concentrated under reduced pressure to afford the title compound (3.0 g). The crude compound was used as such in the next step without further purification.
LC-MS (method 8): Rt = 1.48 min; m/z = 287.22 (M+H*). Step b. fert-butyl (5-bromopyrazin-2-yl){3-(diethyl amino)propyl)carbamate
To a stirred solution of the compound obtained in the previous section, step a, (3.0 g, 10.48 mmol) in DCM (40 mL) was added DMAP (0.639 g, 5.24 mmol), TEA (2.116 g, 20.96 mmol) and Boc?0 (3.426 g, 15.72 mmol) at 0°C and allowed to stir at RT for 16 h. The reaction mixture was diluted with DCM (200 mL) and water (100 mL) and the separated organic layer was dried over anhydrous NajSCv, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography and eluted at 5% MeOH/DCM to afford the title compound (1.5 g, 37%) as a gummy
LC-MS (method 8): R, = 2.09 min; m/z = 387.39 (M+H+).
REFERENCE EXAMPLE 18
Terf-butyl (3-((6-bromopyridin-3-yl)amino)-3-oxopropyl)(phenethyl)carbamate
Step a. W-(6-Bromopyridin-3-yl)-3-chloropropanamide
To a solution of 6-bromopyridin-3-amine (4.0 g, 23.25 mmol) in DCM (60 mL) was added pyridine (5.51 g, 69.75 mmol) and 3-chloropropanoyl chloride (3.515 g, 27.9 mmol) at 0°C and allowed to stir at RT for 12 h. The reaction mixture was diluted with DCM (200 mL) and washed with water (100 mL) and brine solution (100 mL). The separated organic layer was dried over anhydrous Na2SC¼, filtered and concentrated under reduced pressure to afford the title compound (4.5 g, 73%) as a brown colour liquid.
Step b. N-(6-Bromopyridin-3-yl)-3-(phenethylamino)propanamide
To a stirred solution of the compound obtained in the previous section, step a, (4.4 g, 16.79 mmol) in DMF (30 mL) was added TEA (3.391 g, 33.58 mmol) and 2-phenylethanamine (4.063 g, 33.58 mmol) at 0°C and allowed to stir at RT for 16h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (100 mL) and brine solution (2 x 100 mL). The separated organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted at 3% MeOH/DCM to afford the title compound (4.2 g, 72%) as a colorless gummy solid.
LC-MS (method 8): Rt = 1.79 min; m/z = 350.11 (M+H*+2).
Step c. Tert-butyl (3-((6-bromopyridin-3-yl)amino)-3-oxopropyl)(phenethyl)carbamate
To a stirred solution of the compound obtained in the previous section, step b, (4.0 g, 11.52 mmol) in 1 ,4- dioxane/water (1 :1 , 40 mL) was added NaOH (0.922 g, 23.054 mmol) and Boc?0 (7.5 g, 34.58 mmol) at 0°C and allowed to stir at RT for 16 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (100 mL) and brine solution (100 mL). The separated organic layer was dried over anhydrous Na2SC¼, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography and eluted at 25% EtOAc/Pet ether to afford the title compound (4.0 g, 77%) as a colorless gummy solid.
LC-MS (method 9): R, = 2.57 min; m/z = 450.04 (M+H*+2).
Following a similar procedure to that described in reference example 18, but using the corresponding starting material, the following compound was obtained: Reference Starting HPLC Rt
Compound name m/z example material method (min)
Tert-butyl (3-((6-bromopyridin-3- 373.98
18a Ethylamine 1 2.17
yl)amino)-3-oxopropyl)(ethyl)carbamate (M+H++2)
REFERENCE EXAMPLE 19
Tert-butyl (5-bromopyrazin-2-yl)(2-{diethylamino)ethyl)carbamate
Step a. AT-iS-Bromopyrazin^-ylJ-^AP-diethylethane-l ^-diamine
To a stirred suspension of 60% NaH (1.0 g, 43 mmol) in DMF (30 mL), 5-bromopyrazin-2-amine (2.5 g, 14.45 mmol) at RT was added and stirred for 10 min followed by the addition of 2-bromo-A/,W-diethylethan-1-amine dihydrochloride (3.88 g, 21.6 mmol) at RT. The reaction mixture was stirred for 16 h at RT. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SOi and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 0-5% MeOH in DCM as eluent to afford the title compound (1.8 g, 45%) as colorless liquid.
LC-MS (method 1): R, = 1.08 min; m/z = 275.17 (M+H++2).
Step b. Tert-butyl (5-bromopyrazin-2-yl)(2-(diethylamino)ethyl)carbamate
To a stirred suspension of 60% NaH (0.420 g, 17.58 mmol) in DMF (20 mL) the compound obtained in the previous section, step a, (1.6 g, 5.86 mmol) was added followed by the addition of Boc-anhydride (1.9 g, 8.79 mmol) at 0°C and the reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO< and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 0-5% MeOH in
DCM as eluent to obtain the title compound (1.0 g, 45%) as an off-white solid.
LC-MS (method 8): Rt = 1.95 min; m/z = 375.23 (M+H-+2).
REFERENCE EXAMPLE 20
Tert-butyl (3-{(6-bromopyridin-3-yl)amino)-3-oxo-1-phenylpropyl)(ethyl)carbamate
Step a. Methyl 3-amino-3-phenylpropanoate
To a stirred solution of 3-amino-3-phenylpropanoic acid (4.0 g, 24.24 mmol) in MeOH (50 mL) SOCb was added (8.6 g, 72.72 mmol) at 0°C. The resulting solution was heated at 70°C for 16h. The reaction mixture was evaporated under reduced pressure The crude compound was dissolved in DCM (100 mL) and washed with saturated NaHCOs solution (2 x 70 mL), the organic layer were washed with brine solution (50 mL), dried over Na2S04 and concentrated to obtain the title compound (3.1 g, 72%) as a colorless liquid.
LC-MS (method 1): Rt = 0.88 min; m/z = 180.17 (M+H+).
Step b. Methyl 3-(ethylamino)-3-phenylpropanoate
To a stirred solution of the compound obtained in the previous section, step a, (2.0 g, 11.17 mmol) in EtOAc, (10 mL) was added ethyl trifluoromethane sulfonate (2.58 g, 14.52 mmol) and a solution of NaHCOs (3.51 g, 33.51 mmol) in water (10 mL). The resulting solution was stirred at RT for 16h. The reaction mixture was diluted with water (50 mL), and extracted with EtOAc (2 x 70 mL), the combined organic layer were dried over Na2S04 and concentrated to obtain the title compound (1.7 g, crude) as a liquid compound. The crude compound was used for next step without further purification.
LC-MS (method 1): Rt = 1.03 min; m/z = 208.21 (M+H+).
Step c. Methyl 3-((tert-butoxycarbonyl)(ethyl)amino)-3-phenylpropanoate
To a stirred solution of the compound obtained in the previous section, step b, (1.7 g, 8.17 mmol) in ACN (20 mL) was added TEA (1.66 g, 16.42 mmol) and Boc?0 (2.7 g, 12.31 mmol) at RT. The resulting solution was stirred at RT for 16h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layer was dried over is^SO* and concentrated. The crude compound was purified by silica gel (100-200 mesh) flash column chromatography eluted with 30% EtOAc/ pet ether to obtain the title compound (0.9 g, 26%) as a colorless liquid.
Step d. 3-((7ert-butoxycarbonyl(ethyl)amino)-3-phenylpropanoic acid
To a stirred solution of the compound obtained in the previous section, step c, (1.5 g, 4.88 mmol) in THF-MeOH (10 mL, 1 :1) was added a solution of LiOH.H20 (0.61 g, 14.65 mmol) in water (2 mL) at 0°C. The resulting solution was stirred at RT for 3h. The reaction mixture was evaporated under reduced pressure, the residue was dissolved in water (20 mL), acidified (pH ~4) with saturated citric acid solution and extracted with EtOAc (2 x 70 mL), The combined organic layer was dried over Na2Si¾ and concentrated to obtain the title compound (1.2 g, 84%) as a colorless liquid.
LC-MS (method 1): R, = 2.20 min; m/z = 291.92 (M-H+).
Step e. Terf-butyl (3-{(6-bromopyridin-3-yl)amlno)-3-oxo-1-pheny!propyl)(ethyl)carbamate
To a stirred solution of the compound obtained in the previous section, step d, (0.9 g, 3.07 mmol) and 6- bromopyridin-3-amine (0.58 g, 3.37 mmol) in DCM (10 mL) and TEA was added (0.93 g, 9.21 mmol) was added followed by T3P (50% solution in EtOAc) (2.93 g, 9.21 mmol) at 0°C and the reaction mixture was allowed to stir at RT for 16h. The reaction mixture was diluted with water (50 m) and extracted with DCM (2 x 70 mL). The combined organic layers dried over NazSO,, filtered and the filtrate was concentrated under reduced pressure. The obtained crude compound was purified by silica gel flash column chromatography and eluted at 35% EtOAc/ pet ether to afford the title compound (0.6 g, 44%) as an off white solid.
LC-MS (method 8): R, = 2.94 min; m/z = 450.26 (M+H++2).
REFERENCE EXAMPLE 21
Tert-butyl (3-(1W-pyrazol-1-yl)propyl)(5-bromopyrazln-2-yl)carbamate Step a. 3-(1 H-Pyrazol-1 -yl)propanenitrile
A stirred solution of 1 H-pyrazole (5 g, 73.44 mmol) in acrylonitrile (20 mL) was heated to 80°C for 20h. The reaction mixture was concentrated under reduced pressure to remove the excess of acrylonitrile to give the title compound (7 g, crude) as a liquid. The compound was used as such for the next step without any further purification.
LC-MS (method 14): Rt = 3.51 min; m/z = 122.1 (M+H*).
Step b. 3-(1H-Pyrazol-1-yl)propan-1 -amine hydrochloride To a stirred solution of of the compound obtained in the previous section, step a, (5 g, 41.27 mmol) in methanol (15 mL) was added a suspension of Raney-Nickel (1 g, wet) in methanol (15 mL) and then 25% NH4OH solution (5 mL) was added. The reaction mixture was hydrogenated at 75 psi for 8h. The reaction mixture was then filtered through the Celite, the filtrate was evaporated to remove methanol. The aqueous residue was extracted with DCM (30 mL x 2) and the combined organic layer was dried over anhydrous Na2S04, filtered and the filtrate was evaporated to get 3.5 g of 1 H-pyrazol-1 -yl)propan-1 -amine as a liquid. The obtained compound was converted to its hydrochloride by adding 2M HCi in diethyl ether (20 mL) and evaporated to get the title compound (4 g, 77.4 %).
LC-MS (method 1): R, = 0.31 min; m/z = 126.15 (M+H*).
Step c. W-(3-(1 H-Pyrazol-1 -yi)propyl)-5-bromopyrazin-2-arnine
In a microwave vial, a solution of 2,5-dibromopyrazine (1.5 g, 6.30 mmol) in n-BuOH (10 mL) was added to the compound obtained in the previous section, step b, (1.22 g, 7.56 mmol) and DIPEA (3.3 mL, 18.91 mmol). The resulting reaction mixture was irradiated under microwave at 150°C for 30 min. The reaction mixture was diluted with EtOAc (200 mL), washed with water (80 mL), brine (50 mL), dried over anhydrous Na^SO-, filtered and the filtrate was concentrated under reduced pressure to afford the title compound (1.5 g, crude) as a brown gummy liquid.
LC-MS (method 9): Rt = 1.72 min; m/z = 281.84 (M+H").
Step d. Terf-butyi (3-(1 H-pyrazol-1 -yl)propyl)(5-bromopyrazin-2-yl)carbamate
To a stirred solution of the compound obtained in the previous section, step c, (1.5 g, 5.319 mmol) in ACN (15 mL), TEA (2.2 mL, 15.95 mmol), Boc20 (1.73 g, 7.97 mmol) and DMAP (0.12 g, 1.06 mmol) were added at 0 °C. The reaction mixture was allowed to stir at RT for 16h. The reaction mixture was concentrated; the residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (30 mL), dried over anhydrous NazSO^ filtered and the filtrate was concentrated. The crude compound was purified by column chromatography using silica gel and the product was eluted with 20% EtOAc/pet ether to afford the title compound (1.2 g, 54%) as a pale yellow liquid.
LC-MS (method 6): R, = 2.85 min; m/z = 384.31 (M+H++2).
REFERENCE EXAMPLE 22
3-({5-Bromopyrazin-2-yl)oxy}-W,W-diethylpropan-1-amine
To a stirred solution of 3-(diethylamino)propan-1-ol (1.5 g, 11.43 mmol) in DMF (25 mL) 60% NaH (0.91 g, 22.86 mmol) was added at 0°C and the resulting solution was stirred for 5 min at 0°C, then added 2,5- dibromopyrazine (2.9 g, 12.5 mmol) at 0°C. The reaction mixture was stirred at RT for 16 h and quenched with cold water and extracted with EtOAc (3 X 30 mL). The organic layer was dried over anhydrous Na2SO, and concentrated under reduced pressure. The obtained crude compound was purified by Grace column chromatography (reverse phase) eluted with 35% ACN: 0.1% HCOOH (aq) to afford the title compound (670 mg, 20%).
LC-MS (method 1): RT = 1 13 min; m/z = 290.20. (M+H++2). 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
3-((6-Bromopyridin-3-yl)methoxy)-W,W-diet ylpropan-1-amine Step a. 3-Chloro-JV,W-dIethylpropan-1 -amine hydrochloride
To a stirred solution 3-(diethylamino)propan-1-ol (1 g, 7.63 mmol) in DCM (10 mL) was added SOC (1.1 mL, 15.26 mmol) at 0 °C and the mixture was stirred at rt for 3 h. The reaction was concentrated under reduced pressure to obtain the title compound (1 g, 88%).
Step b. 3-((6-Bromopyridin-3-yl)methoxy)-N,W-diethylpropan-1 -amine
To a stirred suspension of 60% NaH (638 mg, 15.95 mmol) in DMF (10 mL) was added a solution of (6- bromopyridin-3-yl)methanol (1 g, 5.31 mmol) in DMF (10 mL) at 0 °C and stirred for 10 min, then added compound obtained in previous section, step a (792 mg, 5.31 mmol) at °0 C. The reaction mixture was allowed to rt and stirred for 6 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was concentrated under reduced pressure and the obtained crude compound was purified by Grace column chromatography (reverse phase), eluted with 35% of 0.1% of FA (aqueous) in ACN to afford the title compound (450 mg, 28%)
LC-MS (method 1): Rt = 1.13 min; m/z = 302.99 (M+H++2).
Following a similar procedure to that described in reference example 23, but using the corresponding starting material, the following compound was obtained;
Reference HPLC Rt
Compound name Starting material m/z example method (min)
4-(2-((6-Bromopyridin-3- 6-Bromopyridin-3-ol and 4- 276.17
23a 8 1.35
yl)oxy)ethyl)morpholine (2-bromoethyl) morpholine (M+H++2)
(6-Bromopyridin-3-
2-((6-Bromopyridin-3- yl)methanol and 2-bromo- 289.11
23b yl)methoxy)-/V,W- 8 1.51
N,W-diethylethan-1 -amine (M+H-+2) diethylethan-1 -amine
dihydrochloride 2-Bromo-5-
2-Bromc~5- 294.22
23c (bromomethyl)pyridine and 21 2.43
(phenethoxymethyl)pyridine (M+H++2)
2-phenylethan-1-ol
2-Bromo-5-((3- (6-Bromopyridin-3-
306.30
23d pheny!propoxy) yl)methanol and (3- 21 2.60
(M+H*) methyl)pyridine bromopropyl)benzene
2-Bromo-5- (6-Bromopyridin-3-
284.28
23e ((cyclohexylmethoxy)methyl) yl)methanol and 21 2.78
(M+H+) pyridine (bromomethyl)cyclohexane
2-Bromo-5- 2-Bromo-5-
270.22
23f ((cyclopentylmethoxy)methyl (bromomethyl)pyridine and 21 2.57
(M+H*) )pyridine) cyclopentylmethanol
5-(3-{ Benzyloxy) propoxy)-2- Reference example 35d
21 322.27
23g and benzyl bromide 2.47
bromopyridine (M+H*)
2-Bbromo-5-
2-Bromo-5-((2-(4,4- (bromomethyl)pyridine and
337.08
23h difluoropiperidin-1-
2-(4,4-difluoropiperidin-1- 24 0.41
(M+H++2) yl)ethoxy)methyl)pyridine yl)ethanol
REFERENCE EXAMPLE 24
3-((6-Bromopyridin-3-yl)oxy)-N,W-diethylpropan-1-amine
To a stirred solution of 6-bromopyridin-3-ol (5.0 g, 28.73 mmol) in THF (50 mL) was added PPh3 (15.0g, 57.47 mmol), DIAD (8.7 g, 43.10 mmol) and followed by 3-(diethyiamino)propan-1-ol (5.64 g, 43.10 mmol),at 0°C. The reaction mixture was allowed to stir at RT for 16h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over anhydrous NajSO,, filtered and the filtrate was concentrated. The crude compound was purified by flash column chromatography using 100-200 silica gel and eluted with 40% EtOAc/pet ether to afford the title compound (3.1 g, 38%) as a gummy liquid.
LC-MS (method 6): R, = 1.50 min; m/z = 287.18 (M+H*)
REFERENCE EXAMPLE 25
fert-butyl (6-bromopyridin-3-yl)(3-(diethylamino)propyl)carbamate Step a. 3-Chloro-M,W-diethylpropan-1 -amine hydrochloride
To a stirred solution 3-(diethylamino)propan-1 -ol (1 g, 7.63 mmol) in DCM (10 mL) was added SOCb (1.1 mL, 15.26 mmol) at 0 °C and the mixture was stirred at rt for 3 h. The reaction was concentrated under reduced pressure to obtain the title compound (1 g, 88%). Step b. Terf-butyl (6-bromopyridin-3-yl)(3-(diethylamino)propyl)carbamate
To a stirred suspension of 60% NaH (0.15 g, 6.598 mmoi) in DMF (50 mL) was added a solution of terf-butyl (6- bromopy rid i n-3-y l)carbamate (1.2 g, 4.399 mmol) in DMF (10 mL) at 0 °C. The mixture was stirred for 15 min, and then the compound obtained in the previous section, step a, was added (0.785 g, 5.274 mmol) to the reaction mixture at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc, concentrated the organic layer under reduced pressure and the obtained crude compound was purified by flash column chromatography using 100% EtOAc as an eluent to obtain the title compound (0.9 g, 53)
LC-MS (method 20): Rt = 1.55 min; m/z = 388.09 (M+H*+2).
Following a similar procedure to that described in reference example 25, but using the corresponding starting material, the following compound was obtained:
Figure imgf000090_0001
2-(1-(6-Bromopyridin-3-yl)-1H-pyrazol-4-yi)-N,N-diethylethan-1-amine Step a. 4-(2-Chloroethyl -1W-pyrazole
A mixture of thionyl chloride (6.318 g, 53.55 mmol) and 2-(1 H-pyrazol-4-yl)ethan-1 -ol (2.0 g, 17.85 mmol) was heated to 70°C for 15 minutes. The reaction mixture was concentrated under reduced pressure, the residue was triturated with ethanol/diethyl ether to the title compound (2.3 g, 98%) as an off-white solid.
LC-MS (method 6): R, = 1.61 min; m/z = 131.06 (M+H+).
Step b. W,Af-Diethyl-2-(1W-pyrazol-4-yl)ethan-1 -amine hydrochloride
To a solution of the compound obtained in the previous section, step a, (2.3 g, 17.69 mmol) in water (10 mL) was added diethyl amine (12.91 g, 176.9 mmol) and heated to 60°C for 16h. The reaction mixture was cooled to RT and concentrated under reduced pressure to the title compound (2.8 g, 94%) as a gummy.
Step c. 2-{1-(6-bromopyridin-3-yl)-1H-pyrazol-4-yl)-W,W-diethylethan-1 -amine
To a solution of the compound obtained in the previous section, step b (2.8 g, 17.96 mmol) in DMSO (20 mL) was added 2-bromo-5-fluoropyridine (6.286 g, 35.92 mmol) and K2CO3 (7.435 g, 53.88 mmol), heated to 90°C for 16h The reaction mixture was cooled to rt, diluted with EtOAc (100 mL) and water (100 mL); the separated organic layer was washed with water (100 mL) and brine solution (100 mL) and dried the organic layer over anhydrous Na2S0 , filtered and concentrated. The crude compound was purified by silica gel flash column chromatography and eluted at 3% MeOH/DCM to afford the title compound (1.5 g, 26%) as an off-white solid. LC-MS (method 1): R, = 1.69 min; m/z =323.22 (M+H+).
REFERENCE EXAMPLE 27
Tert-butyl (3-((6-bromopyridin-3-yl)(methyl)amino)-3-oxopropyl)carbamate Step a. Tert-butyl (6-bromopyridin-3-yl)(methyl)carbamate
To a stirred solution of ferf-butyi 6-bromopyridin-3-ylcarbamate (1.5 g, 5.51 mmol) in THF (20mL) was added NaH (441 mg, 11.02 mmol) at 0°C and then allowed to stir at RT for 30min. The reaction mixture was cooled to 0°C, added Mel (0.7 mL, 11.02 mmol) and then allowed to stir at RT for 2h. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The separated organic layer was washed with water and brine solution and the organic layer was dried over anhydrous Na2S04, filtered and concentrated. The crude compound was purified by column chromatography using silica gel and eluted with 20% EtOAc: pet ether to afford the title compound (1.3 g, 83%) as a white solid.
LC-MS (method 22): Rt = 2.28 min; m/z = 286.82 (M+H++2).
Step b. 6-Bromo-W-methy!pyridin-3-amine
To a stirred solution of the compound obtained in the previous section, step a, (1.3 g, 4.54 mmol) in DCM (5 mL) was added TFA (3 mL) at 0°C and allowed to stir at RT for 3 h. The reaction mixture was concentrated and the residue was washed with n-pentane and diethyl ether. The obtained compound was dissolved in water and basified to pH-8 using saturated NaHC03 solution and the precipitated solid was filtered, washed with water and dried to afford the title compound (0.9 g, 66%) as a free base.
LC-MS (method 1): R, = 1.47 min; m/z = 186.91 (M+H*).
Step c. Tert-butyl (3-((6-bromopyridin-3-yl)(methyl)amino)-3-oxopropyl)carbamate
To a stirred solution of the compound obtained in the previous section, step b, (450 mg, 2.41 mmol) and 3-(tert- butoxycarbonylamino) propanoic acid (457 mg, 2.41 mmol) in DCM (10 mL) was added Eh (1.7 mL, 12.09 mmol) and T3P (2.3 g, 7.25 mmol) at RT. The reaction mixture was stirred at RT for 16h. The reaction mixture was diluted with DCM (20 mL) and water (20 mL). Separated the organic layer, washed with water (20 mL), brine solution (10 mL) and dried over anhydrous Na?SC>4 and concentrated. The crude compound was purified by flash column chromatography and eluted at 50% EtOAc/Pet Ether to afford the title compound (0.3 g, 35%) as a white solid.
LC-MS (method 1): Rt = 1.86 min; m/z = 358.20 (M+H *).
REFERENCE EXAMPLE 28
N-(6-Bromopyridin-3-yl)-3-(ethyl(phenethyS)amino)propanamide
Step a. N-(6-Bromopyridin-3-yl)-3-(phenethyiamino) propanamide hydrochloride
4M HCI in 1 ,4-dioxane (10 mL) was added to a stirred solution of reference example 8 (2.2 g) in 1 ,4-dioxane (5 mL) at 0°C and allowed to stir at rt for 3h. The reaction mixture was concentrated under reduced pressure, the residue was washed with n-pentane and diethyl ether to afford the title compound (1.8 g) as a HCI salt.
LC-MS (method 18): R, = 1.81 min; m/z = 348.26 (M+H*).
Step b. N-(6-Bromopyridin-3-yl)-3-(ethyl (phenethyl) amino) propanamide
To a stirred solution of the compound obtained in the previous section, step a (2.0 g, 5.763 mmol, HCI salt) in MeOH (30 mL) was added acetaldehyde (2.5 g, 57.636 mmol), 4λ molecular sieves (2.0 g) and acetic acid (2 mL) at 0°C and stirred for 30 minutes at the same temperature. NaCNBH3 (0.905 g, 14.409 mmol) was added to the above reaction mixture and allowed to stir at rt for 16h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, basified to pH~8 using saturated NaHCCb solution and filtered through Celite pad. The organic layer was separated from the filtrate and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford the title compound (1.5 g, 69%) as a pale yellow semi solid. LC-MS (method 1): Rt = 1.50 min; m/z = 376.36 (M+H+).
REFERENCE EXAMPLE 29
3-(6-Bromopyridin-3-yl)-N,N-diethylprop-2-yn-1-amine
To a stirred solution of 2-bromo-5-iodopyridine (3.0 g, 10.60 mmol), N,N-diethylprop-2-yn-1-amine (1.64 g, 14.84 mmol) in THF (50 mL) was added Pd (PPh3)?CI? (0.37 g, 0.53 mmol), TEA (5.30 g, 53 mmol), Cul (0.2 g, 1.06 mmol) at rt. The reaction mixture was heated to 60 °C for 18 h in a sealed tube, the mixture was allowed to cool to rt and diluted with water (100 mL) and extracted with ethyl acetate. The organic layer was dried over anhydrous Na?SC"4, filtered, the filtrate was concentrated under reduced pressure and the obtained crude compound was purified by Grace Column chromatography (reverse phase) using 40% acetonitrile in 0.1% aq. formic acid as an eluent to afford the title compound(1.50 g, 53%) as brown liquid.
LC-MS (method 1): Rt = 1.19 min; m/z = 266.91 (M+H*).
REFERENCE EXAMPLE 30
1-(3-Chloropropyl)-1H-pyrazole
To a stirred solution of 1H-pyrazole (5 g, 73.44, mmol) in THF was added NaH (3.52 g, 88.13 mmol) and followed by added 1 -bromo-3-chloropropane (13.8 g, 88.13 mmol) at RT. The reaction mixture was allowed to stir at RT for 24 h. The reaction mixture was poured into cold water and extracted with EtOAc (3 x 100 ml). The organic layer was dried over anhydrous NaiSO*, filtered and concentrated. The crude compound was purified by column chromatography using 230-400 silica gel and the product was eluted with 20 % EtOAc / pet ether to afford 5.7 g (53 %) of the title compound.
LC-MS (method 1): R, = 1.49 min; m/z = 144.86 (M+H+).
REFERENCE EXAMPLE 31
Tert-butyl (3-(1 H-pyrazol-1 -yl)propyl)(6-bromopyridin-3-yl)carbamate To a stirred solution of compound te/f-butyl (6-bromopyridin-3-yl)carbamate (1.0g, 1.0 equiv) in acetonitrile was added compound reference example 30 (1.2 equiv) and CS2CO3 (3.0 equiv) and heated to 70°C for 16h. Progress of the reaction was monitored by LCMS. The reaction mixture was cooled to rt and diluted with acetonitrile, filtered through Celite pad; the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography and eluted with 30% EtOAc/pet ether to afford 700 mg of the title compound.(60.13 % yield)
LC-MS (method 1); Rt = 2.69 min; m/z = 381.28 (M+H+).
REFERENCE EXAMPLE 32
N-(3-(1H-Pyrazol-1-yl)propyl)-6-bromo-N-methylpyridin-3-amine Step a . N-(3-(1H-Pyrazo!-1-yl)propyl)-6-bromopyridin-3-amine
4M HCI in 1 , 4-dioxane (5 mL) was added to a solution of reference example 31 (1.0 g, 1 equiv) in 1, 4-dioxane at 0°C. The reaction mixture was allowed to stir at RT for 3h. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated; the residue was triturated with diethyl ether and under reduced pressure to afford 800 mg of the title compound in quantitative yield.
LC-MS (method 1): F¾ = 1.73 min; m/z = 283.00 (M+H++2).
Step b. N-(3-(1 H-Pyrazo!-1 -yl)propyl)-6-bromo-N-methylpyridin-3-amine
To a stirred solution of the compound obtained in the previous section, step a (750 mg, 1.0 equiv) in MeOH was added paraformaldehyde (10 equiv), molecular sieves and catalytic acetic acid at 0°C and stirred for 30 minutes at the same temperature, followed by added NaCNBH?..(2.5 equiv) and allowed to stir at rt fr 16h and the progress of the reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water and basified to pH~8 using saturated NaHCOj solution, filtered through Celite pad. The separated aqueous layer was extracted with EtOAc (2 x 100 mL) and the combined organic layer was dried over anhydrous feSO^ filtered and concentrated under reduced pressure to afford 700 mg of the title compound (89.5 % yield).
LC-MS (method 6): R, = 2.48 min; m/z = 295.17 (M+H+).
Following a similar procedure to that described in reference example 32, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000093_0001
REFERENCE EXAMPLE 33
4-(6-Bromopyridin-3-yl)-W,Akiiethylbutan-1-amine
Step a . 4-(6-Methoxypyridin-3-yl)but-3-yn-1-ol
To a stirred solution of 5-bromo-2-methoxypyridine (15 g, 1 equiv) and but-3-yn-1-ol (1.5 equiv) in TEA (2 ml) was added Cul (0.2 equiv) and Pd (Ppr^Cb (0.05 equiv). The reaction mixture was heated to 50°C for 16h.
LCMS indicates that 50 % of desired product formation. The reaction mixture was diluted with cold water and extracted with EtOAc (2 x 100 mL) and washed with water and brine solution. The separated organic layer was dried over anhydrous Na2S04, filtered and filtrate was concentrated under reduced pressure to afford 16 g of crude. The crude was purified by column chromatography using 10 % EtOAc/ pet-ether on 100-200 silica to afford 9 g (63.7 % yield) of the title compound, as a light brown gummy liquid.
LC-MS (method 8): Rt = 2.15 min: m/z = 178.16 (M+H+).
Step b . 4-(6-Methoxypyridin-3-yl)butan-1-ol To a stirred solution of the compound obtained in the previous section, step a, (9 g, 1 equiv) and 10% Pd/C (30% w/w) in MeOH (10 ml) was under 80 psi pressure in par hydrogenated for 10 h. The reaction mixture was filtered through Celite pad and washed with MeOH (5 mL). The filtrate was concentrated under reduced pressure to afford 8 g (86.9 % yield) of the title compound, as a light brown gummy liquid.
LC-MS (method 8): Rt = 1.97 min; m/z = 182.17 (M+H+).
Step c , 2-Bromo-5-(4-bromobutyl)pyridine
4-(6-MethoxypyrJdin-3-yl)butan-1 -ol (8 g. 1.0 eq) and POBr3 (2.0 eq) was heated at 110°C for 3 h (. The reaction mixture was allowed to RT and the mixture was quenched with ice cold water (50 mL), neutralized with sat. Na2HCOs solution and extracted with EtOAc (3 x 80 mL) The combined organic layers were dried over anhydrous feSCU, filtered; the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography on 230-400 silica with 5 % EtOAc/pet-ether to afford 5 g (38.7 % yield) of the title compound,
LC-MS (method 8): R, = 2.98 min; m/z = 292.14 (M+H*).
Step d . 4-(6-Bromopyridin-3-yl)-N,W-diethylbutan-1-amine
To a solution of the compound obtained in the previous section, step c, (2 g, 1.0 equiv) in THF (1 mL), diethyl amine (5,0 equiv) was added and allowed to stir at RT. The reaction was concentrated under reduced pressure to get 2.3 g the crude compound 8, as a gummy solid. Purified by column chromatography using, 230-400 silica with 8% MeOH/DCM to afford 1.7 g (87.3 % yield) of the title compound .
LC-MS (method 1): R- = 1.26 min; m/z = 287.04 (M+H++2).
Following a similar procedure to that described in reference example 33, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000094_0001
6-Bromo-N-(2-(pyridin-2-yl)ethyl)pyridin-3-amine
To a stirred suspension of 60% NaH (0.83 g, 34.682 mmol) in DMF (2 mL) was added a solution of 6- bromopyridin-3-amine (1 g, 5.780 mmol) in DMF (2 mL) at rt and stirred for 30 min. Then, 2-(2- bromoethyl) pyrid ine (1.29 g, 6.936 mmol) was added at rt and the resulting mixture was heated at 90 °C for 24 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc (3 x 100 ml). The organic layer was dried over anhydrous NajSO,, filtered and concentrated, the crude compound was purified by column chromatography using 50% EtOAc as an eluent to obtain the title compound (0.3 g, 17%).
LC-MS (method 17): R, = 4.99 min; m/z = 278.1 (M+H-).
Following a similar procedure to that described in reference example 34, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000095_0001
REFERENCE EXAMPLE 35
5-(Benzyloxy)-2-bromopyridine
To a stirred solution of 6-bromopyridin-3-ol (500 mg, 2.87 mmol) in DMF (10 mL), KOH (482 mg, 8.61 mmol) was added at rt. The resulting mixture was stirred for 15 min at rt and then, benzyl bromide (737 mg, 4.31 mmol) was added at 0 "C. The resulting solution was stirred at rt for 16h. Then, it was diluted with water (100 mL), and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na?S04 and concentrated. The crude compound was purified by flash column chromatography and eiuted with 15% EtOAc/ pet ether to obtain the title compound (0.5 g, 66%) as an off white color solid.
LC-MS (method 23): Rt = 1.92 min; m/z = 265.95 (M+H++2).
Following a similar procedure to that described in reference example 35, but using in each case the corresponding starting materials, the following compounds were obtained:
Reference Starting HPLC Rt
Compound name m/z example material method (min)
(2-
278.17
35a 2-Bromo-5-phenethoxypyridine Bromoethyi)be 21 2.52
(M+H+) nzene 6
35b 2-Bromo-5-(3-phenylpropoxy)pyridine (3- 21 2.71 294.18 Bromopropyl)b (M+H++ enzene 2)
2-Bromo-5-butoxypyridine 230.25
35c 1-lodobutane 23 2.07
(M+H+)
3-
3-((6-Bromopyridin-3-yi)oxy)propan-1-
Bromopropan- 232.00
35d oi 27 1.37
1-ol (M+H*)
REFERENC ≡ EXAMPLE 36
2-{[1l1'-Biphenyl]-4-yl)-A/-(6-bromopyridin-3-yl)-W-butylacetamide
Step a. 6-Bromo-N-butylpyridin-3-amine
To a stirred solution of 6-bromopyridin-3-amine (10 g, 57 mmol) in MeOH (100mL), butyraldehyde (4.9 g, 69.36 mmol) was added and stirred for 16h at rt. It was cooled to 0°C and NaBhhCN (7.2 g, 115.6 mmol) was added. The resulting mixture was stirred at RT for 16 h. The reaction mixture was poured in to cold water (100 mL), extracted with EtOAc (2x 200 mL) and washed with brine solution (150 mL). The organic layers were dried over anhydrous NazSO^ filtered and concentrated under reduced pressure to get crude compound that was purified by column chromatography with 13% EtOAc/ pet-ether to afford 7 g (52 %) of the title compound.
LC-MS (method 28): R, = 2.31 min; m/z = 229.16 (M+H*).
Step b. 2-([1 ,1 '-Biphenyl]-4-yl)-N-(6-bromopyridin-3-yl)-A/-butylacetamide
To a solution of the compound obtained in the previous section, step a, (2 g, 8.72 mmol) and 2-(biphenyl-4- yl)acetic acid (2.2 g, 10.47 mmol) in DCM (20 mL), T3P (8.3 mL, 26.18 mmol) and TEA (6 mL, 43.64 mmol) were added at 0°C and allowed to stir at RT for 16h. The reaction mixture was poured into cold water (30 mL), extracted with EtOAc (2 x 50 mL) and washed with brine solution (30 mL). The separated organic layers were dried over anhydrous Na?SO,, filtered and concentrated under reduced pressure to get crude compound that was purified by column chromatography with 15 % EtOAc/ pet-ether to afford 1.9 g (51 %) of of the title compound.
LC-MS (method 27): Rt = 2.54 min; m/z = 423.18 (M+H*).
Following a similar procedure to that described in reference example 36, but using in each case the corresponding starting materials, the following compounds were obtained:
Reference Starting HPLC Rt
Compound name m/z example material method (min)
N-(6-Bromopyridin-3-yl)-A/-butyl-[1 ,1'- [1 ,1'-Biphenyl]-4- 411.20
36a 26 1.40
biphenylj-4-carboxamide carboxylic acid (M+H++2)
W-(6-Bromopyridin-3-yl)-W-butyl-3- 3- 363.25
36b 28 2.50
phenylpropanamide Phenylpropanoic (M+H++2) acid
1-
Methylcyclobutan
N-(6-Bromopyridin-3-yl)-N-butyl-1 - 327.14
36c e-1-carboxylic 29 1.27
methyl cyclobutane carboxamide (M+H*+2) acid
3-((Tert-
Terf-butyl (3-({6-bromopyridin-3- butoxycarbonyl)a
400.14
30
36d yl)(butyl)amino)-3-oxopropyl) mino)propanoic 3.02
(M+H+) carbamate
acid
2-
N-(6-Bromopyridin-3-yl)-W-butyl-2-
Cyclobutylacetic 31 327.26
36e cyclobutylacetamide 2.88
acid (M+H++2)
3-
/V-(6-Bromopyridin-3-yl)-N-butyl-3- Methoxypropanoi 315.12
32
36f 2.40
methoxypropanamide c acid (Μ+Η')
REFERENC E EXAMPLE 37
,1 '-Biphenyl]-4-ylmethyl)-6-bromo-Ai-butylpyridin-3-amine
To a stirred solution of reference example 36a (2 g, 4.88 mmol) in THF (2 mL), BH3-DMS (1.4 mL, 14.6 mmol) was added and heated to 65°C for 16 h. The reaction mixture was allowed to temper and cooled to 0°C. It was quenched with MeOH (10 mL). Then, it was evaporated to get a residue that was solved with EtOAc (100 mL), washed with cold water, dried over NaaSO.-., and evaporated to get a crude residue. The crude compound was purified by column chromatography on 230-400 silica with 10 % EtOAc/pet-ether to afford 350 mg (18 %)of the title compound as a gummy solid.
LC-MS (method 26): R, = 1.57 min; m/z = 397.17 (M+H++2).
Following a similar procedure to that described in reference example 37, but using the corresponding starting material, the following compound was obtained:
Figure imgf000097_0001
terf-butyl (6-bromopyridin-3-yl)(3-(4,4-difiuoropiperidin-1-yi)propyl)carbamate Tert-butyl (6-bromopyridin-3-yl)(3-chloropropyl)carbamate To a stirred solution of tert-butyi 6-bromopyridin-3-ylcarbamate {2.0 g, 7.352 mmol) in DMF (20 mL), 60%NaH (0.529 g, 22.05 mmol) was added at 0°C and stirred at rt for 15 minutes. Then, 1 -bromo-3-chioropropane (2.308 g, 14.705 mmol) was added and the resulting mixture was allowed to stir at rt for 16h. The reaction mixture was cooled to OX, quenched with ice-water and extracted with EtOAc. The organic layers were washed with water and brine solution, dried over anhydrous Na2SO,, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted at 8% EtOAc in pet ether to afford the title compound (2.0 g, LCMS-75%) as a brown colour gummy;
LC-MS (method 26): R, = 1.31 min; m/z = 349.20 (Μ+Η').
Step b Terf-butyl (6-bromopyridsn-3-yl)(3-(4,4-difIuoropiperidin-1-yl)propyI)carbamate
To a stirred solution of 4,4-difluoropiperidine hydrochloride (1.815 g, 11.49 mmol) in ACN (30 mL), Nal (1 ,027 g, 6.896 mmol) and K2CO3 (2.379 g, 17.24 mmol) were added. The reaction mixture was stirred for 10 minutes, the compound obtained in the previous section, step a (2.0 g, 5.747 mmol) was added and heated to 90X for 16h. The reaction mixture was filtered through a celite pad; and washed with 10% MeOH in DCM. The filtrated solution was concentrated under reduced pressure and the crude compound purified by silica gel column chromatography using 25% EtOAc in pet ether as eluent to afford the title compound (1 1 g, 44%) as an off- white solid;
LC-MS (method 26): R, = 0.86 min; m/z = 434.35 (M+H+).
REFERENCE EXAMPLE 39
6-Bromo-W-butyl-A/-(3-(4,4-dlfluoropiperidin-1-yi)propyl)pyridin-3-amine Step a. 6-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)propyl)pyridin-3-amine
To a stirred solution of reference example 38 (1.4g ,0.0032mmol) in DCM (10 mL), TFA (3.0mi) was added at OX and it was allowed to stir at RT for 3h. The reaction mixture was concentrated under reduced pressure. The crude residue was diluted with water, basified to pH-8 using saturated NaHC03 solution and extracted with EtOAc. The organic layers were washed with water and brine solution. The organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford the title compound (1.01g, 94%) as a off white solid ;
LC-MS (method 25): R, = 1.40 min; m/z = 334.11 (M+H-).
Step b. N-(6-Bromopyridin-3-yl)-W-(3-(4,4-difluoropiperidin-1-yl)propyl)butyramide
To a solution of the compound obtained in the previous section, step a, (1.1g,3.303mmol) in DCM(15ml), TEA (2.3ml,13.21 mmol) and butyryl chloride (0.65ml,6.606mmol) were added at OX and allowed to stir at RT for 16h. The reaction mixture was diluted with DCM, washed with water, and the separated organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted at 15% EtOAc in pet ether to afford the title compound (1.00g, 81.8%) as a yellow gummy.
LC-MS (method 33): R, = 2.88 min; m/z = 404.62 (M+H+).
Step c. 6-Bromo-W-butyl-W-(3-(4,4-difluoropiperidin-1 -yj)propyl)pyridin-3-amine To a solution of the compound obtained in the previous section, step b (0.990g, 2.23mmol) in THF(15ml), BH3.DMS (3.34ml,6.69mmol) was added at 0°C and heated at 75°C for 16h. The reaction mixture was concentrated under reduced pressure. MeOH was added to the reaction mixture and stirred at 65°C for 2h and evaporated to dryness. The crude compound was purified by silica gel column chromatography and eluted at 10% EtOAc in pet ether to afford the title compound as a green gummy.
LC-MS (method 25: R, = 1.74 min; m/z = 390.27 (M+H*).
REFERENCE EXAMPLE 40
2-Bromo-5-(3-(4,4-difluoropiperidin-1-yl}propoxy)pyridine
Step a. 2-Bromo-5-(3-chloropropoxy)pyridine
To a stirred solution of 6-bromopyridin-3-ol (2 g, 11.49 mmol) in DMF (20 mL), 1-bromo-3-chloropropane (2.7 g, 17.24 mmoi), and K2CO3 (4.7 g, 34.48 mmol) were added and allowed to stirred at RT. The reaction mixture was poured in to ice water and extracted with EtOAc (2 x 20 mL), washed with water (10 mL) and brine solution (10 mL). It was dried over anhydrous Na?S04, filtered and concentrated under reduced pressure to get 2.2 g (76 %) of the title compound as a gummy solid.
LC-MS (method 26): R, = 1.16 min; m/z = 251.97 (M+H++2).
Step b. 2-Bromo-5-(3-(4,4-difluoropiperidin-1 -yl)propoxy)pyridlne
To a solution of the compound obtained in the previous section, step a (2 g, 7.98 mmol) in acetonitrile, 4,4- difluoropiperidine.HCI (1.88 g, 11.97 mmol), K2CO3 (3.3 g, 23.95 mmol), and Nal (1.19 g, 7.98 mmol) were added at RT and heated to 70°C for 24 h. The reaction mixture was allowed to temper and it was poured into ice water (30 mL) and extracted with EtOAc (2 x 80 mL). The separated organic layers were dried over anhydrous Na?SOi, filtered and concentrated under reduced pressure to get a crude residue that was washed with n-pentane and dried to afford 1.5 g (56 %) of the title compound as a gummy liquid.
LC-MS (method 26): Rf = 0.66 min; m/z = 336.44 (M+H++2).
REFERENCE EXAMPLE 41
Tert-butyl (3-(1H-pyrazol-1-yl)propyl)(6-(trimethylstannyl) pyridin-3-yl)carbamate
In a pressure tube, to a solution of reference example 31 (2.0 g, 5.263 mmol) in toluene (20 mL), hexamethylditin (2.06 g, 6.315 mmol) was added at it The resulting solution was degassed with N2 gas and then Pd(PPh3)4 (0.607 g, 0.526 mmol) was added and heated to 100 °C for 16h. The reaction mixture was diluted with EtOAc (100 mL) and filtered through the Ceiite pad. The filtrate was concentrated under reduced pressure to get a crude compound that was purified by column chromatography using neutral alumina and eluted with 5% EtOAc/pet ether to afford the title compound (1.7 g, 69%) as a brown colour gummy.
LC-MS (method 8): R- = 2.33 min; m/z = 467.41 (M+H*).
REFERENCE EXAMPLE 42
3-((6-Bromopyridin-3-yl)oxy)-W-ethyl-W-phenethylpropan-1-amine Step a. 3-p-Bromopyridin-3-yl)oxy)-W-phenethylpropan-1-amine To a stirred solution of 2-bromo-5-(3-bromopropoxy)pyridine (2.0 g, 6.78 mmol) and 2-phenylethanamine (1.23 g, 10.17 mmol) in ACN (50 mL, Nai (1.01 g, 0.67 mmol) followed by K2C03 (2.80 g, 20.34 mmol) were added and the resulting mixture was heated at 60°C for 16h. The reaction mixture was allowed to temper and filtered. The filtrate was concentrated under reduced pressure to get a crude residue that was purified by grace reverse phase column chromatography using 35% acetonitrile in 0.1% aq formic acid as an eluent to afford the title compound (1.10 g, 48%) as color less liquid.
LC-MS (method 21): R, = 1.73 min; m/z = 335.28 (M+H+).
Step b. 3-(6-Bromopyrldin-3-yloxy)-N-ethyl-N-phenethylpropan-1 -amine
To a solution of the compound obtained in the previous section, step a (1.0 g, 3.17 mmol) and acetaldehyde (0.2 g, 4.75 mmol) in DCE(25 mL), AcOH (90 mg, 1.49 mmol) was added. The resulting mixture was stirred at rt for 4h and Na(OAc)3BH (1.90 g, 8.94 mmol) ewas added. It was stirred at rt for 16 h. The reaction mixture was diluted with satNaHCOs solution amd extracted with DCM. The combined organic layers were dried over Na2S04 and filtered. The filtrated solution was concentrated under reduced pressure to get a crude residue that was purified by flash column chromatography using 80% ethyl acetate in pet ether as an eluent to afford the title compound (0.7 g, 65%) as color less liquid.
LC-MS (method 21): Rt = 1.81 min; m/z = 363.20 (Μ+Η').
REFERENCE EXAMPLE 43
N-([1 ,1 '-Biphenyl]-4-ylmethyl)-5-bromopyrazin-2-amine
To a stirred solution of 5-bromopyrazin-2-amine (300 mg, 1.26 mmol) in DCE (5 mL), [1,f-biphenyl]-4- carbaldehyde (230 mg, 1.26 mmol), and AcOH (0.1 mL) were added at rt and the reaction mixture was stirred for 30 min. Then, Na(OAc)3BH (9 mg, 3.78 mmol) was added and stirred for 16 h. The reaction mixture was diluted with DCM and washed with sat.NaHCOa, water. The organic layers were dried over anhydrous Na?SC>4 and the organic layers were evaporated to dryness. The crude compound was purified by flash column chromatography using 30 % EtOAc: Pet ether as the eluent to get the title compound (260 mg, 60%).
LC-MS (method 21 ): R, = 2.46 min; m/z = 340.30 (M+H+).
REFERENCE EXAMPLE 44
4-(5-Bromopyrazin-2-yl)-W?W-diethylbutan-1-amine
Step a. 4-(5-Methoxypyrazin-2-y!)but-3-yn-1-ol
To a stirred solution of 2-bromo-5-methoxypyrazine (10 g, 53.47 mmol) in DMF (100 mL), but-3-yn-1-ol (2.6 g, 37.38 mmol), TEA (427 mmol), Cul (1 g, 5.3 mmol) and Pd(PPh3)2Cb (6 g, 5.3 mmol) were added at rt for 16 h. The reaction mixture was diluted with cold water, extracted with EtOAc and washed with water and brine solution. The separated organic layers were dried over anhydrous Na2SO<i, filtered and the filtrated was concentrated to get a cruede residue that was purified by flash column chromatography using 20% EtOAc in pet ether as an eluent to obtain 5 g (53 %) of the title compound as a gummy solid.
LC-MS (method 21): R- = 1.68 min; m/z = 179.28 (M+H+).
Step b. 4-(5-Methoxypyrazin-2-yl)butan-1-oi A suspension of the compound obtained in the previous section, step b (5 g, 28.08 mmol) and 10% Pd/C (2.5 g) in MeOH (60 ml) was stirrerd under 80 psi pressure in par hydrogenated for 48 h. The reaction mixture was filtered through Celite pad, washed with MeOH (20 mL) and the filtrated was concentrated under reduced pressure to get a crude residue. The crude compound was purified by flash column chromatography using 20- 25% EtOAc in pet ether as an eluent to obtain 3.2 g (62%) of the title compound, as a light brown gummy liquid. LC-MS (method 23): R, = 1.13 min; m/z = 183.20 (M+H+).
Step c. 2-Bromo-5-(4-bromobutyl)pyrazine
A solution of the compound obtained in the previous section, step b (2.4 g, 13.17 mmol) in POBrs (7.56 g, 26.34 mmol) was heated at 110°C for 3 h. The resulting mixture was allowed to temper and the reaction mixture was quenched with ice cold water (50 mL), neutralized with sat NaHCCh aqueous solution. It was extracted with EtOAc (3 x 100 mL) and. the combined organic layers were dried over anhydrous Na?SO„, and filtered. The filtrated solution was concentrated under reduced pressure to get a crude residue that was purified by column chromatography with 10 % EtOAc/ pet-ether to afford 280 mg of the title compound
LC-MS (method 23): R, = 1.87 min; m/z = 293.01 (Μ+Η').
Step d. 4-(5-Bromopyrazin-2-yl)-W,Af-diethylbutan-1 -amine
A solution of the compound obtained in the previous section, step c (280 mg, 0.95 mmol) and diethyl amine (5 mL) were stirrd at RT for 36 h. The reaction mixture was concentrated under reduced pressure to get a crude residue tahta was purified by column chromatography using, 230-400 silica with 4 % MeOH/DCM to afford 180 mg of the title compound as a gummy solid.
LC-MS (method 21): R, = 1.46 min; m/z = 286.29 (M+H++2).
REFERENCE EXAMPLE 45
,1 '-Biphenyl]-4-ylmethyl)-6-bromo-A/-methylpyridin-3-amine
Step a. W-{6-Bromopyridin-3-yl)-[1 ,1 '-biphenyl]-4-carboxamide
To a stirred solution of 6-bromopyridin-3-amine (500mg, 2.890mmol) in DMF (15 mL) TEA (1.20ml,8.67mmoi) at 0°C, biphenyI-4-carbonyl chloride (813mg,3.75mmol) was slowly added and allowed to stir at RT 3 h. The resulting mixture was diluted with ice cold water (20 mL) extracted with EtOAc (150 mL), dried, concentrated to get a crude compound that was purified by flash column chromatography in 100-200 silica gel column chromatography and eluted at 10% EtOAc in pet ether to afford the title compound (700mg, 68.8%) as a brown solid;
LC-MS (method 25): Rt = 2.20 min; m/z = 353.19 (M+H+).
Step b. ,1 '-Biphenyl]-4-ylmethyl)-6-bromopyridin-3-amine
Following a similar procedure to that described in example 37, but using the compound obtained in the previous section, step a instead of reference example 36a, the desired compound was obtained (41.9% yield).
LC-MS (method 25): R, = 2.32 min; m/z = 339.16 (M+H-).
Step c. /V-{[1 ,1'-Biphenyl]-4-ylmethyl)-6-bromo-A/-methylpyridin-3-amine Following a similar procedure to that described in example 32, section b, but using the compound obtained in the previous section, step a instead of N-(3-(1 H-pyrazol-1-yl}propyl)-6-bromopyndsn-3-amine, the desired compound was obtained (89.5% yield).
LC-MS (method 25): R- = 2.45 min; m/z = 353.19 (M+H>).
REFERENCE EXAMPLE 46
6-Bromo-W-(3-(4-chlorophenyl)propyl)-W-methylpyridin-3-amine Following a similar procedure to that described in example 45, but using reference example 4m instead of N N- (6-bromopyridin-3-yl)biphenyl-4-carboxamide, the desired compound was obtained (89.5% yield).
LC-MS (method 34): R, = 4.15 min; m/z = 339.65 (M+H+).
EXAMPLE 1
5'-(Pip€ridine-4-carboxamido)-[2,2'-bipyridine]4-carboxylic acid
Figure imgf000102_0001
Step a. Methyl S'-il-iferf-butoxycarbonylJpiperidine^-carboxamidoJ-p.Z-bipyridinel-A-carboxylate
To a stirred solution of reference Example 3 (400 mg, 1.5 mmol) and 1 -(ferf-butoxycarbonyl)piperidine-4- carboxylic acid (414 mg, 1.80mmol) in DCM (5 mL) was added T3P (1.43 mL, 2.25 mmol) and TEA (0.83 mL, 6.02 mmol) at 0°C. The reaction mixture was stirred at RT for 24 h. The reaction mixture was diluted with aq.NaHC03 solution and extracted with DCM (3 X 10 mL). The organic layer was dried over anhydrous Na2SO., filtered and concentrated. The crude compound was purified flash column chromatography on 230- 400 silica and eluted with 80% EtOAc/Pet-ether to afford 320 mg (48%) of the title compound.
LC-MS (method 1): Rt = 2.21 min; m/z = 441.35 (M+H+).
Step b. 5'-(1-(7ert-butoxycartonyl)piperidine-4^arboxamido)-[2,2'-bipyridine]-4-carboxylic acid
To a stirred solution of of the compound obtained in the previous section, step a, (200 mg, 0.4545 mmol) in MeOH:THF:H20 (1 :4:1 , 6 mL) was added LiOH.H20 (76.3 mg, 1.818 mmol) at 0eC. 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 DM water and washed with diethyl ether. The aqueous layer was acidified with saturated citric acid solution and the precipitated solid was filtered, washed with pet ether and dried in vacuum to afford 120 mg of the title compound (120 mg, 61.9%) as an off-white solid.
LC-MS (method 1): R, = 1.80 min; m/z = 427.35 (M+H-),
Step c. 5'-(Piperidine4-carboxamido)-[2,2'-bipyridine]-4-carboxylic acid
To a stirred solution of the compound obtained in the previous section, step b, (110 mg, 0,258 mmol) in DCM (1 mL) was added trifluoroacetic acid (1 mL) at 10°C. The reaction mixture was allowed to stir at RT for 4h. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated; the residue was triturated with diethyl ether and n-pentane. The crude compound was dissolved in DM water and lyophilized to afford the title compound (80 mg, 95%) as a light brown solid.
LC-MS (method 1 ): Rt = 1.55 min; m/z = 327.24 (M+H*).
Following a similar procedure to that described in example 1 , but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000103_0001
Figure imgf000104_0001
5'-(2-(Piperidine-3-carboxamido)ethyl)-[2, 2'-bipyrid!ne]-4-carboxylic acid trifluoroacetate
Figure imgf000104_0002
Step a. Methyl 5'-(2-(1 -{ferf-butoxycarbonyl)piperidine-3-carboxamido)ethyl)-[2,2'-bipyridine]4- carboxylate
To a stirred solution of reference example 5 (500 mg, 1.21 mmol) in 1 ,4-dioxane (15 mL) was added reference example 1 (439 mg, 1.45 mmol), CsF (370 mg, 2.43 mmol) and Cul (46 mg, 0.24 mmol). The resulting solution was degassed with argon, then added Pd(PPh3).i (140 mg, 0.12 mmol) and heated at 110°C for 16h. The reaction mixture was cooled to RT and diluted with EtOAc and filtered through a Celite pad. The filtrate was concentrated under reduced pressure. The crude compound was purified by flash column chromatography using silica gel and eluted with 3%MeOH in DCM to afford the title compound (300 mg, 52%) as a white solid. LC-MS (method 1 ): Rt = 2.02 min; m/z = 469.39 (M+H+).
Step b. 5'-(2-(1-(Tert-butoxycarbonyl)piperidine-3-carboxamldo)ethyl)-[2, 2'-bipyridine]-4-carboxylic acid
To a solution of the compound obtained in the previous section, step a, (150 mg, 0.32 mmol) in THF:MeOH:H20 (6 mL, 1 :4:1) was added LiOH.H20 (40 mg, 0.96 mmol) at 0°C. The reaction mixture was allowed to stir at RT for 3h. The reaction mixture was concentrated, the residue was dissolved in water (30 mL) and washed with EtOAc (10 mL) and diethyl ether (10 mL). The aqueous layer was neutralized with 0.5M HCI and the precipitated solid compound was filtered, washed with n-pentane and dried in vacuum to afford the title compound (95 mg, 65%) as a white solid.
LC-MS (method 1): Rt = 1.64 min; m/z = 455.00 (M+H+). Step c. 5'-(2-(Piperidine-3-carboxamido) ethyl)-2,2'-bipyridine-4-carboxy!ic acid di(trifluoroacetate)
To a stirred solution of the compound obtained in the previous section, step b, (90 mg, 0.198 mmol) in DCM (2 mL) was added TFA (0.6 mL) at 0°C. The resulting reaction mixture was stirred at room temperature for 3h. Solvent was removed under reduced pressure, the residue was triturated with n-pentane, diethyl ether and dried under reduced pressure. The compound was dissolved in DM water and lyophilized to the title compound as a di(trifluoroacetate) salt.
LC-MS (method 1): F¾ = 0.93 min; m/z = 354.99 (M+H+).
Following a similar procedure to that described in example 2, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
• Π Using 4M HCI in dioxane instead of TFA/DCM in step c
EXAMPLE 3
5'-((3-{fH-Pyrazol-1-yI)propyl)amino)-[2,2!-bipyridine]-4-carboxylic acid hemipentahydrochloride
Figure imgf000109_0002
Step a. 5'-({3-(fH-Pyrazol-1-yl)propyl)(teit^utoxycarbonyl)amino)-[2,2'-bipyridine]-4-carboxylic acid To a stirred solution of reference example 2 (500 mg, 1.51 mmol) in acetonitrile was added reference example 30, (263 mg, 1.82 mmol) and Cs2C03 (1.48 g, 4.55 mmol). The reaction mixture was heated at 70°C for 16 h. The reaction mixture was cooled to RT, filtered and the filtrate was concentrated. The residue was dissolved in water and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over anhydrous
Figure imgf000110_0001
filtered and concentrated under reduced pressure to get crude compound 600 mg,. The crude compound was purified by Prep-HPLC and lyophilized to afford 55 mg ( 8.6 %) of the title compound
LC-MS (method 1): Rt = 1.93 min; m/z = 424.71 (M+H-).
Preparative HPLC Conditions: Column: Inert sil ODS-3 (20 x 250 mm, 5.0 μ); Mobile phase: A: 10 mm Ammonium bicarbonate in Aq & B: Acetonitrile; Gradient Method (A / B): 1/20, 10/40. 11/80, 15/98; Flow rate: 18.0 mt/min; Wave length: 215 nm & 254 nm.
Step b. 5'-((3-(iW-Pyrazol-1-yl)propyl)amino)-[2,2'-bipyridine]-4-carboxylic acid hemipentahydrochloride To a stirred solution the compound obtained in the previous section, step a, (50 mg, 0.11 mmol) in 1 ,4-dioxane (1 mL) was added 4M HCI in 1 ,4-dioxane (0.6 mL) at 10 °C. Then the reaction mixture was allowed to stir at RT for 3 h. The progress of the reaction was monitored by LCMS. Solvent was removed under reduced pressure and residue was triturated with Acetonitrile (2x3 mL) followed by diethyl ether (2 x 2 mL) dried under vacuum to afford 35 mg (88.3 %) of the title compound as HCI salt.
LC-MS (method 1): Rt = 1.17 min; m/z = 324.16 (M+H+).
EXAMPLE 4
Methyl 5'-((3-(1-methyl-1H-pyrazol-4-yl) propyl)amino)-[2,2'-bipyridine]-4-carboxylate
Figure imgf000110_0002
To a stirred solution of reference example 7 (300 mg, 2.173 mmol) in methanol (10 mL) was added reference example 3 (597 mg, 2.607 mmol) and AcOH (1 mL) at RT and stirred for 30 min. The reaction mixture was cooled to 0°C, added NaCNBH3 (409 mg, 6.519 mmol) and allowed to stir at RT for 16 h. The reaction mixture was concentrated and the residue was dissolved in water (30 mL) and basified to pH~8 using saturated NaHCC>3 solution and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SOi, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography and eluted with 100% EtOAc to afford the title compound (250 mg, 32%) as a pale yellow solid.
LC-MS (method 1): Rt = 1.47 min; m/z = 351.97 (M+H+).
Following a similar procedure to that described in example 4, but using the corresponding starting material, the following compound was obtained: Starting HPLC Rt
Example Compound name m/z
material method (min)
Methyl 5'-((3-(4-fluorophenyl)
propyl)amino)-[2,2'-bipyridine]-4- carboxylate
Reference 366.00
4a 1 2.06
example 9 (M+H+)
EXAMPLE 5
Ethyl 5'-(3-Aminopropanamldo)-[2,2'-bipyridine]-4-carboxylate sesquihydrochloride
Figure imgf000111_0001
Step a, Ethyl 5'-(3-((fert-butoxycarbonyl)amino)propanamido)-[2,2'-bipyridine]-4-carboxylate
In a pressure tube, to a stirred solution of reference example 4a (500 mg, 1.45 mmol) in DMF (5 mL) was added reference example 1a (1.3 g, 4.37 mmol). The resulting solution was degassed with argon for 10 minutes, then Pd(PPh3)2CI? (102 mg, 0.14 mmol) was added, the mixture was again degassed and then heated at 110°C for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to RT, diluted with EtOAc (2 x 50 mL) and water (100 mL), filtered through the Celite pad, washed with ethyl acetate and separated the organic layer. The aqueous layer was extracted with EtOAc (25 mL) and the combined organic layers were dried over anhydrous Na2S04, filtered and the filtrate was concentrated under reduced pressure to get a crude compound (LCMS purity-22%). The crude was purified by column chromatography using silica gel and eluted with 5% MeOH/DCM to afford the title compound (240 mg, 39.8 %) as a white solid.
LC-MS (method 2): Rt = 2.68 min; m/z = 415.38 (M+H+).
Step b. Ethyl 5'-{3-aminopropanamidoH2,2'-bipyridine]4-carboxylate sesquihydrochloride
4M HCI in 1 ,4-dioxane (1 mL) was added to a stirred solution of the compound obtained in the previous section, step a, (100 mg, 0.24 mmol) in 1 ,4-dioxane (1 mL) at 10°C. The reaction mixture was stirred at the same temperature for 6h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated at <30°C, the residue was triturated with diethyl ether, n-pentane and dried in vacuum to get crude compound, The crude compound was dissolved in DM water and lyophilized to afford the title compound (60 mg, 71.6 %) as a sesquihydrochloride salt.
LC-MS (method 2): R, = 1.87 min; m/z = 313.22 (M-H+).
Following a similar procedure to that described in example 5, but using the corresponding starting material, the following compound was obtained:
Figure imgf000112_0002
Methyl 5'-((3-(4-chlorophenyl)propyl)amino}-[2,2'-bipyrid!ne]-4-carboxyiate
Figure imgf000112_0001
To a stirred solution of reference example 3 (600 mg, 2.620 mmol) in 1 ,2 DCE (15 mL) was
example 8 (483 mg, 2.88 mmol) and AcOH (1 mL), stirred for 1h at RT. The reaction mixture was cooled to 0°C and added sodium triacetoxy borohydride (1.658 g, 7.86 mmol) and the allowed to stir at RT for 16 h. The reaction mixture was basified to pH~8 using saturated NaHCCb solution and extracted with DCM (2 x 100 mL), The combined organic layer was dried over anhydrous NazSCU, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography and eluted at 25%EtOAc/ pet ether to afford the title compound (300 mg, 30%) as a pale yellow solid.
LC-MS (method 1): R, = 2.22 min; m/z = 382.02 (M+H+).
EXAMPLE 7
Methyl S'-fS-idiethylaminoJpropanamidoJ-p^'-bipyridinel^-carboxylate
Figure imgf000113_0001
Step a. Methyl S'-iS-chloropropanamidoJ-^.Z-bipyridinel^-carboxylate.
To a stirred solution of reference example 3 (0.5 g, 2.18 mmol) in DCM (10 mL) was added pyridine (0.5 g, 6.55 mmol) at 0 °C, stirred for 10min, and then added 3-chloropropanoyl chloride (0.41 g, 3.27 mmol) at 0 X. The reaction mixture was allowed to stir at RT for 16h. The reaction mixture was evaporated under reduced pressure and diluted with water (50 mL) and extracted with EtOAc (2 X 50 mL). The combined organic extract was dried over anhydrous NajSO*, filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography and eluted with 30% EtOAc/ pet ether to afford the title compound (0.3 g, 43%) as a white color solid.
LC-MS (method 1): F¾ = 1.82 min; m/z = 319.84 (M+H*).
Step b. Methyl 5'-(3-(diethylamino)propanamido)-2,2'-bipyridine-4-carboxylate
To a stirred solution of the compound obtained in the previous section, step a, (0.3 g, 0.94 mmol) in THF (5 mL) was added diethyl amine (0.68 g, 9.40 mmol) at RT. The resulting reaction mixture was heated at 70 °C for 16h. The reaction mixture was cooled to RT and evaporated under reduced pressure. The crude compound was triturated with diethyl ether (2 x 20 mL) to obtain the title compound (0.15 g, 45%) as a gummy liquid. LC-MS (method 1): R, = 1.31 min; m/z = 357.09 (M+H*).
EXAMPLE 8
Methyl 5'-(2-([1 ,1 !-biphenyl]4-yl)acetamidoH2,2^bipyridine]4-carboxylate
Figure imgf000113_0002
To a stirred suspension of reference compound 4d (600 mg, 1.63 mmol), reference example 1 (733 mg, 2.45 mmol), Cul (155 mg, 0.81 mmol), Pd(PPh3)4 (188 mg, 0.16 mmol) and CsF (497 mg, 3.26 mmol) in 1,4- dioxane (30 mL) was degassed under nitrogen for 10 min. The reaction mixture was heated at 100°C for 16 h in a sealed tube. The reaction mixture was filtered through a pad of celite, the filtrate was concentrated under reduced pressure and the obtained crude compound was purified by flash column chromatography using 60% EtOAc in petroleum ether as an eluent to afford the title compound (130 mg, 18%) as brown solid.
LC-MS (method 2): R, = 3.02 min; m/z = 424.53 (M+H*).
Following a similar procedure to that described in example 8, but using in each case the corresponding starting materials, the following compounds were obtained:
Figure imgf000114_0001
Figure imgf000115_0001
Methyl 2-(5-((3- phenylpropyl)amino)pyrazin-2- yl)isonicotinaie
348.99 k Reference example 16 1 2.47
(M+H+)
Methyl 2-(5-(3-
(diethylamino)propoxy)pyrazin-2- yl)iso-nicotinate
345.04
81 Reference example 22 1 1.41
(M+H+).
Methyl 2-(5-(2-
(diethylamino)ethoxy)pyrazin-2- yl)iso-nicotinate
Reference example 331.14m 1 1.33
22a (M+H-).
Methyl 5'-{(3-
358.39 n (diethylamino)propoxy)methyl)-[2,2'- Reference example 23 1 1.83
(M+H+). bipyridine]-4-carboxylate Methyl 5,-(2-morpholinoethoxy)-[2!2 - bipyridinej-4-carboxylate
Reference example 344.03ο V 1 1.22
23a (Μ+Η·).
Methyl 5'-(3-(diethylamino)propoxy)-
[2,2'-bipyridine]-4-carboxylate
344.36p Reference example 24 1 1.80
(M+H+).
Methyl 5'-(4-(2-(diethyl amino)ethyl)- 1 H-pyrazol-1 -y!)-[2,2'-bipyridine]-4- carboxylate
380.02q Reference example 26 1 1 ,47
(M+H+).
Methyl 5'-{3-
(ethyl(phenethyl)amino)propanamido
)-[2,2'-bi pyrid i ne]-4-ca rboxylate
433.45r Reference example 28 8 2.19
(M+H+).
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
1
Methyl 5'-(3-(benzyloxy)propoxy)- [2,2'-bipyridine]-4-carboxylate
379.33at Reference example 23
2.16
(M+H*) 23g
Methyl 5'-(3-
(ethyl(phenethyl)amino)propoxy)-
[2, 2'-bi pyrid i ne]-4-carboxy late
420.41au Reference example 42 21
1.89 (M+H")
k
Methyl 2-(5-(([1 ,1 '-biphenyl]-4- ylmethyl)amino)pyrazin-2- yl)isonicotinate
397.37av Reference example 43 21
2.56 (M+H*)
Methyl 5'-((2-(4,4-difluoropiperidin-1- yl)ethoxy)methyl)-[2,2'-bipyridineH- carboxylate
Reference example 392.26
25
aw 23h 1.59 (Μ+Η·)
Figure imgf000125_0001
carboxylate
Figure imgf000126_0001
EXAMPLE 9
Methyl 5'-(4-(dimethylamino)butanamido)-[2,2'-bipyridine]-4-carboxylate
Figure imgf000126_0002
To a stirred solution of reference example 3 (500 mg, 2.18 mmol) and 4-(dimethylamino)butanoic acid (474 mg, 2.83) in DCM (25 mL) was added TEA (0.89 g, 8.73 mmol) followed by T3P (1.73 g, 5.40 mmol) at OX. The reaction mixture was allowed to RT and stirred for 24 h. The progress of the reaction was monitored by LCMS. The reaction mixture was diluted with saturated NaHCOs solution (50 mL) and extracted with DCM (2X30 mL). The organic layer was dried over anhydrous Na2SC¾, filtered and the filtrate was concentrated under reduced pressure and the obtained crude compound was purified by grace chromatography on reverse phase column using 30% of (0.1% formic acid in aqueous: acetonitrile) as an eluent to afford the title compound (320 mg. 42%).
LC-MS (method 1): R, = 1.25 min; m/z = 343.31 (M+H+).
Following a similar procedure to that described in example 9, but using in each case the corresponding starting materials, the following compounds were obtained:
Startlng HPLC
Example Compound name m/z
material method (min)
Methyl 5'-(2-(diethylamino)acetamido)- [2,2'-bipyridine]-4-carboxylate
343.31
9a Diethylglycine 1 1.29
(M+H+)
Methyl 5'-(3-(piperidin-1- 3-(Piperidin-1- 369.34
9b 1 1.32
yl)propanamido)-[2,2'-bipyridine]-4- yi)propanoic (M+H-)
Figure imgf000127_0001
^-(([l .l'-Biphenylj^-ylmethylJaminoJ-^.Z-blpyridinel^carboxylic acid sesquihydroch!oride
Figure imgf000127_0002
Step a. Tert-butyl (6-bromopyridin-3-yl)carbamate
To a stirred solution of 6-bromopyridin-3-amine (5 g, 28.90 mmol) and TEA (8.75 g, 86.70 mmol) in DCM (50 mL) was added B0C2O (12.6 g, 57.80 mmol) at 0°C and stirred for 16 h at RT. The reaction mixture was diluted with DCM washed with water. The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The obtained crude compound was purified by flash column chromatography using 20% EtOAc in petroleum ether as eluent to obtain the title compound (2.0 g, 25%) as white solid.
LC-MS (method 2): Rt = 2.65 min; m/z = 275.17 (M+H++2).
Step b. Tert-butyl {(1 ,1'-biphenyl]-4-ylmethyl)(6-bromopyridin-3-yl)carbamate
To a stirred suspension of 60% NaH (131 mg, 5.49 mmol) in DMF (10 mL) was added the compound obtained in the previous section, step a, (0.5 g, 1.83 mmol) portionswise at 0°C followed by the addition of 4- (bromomethyl)-l ,1'-biphenyl (0.45, 1.83 mmol) in DMF (5 mL) at 0°C. The reaction mixture was allowed to RT and stirred for 15 h and the mixture was quenched with cold ice water, extracted with ethyl acetate. The organic layer was dried over anhydrous NfeSQi, filtered, the filtrate was concentrated under reduced pressure and the obtained crude compound was purified by flash column chromatography using 20% EtOAc in petroleum ether as eluent to obtain the title compound (500 mg, 62%) as a brown solid.
LC-MS (method 2): Rt = 3.48 min; m/z = 439.29 (M+H*).
Step c, Methyl 5'-(([1 ,1 '-biphenyl]-4-ylmethyl)( iert-butoxycarbonyl)amino)-[2,2'-bipyridine]-4-carboxylate To a stirred solution of the compound obtained in the previous section, step b, (0.5 g, 1.14 mmol), reference example 1 (0.446 g, 1.48 mmol), Cul (0.043 g, 0.228 mmol), Pd(PPh3)4 (0.131 g, 0.114 mmol) and CsF (0.346 g, 2.28 mmol) in 1 , 4-dioxane (20 mL) was degassed under argon for 5 min. Then the mixture was heated at 100°C for 16 h in a sealed tube and allowed to RT. The mixture was filtered through a pad of celite, the filtrate was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous Na2S04, filtered and the filtrate was concentrated under reduced pressure. The resultant crude compound was purified by flash column chromatography using 40% EtOAc in petroleum ether as eluent to obtain the title compound (150 mg, 26%) as a brown solid.
LC-MS (method 2): Rt = 3.66 min; m/z = 496.95 (M+H*).
Step d. 5'-(([1J'-BiphenylH7lmethyl)(fert-buto^ acid
To a stirred solution of the compound obtained in the previous section, step c, (150 mg, 0.30 mmol) in MeOH:H20 (8 mL: 2 mL) was added NaOH (24 mg, 0.60 mmol) at RT and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the obtained crude was dissolved in water and washed with EtOAc. The aq. layer was acidified with sat. citric acid solution and extracted with EtOAc (3 x 100 mL) and the organic layer was dried over anhydrous Na∑SC>4 and filtered. The filtrate was concentrated under reduced pressure and the obtained crude compound was triturated with n-pentane to afford the title compound (60 mg, 41%) as white solid.
LC-MS (method 2): Rt = 3.27 min; m/z = 482.37 (M+H+).
Step e. 5'-(([1,1'-Biphenyl]-4-y!methyl)amino)-[2,2'-bipyridine]-4-carboxylic acid sesquihydrochloride To a stirred solution of the compound obtained in the previous section, step d, (60 mg, 0.124 mmol) in DCM (5 mL) was added 4M HCI in 1 ,4-dioxane (0.6 mL) at 0°C and the reaction mixture was allowed to RT, stirred for 6 h. The reaction mixture was concentrated under reduced pressure and the obtained crude compound was triturated with n-pentane to afford the title compound (35 mg, 74%), a yellow solid, as a sesquihydrochloride salt.
LC-MS (method 2): Rt = 2.29 min; m/z = 382.33 (Μ+Η').
EXAMPLE 11
5'-((3-Aminopropyl)amino)-[2,2'-bipyridine]-4-carboxylic acid hemlpentahydrochloride
Figure imgf000128_0001
Step a. 7ert-butyl (3-oxopropyl)carbamate
To a stirred solution of tert-butyl (3-hydroxypropyl)carbamate (2.0 g, 11 ,41 mmol) in DCM (30 mL) was added Dess-Martin periodinane (5.80 g, 13.69 mmol) at 0°C and resulted mixture was stirred at RT for 16 h. The reaction mixture was diluted with 20% aqueous Na2S203 (40 mL) and saturated aqueous NaHCCb (40 mL) at RT. The precipitated solids were filtered through a pad of celite and the filtrate was extracted with DCM (2 X 30 mL). The combined organic layers were washed sequentially with 20% aqueous Na2S203 (50 mL), saturated aqueous NaHCCb (50 mL), and brine (50 mL). The separated organic layer was dried over anhydrous Na2SO,, and concentrated under reduced pressure to afford the title compound 19 (1.2 g, 46%) as yellow liquid.
Step b. Methyl 5'-{(3-(.ert-butoxycarbonyl)amino)propyl)amino)-[2,2'-bipyridine]-4-carboxylate To a stirred solution of reference example 3 (500 mg, 2.18 mmol) in methanol (20 mL) was added the compound obtained in the previous section, step a, (491 mg, 2.83 mmol), molecular sieves (500 mg) and cat. AcOH (50 mg) at 0°C. The mixture was stirred for 30 min and then NaCNBhh (406 mg, 6.55 mmol) was added at 0°C. The reaction mixture was stirred at RT for 24 h. Water (30 mL) was added to the reaction mixture and filtered through a pad of celite, the filtrate was extracted with EtOAc (3X20 ml). The combined organic layers were dried over anhydrous NajSOa. The organic layer was concentrated under reduced pressure and the resultant crude compound was purified by Grace column chromatography (reverse phase) e!uting with 40% Acetonitrile in 0.1% aqueous formic acid to afford the title compound (430 mg, 51%).
LC-MS (method 1): Rt = 1.70 min; m/z = 387.00 (M+H*).
Step c. 5'-((3^Tert-butoxycarbonyl)amino)propylamino)-[2,2'-bipyridine]-4-carboxylic acid
To a stirred solution of the compound obtained in the previous section, step b, (200 mg, 0.51 mmol) in THF:MeOH;H20 (3 mL:3ml_:3mL) was added LiOH.H20 (63 mg, 1.55 mmol ) at 0°C. The reaction mixture was stirred at RT for 4 h and concentrated under reduced pressure and the obtained residue was diluted with water (5 mL) washed with EtOAc. The pH of the aqueous layer was adjusted to 5.0 with citric acid and extracted with 10% MeOH in DCM (5X15 mL). The organic layer was dried over anhydrous Na2SO.», filtered and the filtrate was concentrated under reduced pressure. The resultant crude compound was triturated with diethyl ether to afford the title compound (120 mg, 62%) as yellow solid.
LC-MS (method 1): Rt = 1.42 min; m/z = 373.14 (M+H*).
Step d. 5'-((3-Aminopropylamino)-[2,2'-bipyridine]-4-carboxyllc acid hemipentahydrochloride
To a stirred solution of the compound obtained in the previous section, step c, (120 mg, 0.32 mmol) in DCM:THF (10 mL:5 mL) was added 4M HCI in 1 ,4-dioxane (1.0 mL) at RT and the resulting solution was stirred for 6 h. The reaction mixture was concentrated under reduced pressure and the resultant crude compound was triturated with acetonitrile and diethyl ether to afford the title compound (80 mg, 81%) , a yellow solid, as hemipentahydrochioride salt.
LC-MS (method 13): Rt = 4.18 min; m/z = 272.92 (M+H4).
EXAMPLE 12
2-(5-(2-Phenylacetamido)pyrazin-2-yl)isonicotinic acid
Figure imgf000129_0001
To a stirred solution of example 8j (120 mg, 0.344 mmol) in THF (25 mL) Me3SiOK (88.4 mg, 0.689 mmol) was added at 0°C. The resulting solution was stirred at RT for 3 h, the mixture was concentrated under reduced pressure and the resultant crude was dissolved in water and washed with EtOAc. The aqueous layer pH was adjusted to 4.0 with sat. citric acid and the precipitated solid was washed, filtered and dried under vacuum to afforded the title compound (60 mg, 52%) as an off- white solid. LC-MS (method 1): Rt = 1.77 min; m/z = 334.92 (M+H+).
EXAMPLE 13
Methyl 5'-(3-<pyrrolid 2'-bipyridine-4-carboxyiate
Figure imgf000130_0001
Step a. N-(6-Bromopyridln-3-yl)-3-chloropropanamide
To a solution of 6-bromopyridin-3-amine (3.0 g, 1.0 equiv) in DCM was added pyridine (3.0 equiv) and 3- chloropropanoyl chloride (1.2 equiv) at 0°C and allowed to stir at RT for 12 h and the progress of the reaction was monitored by TLC. The reaction mixture was diluted with DCM and washed with water and brine solution. The separated organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford 3.5 g of the title compound.
LC-MS (method 1): R, = 1.65 min; m/z = 263.08 (M+H*).
Step b. N-(6-Bromopyridin-3-yl)-3-(pyrrolidin-1-yl)propanamide
To a solution of the compound obtained in the previous section, step a, (3.5 g, 1.0 equiv) in DMF was added pyrrolidine (3.0 equiv) and stirred at RT for 16 h and the progress of the reaction was monitored by LCMS. The reaction mixture was diluted with water and extracted with EtOAc; the organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography and eluted at 4%MeOH/DCM to afford 3.0 g of the title compound
LC-MS (method 1): Rt = 0.98 min; m/z = 298.2 (M+H+).
Step c. 3-(Pyrrolidin-1-yl)-N-(6-(trimethylstannyl)pyridin-3-yl)propanamide
To a stirred solution of the compound obtained in the previous section, step b, (1.0 g, 3.355 mmol) in toluene (10 mL) was added hexamethylditin (1.317 g, 3.690 mmol) and the resulting solution was degassed with argon and Pd (PPh3)4 (0.387 g, 0.335 mmol) was added. The mixture was again degassed and heated at 110°C for 16h. The reaction mixture was cooled to RT and diluted with EtOAc (100 mL), filtered through the Celite pad; the filtrate was concentrated under reduced pressure. The crude compound was purified by flash column chromatography using neutral alumina and eluted with 10% MeOH/DCM to afford the titie compound (1.0 g, 77%) as a gummy.
LC-MS (method 1): Rt = 0.90 min; m/z = 384.12 (M+H-).
Step d. Methyl 5'-(3-(pyrrolidin-1-yl)propanamido)-[2,2'-blpyridine]-4-carboxylate
To a stirred solution of methyl 2-bromo isonicotinate (300 mg, 1.388 mmol) in 1 ,4-dioxane (8 mL) was added the compound obtained in the previous section, step c, (689 mg, 1.804 mmol), CsF (421 mg, 2.776 mmol) and followed by addition of Cul (52 mg, 0.277 mmol). The resulting solution was degassed with nitrogen, Pd(PPh3)4 (160 mg, 0.138 mmol) was added and the mixture was again degassed and heated at 110 °C for 16 h. The reaction mixture was diluted with 10% MeOH/DCM (100 mL) and filtered through Celite pad, the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel flash column chromatography and eluted with 10% MeOH/DCM to afford the title compound (180 mg, 36%) as a pale yellow solid.
LC-MS (method 1 ): Rt = 1.25 min; m/z = 355.24 (M+H+).
EXAMPLE 14
Methyl 5'-(3-(cyclopentylamino)propanamido)-[2,2'-bipyridine]-4-carboxylate
Figure imgf000131_0001
Step a. Methyl S'^S-fterf-butoxycarbonyHcyclopentyOaminoJpropanamidol-p^'-bipyridine]^ carboxylate
To a stirred solution of reference example 3 (500 mg, 2.183 mmol) in DCM (50 mL) was added 3-((tert- butoxycarbonyl)(cyclopentyl)amino)propanoic acid (786 mg, 3.05 mmol), TEA (881 mg, 8.732 mmol), followed by the addition of T3P (1.73 g, 5.45 mmol) at 0°C and the reaction mixture was stirred at rt for 48 h. The reaction mixture was diluted with DCM (50 mL) washed with aq.NaHCOs solution (50 mL), Brine solution (50 mL). The organic layer was dried over anhydrous filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by Grace column chromatography (reverse phase) using 30% ACN: 0.1% HCOOH (Aq) to afford the title compound (440 mg, 43%) as an off-white solid.
LC-MS (method 1): R, = 2.61 min; m/z = 469.31 (M+H~).
Step b. Methyl 5'-{3-(cyclopentylamino)propanamido)-[2,2'-bipyridine]-4-carboxylate hydrochloride
To a stirred solution of the compound obtained in the previous section, step a (310 mg, 0.66 mmol) in DCM (10 mL), 4M HCI in 1 ,4-dioxane (2.5 mL) was added at RT and resulting solution was stirred at rt for 6 h. The reaction mixture was concentrated under reduced pressure and the crude compound was triturated with diethyl ether to afford the title compound (260 mg, 91%) as hydrochloride salt.
LC-MS (method 8): R, = 1.82 min; m/z = 369.35 (M+H*).
EXAMPLE 15
Methyl 5'-(3-(cyclopentyl(ethyl)amino)propanamido)-[2,2'-bspyndine]-4-carboxylate
Figure imgf000132_0001
To a stirred solution of example 14 (260 mg, 0.705 mmol) in DMF (10 mL) K2C03 (291 mg, 2.115 mmol) was added at 0 °C followed by the addition of Etl (143 mg, 0.917 mmol) at 0 °C, The mixture was allowed to rt and stirred for 16 h. The reaction was diluted with water (35 mL) and extracted with EtOAc (3 X 30 mL), the separated organic layer was dried over anhydrous Na2SO<i. The organic layer was concentrated under reduced pressure and the crude compound was purified by Grace column chromatography (reverse phase) and eluted with 45 % ACN:0.1 % HCOOH (aq.). The fractions were basified using with sat NaHC03 sol and extracted EtOAc (3 X 30 mL). The organic layer was dried over Na2S04 and concentrated under reduced pressure to afford the title compound (240 mg, 60%).
LC-MS (method 1): R, = 1.48 min; m/z = 397.16 (M+H+).
EXAMPLE 16
Methyl 5'-(2-(4-(aminomethyl)phenyl)acetamido)-[2,2'-bipyridine]-4-carboxylate
Figure imgf000132_0002
Step a. 2-(4-(Aminomethyl)phenyl)acetic acid
A solution of 2-(4-cyanophenyl) acetic acid (3 g, 18.63 mmol) in water (50 mL) and concentrated aqueous ammonia (20 mL) was stirred at room temperature and raney nickel (2.0 g) was added. The resulting suspension was stirred under a hydrogen atmosphere for 48 hours. The reaction mixture was filtered through Celite pad and the filtrate was concentrated under reduced pressure to afford the title compound (2.9 g, 94%) as a bluish solid.
LC-MS (method 1): Rt = 0.23 min; m/z = 166.15 (M+H+).
Step b. 2-(4-(((rert-butoxycarbonyi)amino)methyl)phenyl)acetic acid
A solution of the compound obtained in the previous section, step a, (2.9 g, 17.57 mmol) in water (20 mL) and 1 ,4-dioxane (20 mL) was stirred at room temperature and sodium hydroxide (0.702 g, 17.57 mmol) and BocjO (3.83 g, 17.57 mmol) were added simultaneously and allowed to stir at rt for 24 hours. The reaction mixture was concentrated and the crude compound was dissolved in water and acidified with saturated citric acid solution. The compound was precipitated; solid was filtered and washed with water and dried under vacuum to afford the title compound (2.5 g, 53%) as an off-white solid. Mass: 531.29 (2M+H). LC-MS (method 1): R? = 0.23 min; m/z = 531.29 (2M+H+).
Step c. Methyl 5'-{2-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)acetamido)-[2,2'-bipyridineJ-4- carboxylate
To a stirred solution of methyl reference example 3 (1.0 g, 4.366 mmol) in DCM (15 mL) was added of the compound obtained in the previous section, step b, (1.272 g, 4.802 mmol), TEA (1.322 g, 13.09 mmol) and T3P (4.162 g, 13.09 mmol) at 0°C and allowed to stir at rt for 16 h. The reaction mixture was diluted with DCM (100 mL) and washed with water (100 mL), aq.NaHCCb solution (50 mL) and brine solution (50 mL). The separated organic layer was dried over anhydrous NaiSO*, filtered and concentrated under reduced pressure. The crude compound was triturated with DCM and pentane, filtered the solid and dried under vacuum to afford the title compound (750 mg, 36%) as a pale yellow solid.
LC-MS (method 1): R, = 2.24 min; m/z = 477.38 (M+H*).
Step d. Methyl 5,-(2-(4-{aminomethyl)phenyl)acetamido}-[2,2'-bipyridine]-4-carboxylate
To a stirred solution of the compound obtained in the previous section, step c, (500 mg, 1.082 mmol) in 1 ,4- dioxane (5 mL) was added 4M HCI in 1 , 4-dioxane (8 mL) at 0°C and allowed to stir at rt for 3 h. The reaction mixture was concentrated under reduced pressure and the obtained compound was triturated with di-ethyl ether, followed by dried under vacuum. The crude compound was dissolved in water (10 mL) and washed with EtOAc (2 x 20 mL) and the separated aqueous layer was basified to pH~8 using saturated NaHC03 solution and extracted with 10% MeOH/DCM (3X 50 mL), the combined organic layers were concentrated to afford the title compound (200 mg, 49%) as a pale yellow solid.
LC-MS (method 19); Rt = 1.10 min; m/z = 377.1 (M+H-).
EXAMPLE 17
5'-(2-(4-(Aminomethyl)phenyl)acetamido)-[2,2'-bipyridine]-4-carboxylic acid trihydrochloride
Figure imgf000133_0001
Step a. 5'-(2-{4-(((7ert-butoxycarbonyl)amino)methyl)phenyl)acetamido)-[2, 2'-bipyridine]4-carboxy!ic acid
To a solution of the compound obtained in example 16 section c, (180 mg, 0.389 mmol) in THF: EtOH: H?0 (2:1 :1 , 8 mL) was added UOH.H2O (49 mg, 1.167 mmol) at 0°C and allowed to stir at RT for 3h. The reaction mixture was concentrated and the crude compound was dissolved in water (10 mL) and washed with EtOAc (2 x 20mL), the separated aqueous layer was acidified to pH-4 using 1 N HCI solution, the compound was solidified, filtered and washed with water and pentane, followed by dried under vacuum. The obtained compound was further triturated with acetonitrile, filtered and dried under vacuum to afford the title compound (60 mg, 33%) as a pale yellow solid. LC-MS (method 1): Rt = 1.86 min; m/z = 463.22 (M+H+).
Step b, 5'-(2-(4-(Aminomethy!)phenyl)acetamido)-[2,2'-bipyridine]-4-carboxylic acid trihydrochloride
To a stirred solution of the compound obtained in the previous section, step a, (60 mg, 0.129 mmol) in 1 ,4- dioxane (2 mL) was added 4M HCI in 1 , 4-dioxane (4 mL) at 0°C and allowed to stir at RT for 3 h. The reaction mixture was concentrated under reduced pressure and the obtained compound was triturated with pentane, diethyl ether and acetonitrile, followed by dried under reduced pressure. The compound was dissolved in DM- water (10 mL) and lyophilized to afford the title compound (50 mg) as a pale yellow solid. The compound is in the form of trihydrochloride salt.
LC-MS (method 1): R, = 1.04 min; m/z = 363.17 (Μ+Η').
EXAMPLE 18
Methyl 5'-(3-(diethylamino)prop-1-ynyl)-2,2'-bipyridine-4-carboxylate
Figure imgf000134_0001
To a stirred solution of reference example 29 (1.50 g, 5.61 mmol), and reference example 1 (2.02 g, 6.74 mmol) in 1 , 4-dioxane (30 mL) was added Pd(PPh3), (0.64 g, 0.56 mmol), Cul (0.57 g, 3.0 mmol), CsF (1.70 g, 11.23 mmol) at rt. The resulting suspension was degassed under nitrogen for 5 min, and the reaction mixture was heated to 110 °C for 16 h in a sealed tube. The reaction mixture was allowed to cool to rt and filtered through a ceiite pad, the filtrate was concentrated under reduced pressure. The crude compound was purified by Grace Column chromatography (reverse phase) using 35% acetonitrile in 0.1 % aq. formic acid as an eluent to afford the title compound (0.65 g, 36%) as brown liquid.
LC-MS (method 1): Rt = 1.92 min; m/z = 334.32 (M+H*).
EXAMPLE 19
Methyl 5'-(3-(diethylamino)propyl)-2,2'-bipyridine-4-carboxylate
Figure imgf000134_0002
A suspension of example 18 (0.6 g, 1.84 mmol) and 10% Pd/C (180 mg) in ethyl acetate (25 mL) was hydrogenated at 50 psi at rt for 4h. The reaction mixture was filtered through a pad of Ceiite and the filtrate was concentrated under reduced pressure. The crude compound was purified by Grace Column chromatography (reverse phase) using 30% acetonitrile in 0.1% aq. formic acid as an eluent to afford the title compound (0.25 g, 41%) as brown liquid.
LC-MS (method 8): Rt = 1.75 min; m/z = 328.32 (M+H*).
EXAMPLE 20 5'-{2-([1,1,-Biphenyl]-4-yl)acetamidoH2!2,-bipyridine]-4-carboxylic acid
Figure imgf000135_0001
To a stirred solution of example 8 (85 mg, 0.20 mmol) in THF (5 mL) and water (2 mL) was added UOH.H20 (24 mg, 0.6 mmol) at 0°C. The resulting solution was allowed to RT and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the resultant aqueous layer was washed with EtOAc. The aqueous layer pH was adjusted to 5.0 with citric acid and the precipitated solid was filtered and dried under vacuum to obtain the title compound (27 mg, 32%) as an off- white solid.
LC-MS (method 2): Rt = 2.65 min; m/z = 410.27 (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 imgf000135_0002
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
5'-((3-(1 H-Pyrazol-1 -yl)propyl)amlno}-3-fluoro-[2,2'-bipyridine]-4-carboxyllc acid
Figure imgf000149_0002
Step a. Methyl 3-f!uoro-2-(trimethylstannyl)isonicotinate
In a pressure tube, to a solution of compound methyl 2-bromo-3-fluoroisonicotinate (2000 mg, 1.0 equiv) in toluene was added hexamethylditin (1.1 equiv), the resulting solution was degassed with l\½ gas and then added Pd(PPh3)4 (0.1 equiv.), heated to 100 °C for 16h. The reaction mixture was diluted with EtOAc and filtered through the Ceiite pad, the filtrate was concentrated to get the crude compound. The crude compound was purified by column chromatography using neutral alumina and the product was eiuted with 5% EtOAc/pet ether to afford 1.5 g (55.2 % yield) of the title compound. Step b. Methyl 5'-((3-(iH-pyrazol-1-yl)propyl)(tert-butoxycarbonyl)amino)-3-fluoro-[2,2'- bipyridine]-4-carboxylate
To a stirred solution of reference example 31 (1.0 g, 1 equiv) in 1 ,4-dioxane (10 mL), the compound obtained in the previous section, step a (1.5 equiv), CsF (2 equiv) and Cul (0.2 equiv) were added. The resulting solution was degassed with nitrogen and Pd(PPhsM0.1 equiv) was addedn degassed. The reaction mixture was diluted with water (100 ml) and EtOAc (100 ml), and the separated organic layers weres dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with 30% EtOAc/ pet ether to afford 600 mg (50.0 yield) of the title compound. LC-MS (method 8): R, = 1.40 min; m/z = 342.31 (M+H*).
Step c. 5'-((3^fW-Pyrazol-1-yl)propyl)(tert-butoxywrbonyl)amino)-3-fluoro-[2,2'-bipyridine]^carboxylic acid
Following a similar procedure to that described in example 20, but using the compound obtained in the previous section, step b instead of example 8, the desired compound was obtained (30.9% yield).
LC-MS (method 1 : Rt = 1.72 min; m/z = 442.86 (M+H+).
Step d. 5'-((3-(fH"Pyrazoi-1-yl)propyl)amino)-3-fluoro-[2(2'-bipyridine]-4-carboxylic acid
4M HCI in 1 ,4 dioxane was added to a stirred solution of the compound obtained in previous section, step c (90 mg) in 1 ,4 dioxane at OX and it was allowed to stir at rt for 24 h The reaction mixture was concentrated under reduced pressure: The crude residue obtained was triturated with pentane, diethyl ether and acetonitiile and it was concentrated under reduced pressure. The obtained compound was further Iyophiiized to afford 65 mg (93.4 % yield) of the title compound
LC-MS (method 23): R, = 0.96 min; m/z = 341.26 (M+H*).
EXAMPLE 22
5'-Pentyl-[27-bipyridine]-4-carboxylic acid
Figure imgf000150_0001
Step a. 2-Bromo-5-(pent-1-yn-1-yl)pyridine
in a pressure tube, to a stirred solution of 2-bromo-5-iodopyridine (2.0 g, 7.042 mmol) in THF (20 mL), pent-1- yne (0.718 g, 10.563 mmol), TEA (3.556 g, 35.21 mmol) and Cul (0133 g, 0.704 mmol) were added. The resulting solution was degassed with N2. and Pd2{PPh3)2CI? (0.247 g, 0.3521 mmol) was added. The resulting mixture was heated at 60°C for 16h. The reaction mixture was diluted with water (100 ml) and EtOAc (100 ml), and the separated organic layers weres dried over anhydrous ^SCv, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted at 5%EtOAc/ pet ether to afford the title compound (1.2 g, LCMS-74%) as a gummy solid.
LC-MS (method 23): R, = 2.15 min; m/z = 223.99 (M+H+). Step b. Methyl 5'-(pent-1 -yn-1 -yl)-[2,2'-bipyridine]-4-carboxyiate
To a solution of the compound obtained in the previous section, step a (500 mg, 2.242 mmol, LCMS-74%) in 1 ,4-dioxane (10 mL), reference example 1 (809 mg, 2.690 mmol), CsF (681 mg, 4.484 mmol) and Cul (85 mg, 0.448 mmol) were added. The resulting solution was degassed with N¾ and Pd2(PPh3)?Cb (258 mg, 0.224 mmol) was added. The resulting mixture was heated at 90°C for 16h. The reaction mixture was diluted with water (100 ml) and EtOAc (100 ml), and the separated organic layers weres dried over anhydrous NajSO,, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted at 15% EtOAc/ pet ether to afford the title compound (300 mg, LCMS-76%) as a colour less gummy;.
LC-MS (method 21): R, = 2.74 min; m/z = 281.28 (M+H*).
Step c. Methyl 5'-pentyl-(2,2'-bipyridine]-4-carboxylate
To a solution of the compound obtained in the previous section, step b (250 mg, 0.892 mmol) in MeOH (8 mL) Pd/C (200 mg) was added under N? atmosphere and the resulting mixture was stirred under h½ balloon pressure at rt for 16 h. The reaction mixture was filtered through ce!ite pad; the filtrated solution was concentrated under reduced pressure to afford the title compound (200 mg, 79%) as an off-white solid. The compound was taken forward to the next step without purification;
LC-MS (method 21): R, = 2.88 min; m/z = 285.34 (Μ+Η').
Step d. 5'-Pentyl-[2,2'-bipyridine]-4-carboxylic acid
Following a similar procedure to that described in example 21 , step c, but using the compound obtained in the previous section, step c instead of methyl 5'-((3-(1 H-pyrazol-1-yl)propyl)(tert-butoxycarbonyl)amino)-3-fluoro- [2,2'-bipyridine]-4-carboxylate, the desired compound was obtained (78% yield).
LC-MS (method 21): R, = 2.22 min; m/z = 271.31 (M+H*).
EXAMPLE 23
5'-((3-(1H-Pyrazol-1-yl)propyl)amino)-5-fluoro-[2, 2'-bipyridine]-4-carboxylic acid sesquihydrochloride:
Figure imgf000151_0001
Step a. Methyl 2-bromo-5-f!uoroisonicotinate
To a stirred solution of 2-bromo-5-fluoroisonicotinic acid (2.8 g, 12.78 mmol) in MeOH (30 mL), SOCb (7.54 g, 63.9 mmol) was added at 0°C and it was allowed to stir at rt for 16h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (100 mL), basified to pH~8 using saturated NaHCOs solution, and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous NazSO., filtered and concentrated under reduced pressure to afford the title compound (2.2 g, 73%) as a pale yellow solid;
LC-MS (method 8): R, = 2.41 min; m/z = 234.07 (M+H*). Step b. Methyl 5'-((3-(1/ pyrazol-1-yl)propyl)(fert-butoxycarbonyl)amino)-5-fluoro-[2,2'-bipyridine]-4- carboxylate
To a stirred solution of reference example 41 (1.7 g, 3.648 mmol) in 1 , 4-dioxane (10 mL), the compound obtained in the previous section, step a (0.849 g, 3.648 mmol), CsF (1.108 g, 7.296 mmol) and Cul (0.138 g, 0.729 mmol) were added. The resulting solution was degassed with nitrogen and Pd(PPh3)<s (0.421 g, 0.364 mmol) was added. The resulting mixture was heated at 110°C for 16h. The reaction mixture was diluted with water (100 ml) and EtOAc (100 ml), and the separated organic layers we res dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with 30% EtOAc/ pet ether to afford the title compound (0.750 g, 45%) as an off- white solid;
LC-MS (method 21): R, = 3.06 min; m/z = 456.49 ( +H+).
Step c, 5'-{(3-(1H-Pyrazol-1-yl)propyl) (fert-butoxycarbonyl) amino)-5-fluoro-[2,2'-bipyridine]-4- carboxylic acid
To a solution of the compound obtained in the previous section, step b (300 mg, 0.659 mmol) in THF: MeOH: H?0 (2:1 :1 , 8 mL), LiOH.H20 (83 mg, 1.977 mmol) was added at 0°C and allowed to stir at RT for 3h. The reaction mixture was concentrated under reduced pressure and the crude compound was dissolved in water (10 mL) and acidified to pH~ 3 using 1 HCI aqueous solutions. It was extracted with 10% eOH/DC (3 x 25 mL). The combined organic layers were dried over anhydrous Na?SO,, filtered and concentrated under reduced pressure. The crude compound was purified by prep.HPLC and prep. fraction was lyophilized to afford the title compound (170 mg) as an off-white solid.
Prep.HPLC condition: Column: X-Bridge C18 (19*250) mm 5.0μ Pump (A): 0.05% Formic Acid In aq. Pump (B): Acetonitrile GRADIENT: time/% of B: 0/10,1/,10/,10/75.10.1/98 Flow: 18.0 ml/min? Max: 215nm & 254 nm; LC-MS (method 21): Rt = 2,17 min; m/z = 442.43 (Μ+ ή.
Step d. 5'-({3-{1H-Pyrazol-1-yl)propyl)amino)-5-fluoro-[2,2'-bipyridine]-4-carboxylic acid sesquihydrochloride
Following a similar procedure to that described in example 21 , step d, but using the compound obtained in the previous section, step c instead of 5'-((3-(1 H-Pyrazol-1-yl)piOpyl)(tert-butoxycarbonyl)amino)-3-fiuoro-[2,2'- bipyridine]-4-carboxylic acid, the desired compound was obtained (40 mg, 34% yield).
Prep.HPLC condition: Column: Inertsil ODS-3 20*250mm 5.0 μ Pump (A): 0.05%HCL In aq. Pump (B): Acetonitrile GRADIENT: time B/% of B: 0/5,2/5,10/70,10.1/98, Flow: 16.0 ml/min? Max: 215nm & 254 nm; LC-MS (method 23): R, = 1.02 min; m/z = 342.30 (M+H+).
EXAMPLE 24
Methyl 5'-(hydroxymethyl)-[2,2'-bipyridine]-4-carboxylate
Figure imgf000153_0001
Step a. 2-Bromo-5-(((iert-butyldimethylsilyl)oxy)methyl)pyridine
To a stirred solution of (6-bromopyridin-3-yl)methanol (4 g, 0.021 mol) in DCM (15 mL), imidazole (2.1 g, 0.032 mol) and TBDMS-CI (3.8 g, 0.025 mol) were added at 0°C. The resulting mixture was allowed to stir at RT for 16h. The reaction mixture was diluted with DCM (150 mL), and washed with water (100 mL). The organic layers were dried over anhydrous NajSO., filtered and the filtrate was concentrated. The crude compound was purified by column chromatography using silica gel and the product was eluted with 10% EtOAc/pet ether to afford the title compound (4.5 g, 70%) as a white solid.
LC-MS (method 21): Ri = 2.71 min; m/z = 302.20 (M+H+).
Step b. Methyl 5'-(((terf-buty IdimethylsilyOoxylmethylJ-p^'-bipyridinel^carboxylate
To a solution of the compound obtained in the previous section, step a (2 g, 6.644 mmol) in 1 , 4-dioxane (30 mL), reference example 1 (2.39 g, 7.973 mmol), CsF (2 g, 13.28 mmol) and Cul (0.25g, 1.328 mmol) were added. The resulting solution was degassed, Pd(PPI¾)4 (0.77g, 0.666 mmol) was added and it was heated at 110 °C for 16h. The reaction mixture was allowed to temper, filtered through Celite, and washed with EtOAc (100 mL). The filtrated solution was dried over anhydrous
Figure imgf000153_0002
filtered and concentrated under vacuum. The crude compound was purified by column chromatography using silica gel and the product was eluted with 25% EtOAc/pet ether to afford the title compound (1.2 g, 52%) as an off-white solid.
LC-MS (method 21): Rt = 2.84 min; m/z = 359.38 (M+H+).
Step c. Methyl S'-fhydroxymethylJ-p^'-bipyridinej^-carboxylate
To a solution of the compound obtained in the previous section, step b (2 g, 5.58 mmol) in THF (20 mL), TBAF (1 M solution in THF) (2.91 g, 11.17 mmol) was added at 0 °C. The resulting reaction mixture was allowed to stir at RT for 16h. The reaction mixture was concentrated and the crude residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic layers were washed with brine(30 mL), dried over anhydrous NajSCu, filtered and the filtrate was concentrated to afford the title compound (1.1 g, 80%) as an off-white solid. LC-MS (method 23): R, = 1.14 min; m/z = 245.03 (M+H+).
EXAMPLE 25
5XBenzyloxymethyl)-[2,2'-bipyridine]-4-carboxylic acid
Figure imgf000153_0003
A solution of example 24 (250 mg, 1.024 mmol) in THF (3 mL) was added to a stirred suspension of NaH (60%), (53.2 mg, 1.33 mmol) in THF (7 mL) at 0°C. The reaction mixture was allowed to stir at RT for 30 min, cooled to 0°C, and benzyl bromide (208.8 mg, 1.228 mmol) was then added. The rsulting mixture was allowed to stir at RT for 16h. The reaction mixture was poured into ice water (50 mL) and extracted with EtOAc. The aq. layer was acidified with saturated citric acid solution and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO,, and filtered. The filtrated solution was concentrated and the crude compound was purified by prep.HPLC to afford the title compound (15 mg, 5%) as a pale pink solid.LC-MS (method 21 ): R, = 2.18 min; m/z = 321.28 (M+H+).
Following a similar procedure to that described in example 25, but using the corresponding starting material, the following compound was obtained:
Figure imgf000154_0001
EXAMPLE 26
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 table below. For IC50 determination, inhibitors are tested at eight logarithmic serial dilutions.
Enzyme Substrate Cofactors Acceptor beads Donor beads Cat. number Cat. number Cat. number and Cat. number and Cat. number
Enzyme
and final and final final concentration final and final concentration concentration concentration concentration a-Ketoglutarate
(Sigma #K2000)
Alpha
BPS #50105 Anaspec 4 uM Anti-H3K9me2
streptavidin (aa 2-372 #64360 Ammonium Conjugated
donor beads N-terminal H3K9me3 - iron(ll) sulphate (Perkin Elmer
KDM4C (Perkin Elmer
GST-tag) biotin (1-21) (Sigma #215406) #AL117)
#6760002) 5 uM
0.2 nM 50 nM Sodium Ascorbate 5 ug/ml
40 ug/ml (Sigma #11140)
100 uM
BPS #50121 Anaspec a-Ketoglutarate Anti-H3K4me1-2 Alpha
(aa 2-751 #64357 (Sigma #K2000) Conjugated streptavidin
KDM5B
N-terminal H3K4me3 - 3 uM (Perkin Elmer donor beads His-FLAG- biotin (1-21) Ammonium #AL116) (Perkin Elmer
Figure imgf000155_0001
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.
Assay conditions for KDM5B and KDM4C: 5 ul of enzyme in Assay Buffer (50 mM Hepes pH 7.5, 0.1% BSA, 0.01% Tween-20) is incubated with 2.5 ul of test compound in 2% DMSO at the desired concentrations for 10 minutes. Reaction is started with 2.5 ul of substrate/cofactors mix in Assay Buffer. After 45 minutes, 5 ul of acceptor beads in 1X AlphaLISA Epigenetics Buffer 1 (Perkin Elmer # AL008) are added to the reaction mixture. After 60 minutes incubation at room temperature, 10 ul of Alpha streptavidin donor beads in 1X AlphaLISA 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 multimode plate reader (Perkin Elmer HH34000000) in Alpha mode.
Assay conditions for KDM6B: 5 ul of enzyme in Enzyme Buffer (50 mM Hepes pH 7.5, 0.1% BSA, 0.003% Tween-20, 5 uM Ammonium iron(ll) sulphate (Sigma #215406) ) 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 (50 mM Hepes pH 7.5, 0.1% BSA, 0.003% Tween-20). After 30 min, 5 ul of acceptor beads in 1X AlphaLISA Epigenetics Buffer 1 (Perkin Elmer # AL008) are added. After 60 minutes incubation at room temperature, 10 ul of Alpha streptavidin donor beads in 1X AlphaLISA 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 multimode 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. I CM 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 imgf000156_0001
u 100 101
44 3 87
2003 349
23 442
a 19 n
h 62 n
0 55 38 37
1 5 1 99
2 75 44
7 13 2 800 29 16 17
a 68 17 55
b 100 1 87
c 99 1 87
d 100 2 78
e 109 3 46
0f 78 8 49
g 73 10 56
h 37 19 76
0i 95(*) 37 71
0j 94 3 61
k 24 4 96
0I 133 9 90
m 67 17 93
n 12 2 69
o 375 4 51
p 216 9 56
q 310 14 84
r 99(***) 1 44(****) s 100 2 93
t 99 2 100
u 96 2 18
v 99 33 99
Figure imgf000158_0001
20bd 7 84
20be 100 <1 100
20bf 20 65
20bg 102
20bh 13.4
20bi 6.9
20bj 18
20bk 47 19 63
20bl 19 80
20bm 52 3 36
21 84 99 7 84
22 62 12 79
23 69 11 2
25 85 8 77
25a 93 3 93
0 KDM4C % inhibition @ 5000 nM instead of KDM4C % inh @ 500 nM
Γ) KDM5B % inhibition @ 5000 nM instead of KDM5B % inh @ 500 nM
(***)KDM4C % inhibition @ 250 nM instead of KDM4C % inh @ 500 nM
(****)KDM6B % inhibition @ 250 nM instead of KDM6B % inh @ 500 nM
EXAMPLE 27
IN VITRO CELL-BASED KDM INHIBITION 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, 2x1ο6 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% C02. 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 Imaged 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 H3 normalised H3K4me3 fold induction relative to vehicle is <2.
Example # Score Example # Score
2f * **
20al
2g * *
20am
2p * *
20an
2r * 20ao *
2s * 20ap *
2t ** 20ar *
3 20at **
10 20au
**
20 20av *
20k 20aw *
20I *
20ax **
20m ** **
20az
20q **
20ba
20x * **
20bb
20y ** **
20bc
20z ** *
20bd
** **
20aa 20be
* *
20ab 20bf
20ac * 20bg
20ae * *
20bk
**
20af * 20b!
20ag * 20bm *
* **
20ah 22
20ai ** *
23
20aj * *
25
20ak * **
25a

Claims

1. A compound of Formula (I) or a salt thereof:
Figure imgf000161_0001
(I)
wherein
Z1, Z2, and Z3are each independently selected from CR4 and N, and Z4 and Z5 are each independently selected from CR2 and N, with the proviso that only one of Z\ Z2, Z3, Z4 and Z5 can be N;
R1 is selected from hydrogen, C-,.6 alkyl, Ci-6 haioaikyi, -(Ci 5 alkylene)-OR5, -(Ci.6 alkylene)-NR5R?, -L3- carbocyclyl, -L3-aryi,-L3-heterocyclyl and -L3-heteroaryl, wherein the carbocyclyl in -L3-carbocyclyl, the aryl in - L3-aryl, the heterocyclyl in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R8,
each R2 is independently selected from hydrogen, halo, Ci e alkyl, Ci-e haioaikyi, Ci 6 alkoxy, C<s hydroxyalkyl, -OH and -NH2;
each R4 is independently selected from hydrogen and halo;
Y is selected from -NR1*-, -0-, -CH2-, -NR3C{=0)- and -R11-, wherein said -NRsC(=0)- is linked to -(L1)m- via the NR9 group and to -(L2)n-R3 via the C(=0) group;
L1 is Ci-4 alkylene, C?, alkenylene or Cu alkynylene, wherein said Cu alkylene, said C2-4 alkenylene and said C2-4 alkynylene are optionally interrupted by 0, S or NR10, and wherein said Cu alkylene, said C2-4 alkenylene and said C2-4 alkynylene are optionally substituted with one or more R12;
L2 is C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene, wherein said C1-6 alkylene, said C2.6 alkenylene and said C2-6 alkynylene are optionally interrupted by 0, S or NR12, and wherein said Ci.,3 alkylene, said C? s alkenylene and said C? s alkynylene are optionally substituted with one or more R12;
m and n are each independently selected from 0 and 1;
R3 is selected from -NR13R14 , -OR15 and R1S;
R6 and R7 are each independently selected from hydrogen and C1-6 alkyl, or R6 and R7 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 substituents independently selected from halo, O-e alkyl, -OH, -NH2, -NH(0-5 alkyl), and -N(C, 6 alkyl)2;
each L3 is independently selected from a bond and Cu alkyiene;
R9 and R10are each independently selected from hydrogen, Ci e alkyl and 0-6 haloalkyl;
-R11- is a biradicai of a 5-membered heteroaryl ring containing from 1 to 3 heteroatoms independently selected from N, 0 and S with the proviso that at least one is a N atom, and wherein -R11- is linked to -(L1)m- and -(L2)n-
R3 in a 1 ,3-disposition;
each R12 is independently selected from 0.6 alkyl, halo, 0-6 haloalkyl, -LAcarbocyclyl, -L3-aryl,-L3-heterocyclyl and -LAheteroaryl, wherein the carbocyciyi in -L3-carbocyclyi, the aryl in -LAary!, the heterocyclyi in -LA heterocyclyl and the heteroaryl in -LAheteroaryl are each optionally substituted with one or more R17, and wherein two groups R12 attached to a same C atom of the alkyiene, aikenylene or alkynyiene group are optionally linked together to form with said C atom a C3-6 cycloalkyl group or a saturated 4- to 6-membered monocyclic heterocyclic ring containing 1 heteroatom selected from N, 0 and S, wherein said C3-6 cycloalkyl and 4- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from halo and O 6 alkyl;
R13, R14and R15 are each independently selected from hydrogen, 0-6 alkyl, 0-6 haloalkyl, -(0-6 alky!ene)-OR18, -LAcarbocyclyl, -L3-aryl,-L3-heterocyclyl and -LAheteroaryl, wherein the carbocyciyi in -LAcarbocyclyl, the aryl in -LAary!, the heterocyclyi in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are optionally substituted with one or more R19;
R16 is selected from O-e alkyl, carbocyciyi, aryl, heterocyclyi and heteroaryl, wherein said alkyl is optionally substituted with one or more R20 and said carbocyciyi, said aryl, said heterocyclyi and said heteroaryl are each optionally substituted with one or more R21;
each R20 is independently selected from halo, 0-s alkoxy, O-e haloalkoxy, -OH, -NH2, -NH(0 s alkyl), -N(0-e alkyl)?, -CN, -C(=0)R22 -C(=0)NR23R24 -NR23C(=0)R22, -NR23C(=0)NR23R24, -NR23S02R22, -S02NR23R¾ and each R21 is independently selected from 0-6 alkyl, O-e haloalkyl, halo, O s alkoxy, 0-6 haloalkoxy, -OH, -NH2, -NH(0-6 alkyl), -N(O s alkyl)2, -CN, -C(=0)R22, -C(=0)NR23R24, -NR23C(=0)R22, -NR?3C(=0)NR23R24, -NR23S02R22, -S02NR23R24, -S02R22, -(C,.6 alkylene)-0R25, -(0-6 alkylene)-NR26R27, -LAcarbocyclyl, -L3-aryl, -L3-heterocyclyl and -LAheteroaryl, wherein the carbocyciyi in -LAcarbocyclyl, the aryl in -LAary!, the heterocyclyi in -LAheterocyclyl and the heteroaryl in -LAheteroaryl are optionally substituted with one or more R28;
each R8, each R17, each R19 and each R28 is independently selected from O s alkyl, O e haloalkyl, halo, O-e alkoxy, O-e haloalkoxy, -OH, -NH2, -NH(0.6 alkyl), -N(0-6 alkyl)?, -CN, -C(=0)R22, -C(=0)NR23R24, -NR23C(=0)R22, -NR23C(=0)NR23R24, -NR23S02R22, -S02NR23R24 and -S0?R22;
each R22 is independently selected from 0.6 alkyl; and each R5, each R13, each R23, each R24, each R25, each R26 and each R27 is independently selected from hydrogen and Ci s alkyl.
is a compound of Formula (if):
Figure imgf000163_0001
or a salt thereof.
3. The compound of claim 1 , which is a compound of Formula (la) or (lb):
Figure imgf000163_0002
thereof.
compound of Formula (la):
Figure imgf000163_0003
(la)
or a salt thereof.
5. The compound of any of claims 1 to 4, wherein R1 is hydrogen, Cu alkyl or C1-6 haloalkyi.
6. The compound of any of claims 1 to 4, wherein R1 is hydrogen or CM alkyl.
7. The compound of any of claims 1 to 4, wherein R1 is hydrogen.
8. The compound of any one of claims 1 to 4, wherein R1 is hydrogen, Cu alkyl or CM haloalkyi, and each R2 is hydrogen.
9. The compound of any one of claims 1 to 4, wherein R1 is hydrogen or CM alkyl, and each R2 is hydrogen.
10. The compound of any one of claims 1 to 4, wherein R1 is hydrogen and each R2 is hydrogen.
11. The compound of any one of claims 1 to 10, wherein each R2 and each R4 is hydrogen.
12. The compound of any one of claims 1 to 11 , wherein L1 is (CH2H2, wherein said (CH2)1-2 is optionally substituted with one or more R12.
13. The compound of any one of claims 1 to 12, wherein L1 is CH2.
14. The compound of any one of claims 1 to 13, wherein L2 is (CH2)1-,6 wherein said (CH2)1-6 is optionally substituted with one or more R12.
15. The compound of any one of claims 1 to 14, wherein L2 is (CH2)1-4.
16. The compound of any one of claims 1 to 15, wherein Y is selected from -NR10-, -0-, -CHr, and -NR9C(=0)-, wherein said ~NR9C(=0)- is linked to -(L%- via the NRS group and to -(L2)„-R3 via the C(=0) group.
17. The compound of any one of claims 1 to 16, wherein Y is selected from -NR10-, -O- and -CHr.
18. The compound of any one of claims 1 to 17, wherein n is 1.
19. The compound of claim 3, wherein: R1 is hydrogen or C1-4 alky!;
each R2 is hydrogen;
m and n are each independently selected from 0 and 1 ;
U is (CH2)1-2 and
L2 is (CH2)1-,6 wherein said (CH2)1-6 is optionally substituted with one or more R12.
20. The compound of claim 19 wherein n is 1 ; and L2 is (CH2)i 4 wherein said (CH2)i-4 is optionally substituted with one or more R12.
21. The compound of claim 19 or 20, wherein Y is selected from -NR10-, -0-, -CH2- and -NR9C(=0)-.
22. The compound of claim 20 wherein Y is selected from -NR10-, -O- and -CH2-
23. The compound of claim 21 or 22, wherein U is CH2; and L2 is (CH2)i-4.
24. The compound of any of claims 19 to 23, wherein m is selected from 0 and 1 with the proviso that when m is 1 then Y is -0-.
25. The compound of any of claims 19 to 23, wherein m is O.
26. The compound of any one of claims 19 to 25, wherein R1 is hydrogen.
27. The compound of any one of claims 19 to 26, wherein each R4 is hydrogen.
28. The compound of any one of claims 1 to 27. wherein R3 is R16,
29. The compound of claim 3 or 4, wherein:
R1 is hydrogen;
each R2 is hydrogen;
Y is selected from -NR10-, -0-, -CH2- and -NR3C(=0)-,
m and n are each independently selected from 0 and 1 ;
L1 is CH2;
L2 is (CH2)u; and
R3 is R16.
30. The compound of claim 3 or 4, wherein: R1 is hydrogen;
each R2 is hydrogen;
Y is selected from -NR10-, -0- and -CH2-;
m is selected from 0 and 1 , with the proviso that when m is 1 then Y is -0-,
n is 1 ;
L1 is CH2;
L2 is (CH2)u; and
R3 is R16.
31. The compound of claim 30, wherein m is 0.
32. The compound of any of claims 29 to 31 , wherein each R4 is hydrogen.
33. The compound of any one of claims 1 to 32, wherein R3 is R16 and R16 is selected from aryl and heteroaryl, wherein said aryl and said heteroaryl are each optionally substituted with one or more R21.
34. The compound of claim 33, wherein R3 is R16 and R16 is aryl, wherein said aryl is optionally substituted with one or more R21.
35. The compound of claim 34, wherein R3 is R16 and R16 is phenyl, wherein said phenyl is optionally substituted with one or more R21.
36. The compound of claim 35, wherein R3 is R16 and R16 is phenyl, wherein said phenyl is optionally substituted with one or more halo.
37. The compound of claim 35, wherein R3 is R16 and R16 is 4-biphenyi.
38. The compound of any one of claims 1 to 32, wherein R3 is R16and R16 is C3-7 cycloalkyl, wherein said C3.7 cycloalkyl is optionally substituted with one or more R21.
39. The compound of claim 38, wherein R3 is R16 and R16 is cyclopropyl.
40. The compound of any one of claims 1 to 32, wherein R3 is R,sand R16 is a saturated 4- to 7-membered heterocyclic group which contains one or two heteroatoms selected from N, 0 and S, wherein R16 is optionally substituted with one or more R21.
41. The compound of claim 40, wherein R3 is R16 and R16 is piperidinyl, pyrrolidinyl or morpholinyl, wherein said piperidinyl, pyrrolidinyl or morpholinyl is optionally substituted with one or more R21,
42. The compound of any one of claims 38, 40 or 41 , wherein each R21 is independently selected from Cu alkyl, O-e ha!oalkyl and halo.
43. The compound of claim 40, wherein R3 is R16 and R16 is 1 -piperidinyl substituted with one or more fluoro.
44. The compound of claim 43, wherein R3 is R16and R16 is 4,4-difiuoropiperidin-l-yl.
45. The compound of any one of claims 1 to 32, wherein R3 is R16and R16 is 0-. alkyl, wherein said C1.5 alkyl is optionally substituted with one or more R20.
46. The compound of claim 45, wherein each R20 is independently selected from halo.
47. The compound of claim 1 , wherein the compound is selected from:
5!-(Piperidine~4-carboxamido)-[2,2'-bipyndine]-4-carboxylic acid;
5'-(Pyrrolidine-2-carboxamido)-2,2'-bipyridine-4-carboxylic acid;
5'-(2-(Piperidin-2-yl)acetamido)-2,2'-bipyridine-4-carboxylic acid;
5'-(3-(Phenylamino)propanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-(Benzylamino)propanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-Amino-2-benzylpropanamido)-2,2'-bipyridine4-carboxylic acid;
5'-(4-Amino-3-phenylbutanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(2-(Piperidine-3-carboxamido)ethyl)-[2, 2'-bipyridine]-4-carboxyli:c acid;
5'-(3-Amino-3-phenylpropanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(Piperidine-3-carboxamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-Aminopropanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(5-Amino-1,3,4-oxadiazol-2-yl)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(Benzylamino)-[2!2'-bipyridine]-4-carboxylic acid;
5'-(Phenethylamino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((3-Phenylpropyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
2-{5-(3-Aminopropanamido)pyrazin-2-yl)isonicotinic acid;
5'-(1-Methylpipendine-4-carboxamido)-[2,2'-bipyridine]-4~carboxylic acid;
5'-(1-IVIethylpiperid!ne-3-carboxamido)-[2,2'-bipyridine]-4-carboxylic acid;
2-(5-((3-(Diethyl amino)propyl)amino)pyrazin-2-yi)isonicotinic acid;
5'-(3-(Phenethylamino) propanamido)-[2, 2'-bipyridine]-4-carboxylic acid;
2-(5-((2-(Diethylamino)ethyl)amino)pyrazin-2-yl)isonicotinic acid;
5'-(3-(Ethyiamino)-3-phenylpropanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-(Ethylamino)propanamido)-[2,2'-bipyridine]-4-carboxylic acid;
2-(5-((3-(1H-Pyrazol-1-yl)propyl)amino)pyrazin-2-yl)isonicotinic acid; 5'-((3-{Diethylamino)propyl)amino}-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-Amino-N-methylpropanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-{4-{pyridin-3-ylamino)butyl)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(butylamino}-[2,2'-bipyridine]-4-carboxyiic acid;
5'-(3-amino-N-butyipropanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-({3-(1 H-Pyrazol-1-yl)propyi)amino)-[2,2'-bipyridine]-4-carboxylic acid;
Methyl 5'-((3-(1-methyl-1 H-pyrazol-4-yl) propyl)amino)-[2,2'-bipyridine]-4-carboxylate
Methyl 5'-((3-(4-fluorophenyl) propy!)amino)-[2,2'-bipyridine]-4-carboxy!ate;
Ethyl 5'-(3-Aminopropanamido)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-((3-(4,4-Difiuoropiperidin-1-yl)propyl)amino)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-((3-(4-chiorophenyl)propyl)amino)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(3-(diethylamino)piOpanamido)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(2-([1 ,1 '-biphenyl]-4-yl)acetamido)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(3-pheny!propoxy)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(3-methoxypropanamido)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(2-cyclobuty!acetamido)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(5-(benzylamino)-1 ,3,4-oxadiazol-2-yl)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(5-(phenethylamino)-1 ,3,4-oxadiazol-2-yl)-[2,2'-bipyridine]-4-carboxylate
Methyl 5'-(phenylamino)-[2,2'-bipyridine]-4-carboxylate) ;
Methyl 5'-(3-phenylpropanamido)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(2-phenylacetamido)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(4-phenylbutanamido)-[2,2'-bipyridine]4-carboxylate;
Methyl 2-(5-(2-pheny!acetamido)pyrazin-2-y!)isonicotinate;
Methyl 2-(5-((3-phenyipropyl)amino)pyrazin-2-yl)isonicotinate;
Methyl 2-(5-(3-{diethylamino)propoxy)pyrazin-2-yl)iso-nicotinate;
Methyl 2-(5-(2-(diethylamino)ethoxy)pyrazin-2-yl)iso-nicotinate;
Methyl 5'-((3-(diethylamino)propoxy)methyl)-[2,2'-bipyridine]-4-cartx)xylate;
Methyl 5'-(2-morpholinoethoxy)-[212'-bipyridine]-4-carboxylate;
Methyl 5'-(3-(diethylamino)propoxy)-[2,2'-bipyridine3-4-carboxylate;
Methyl 5'-(4-(2-(diethyl amino)ethyl)-1 H-pyrazcl-1-yl)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(3-(ethyl(phenethyl)amino)propanamido)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-((3-(1 H-pyrazol-1 -yl)piOpyl)(methyi)amino)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(4-(diethylamino)butyl)-[2!2'-bipyridine]-4-carboxylate;
Methyl 5'-(2-{pyridin-2-yl)ethylamino)-2,2'-bipyridine-4-carboxylate;
Methyl 5'-((2-(diethylamino)ethoxy)methyl)-2,2'-bipyridine4-carboxylate;
Methyl 5'-(4-(4,4-difluoropiperidin-1-yl)butyl)-[2,2'-bipyridine]-4-carboxylate; Methyl 5'-(4-(1 H-pyrazol-1-yl)butyl)-[2,2'-bipyridine]4-carboxyiate;
Methyl 5'-(phenethoxymethyl)-[2,2'-bipyridine]-4-carboxyiate;
Methyl 5'-((3-phenylpropoxy)methyl)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-((cyclohexylmethoxy)methyl)-[2,2'-bipyridine]4-carboxylate;
Methyl 5,-((cyclopentylmethoxy)methyl)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(benzyloxy)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-phenethoxy-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(3-phenylpropoxy)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-butoxy-[2,2'-bipyridineJ-4-carboxylate;
Methyl 5'-(butyl(methyl)amino)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(2-{[1,1'-biphenyl]-4-yl)-N-butylacetamido)-[2,2'-bipyndine]-4-carboxylate;
Methyl 5'-{([1 ,1'-biphenyl]-4-ylmethyl){buiyl)amino)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(N-butyl-3-phenylpropanamido)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(butyl(3-phenylprOpyl)amino)-[2!2'-bipyridine]-4-ca*oxylate;
Methyl 5'-(N-butyl-1-methylcyclobutane-1-carboxamido)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(N-butyl-2-cyclobutylacetamido)-[2,2'-bipyridine]-4-carboxylate;
Methyl S'-iN-butyl-S-methoxypropanamidoJ-^^'-bipyridineH-carboxylate;
Methyl 5'-((3-(4,4-difluoropipendin-1-yl)propyl)(methyl)amino)-[2,2'-bipyridine]4-carboxylate
Methyl 5,-(butyl(3-(4,4-dif!uoropiperidin-1-yl)propyl)amino}-[2!2i-bipyridine]-4-carboxyiate;
Methyl 5'-(3-(4!4-difluoropiperidin-1-yl)propoxy)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-((cyclopropylmethyl)(methyl)amino)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5!-({2-cyciopropylethy1)(methyl)amino)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(3-(benzyloxy)propoxy)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(3-(ethyl(phenethyl)amino)propoxy)-[2,2'-bipyridine]-4-carboxylate;
Methyl 2-(5-(([1 ,1'-biphenyl]-4-ylmethyl)amino)pyrazin-2-yl)isonicotinate;
Methyl 5'-((2-(4,4-difluoropiperidin-1-y!)ethoxy)methyl)-[2,2'-bipyridine]-4-carboxylate;
Methyl 2-(5-(4-(diethylamino)butyl)pyrazin-2-yl)isonicotinate;
Methyl 5'-(methyl(10,10,10-trifluorodecyl)amino)-[2,2,-bipyridine]-4-carboxylate;
Methyl 5'-{([1 , 1 '-bipheny!]-4-ylmethyl)(methyl)amiTO)-[2!2'-bipyridine}-4-carboxylate;
Methyl 5'-((3-(4-chlorophenyl)propyl)(methyl)amino)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(3-methyloxetane-3-carboxamido)-2,2'-bipyridine-4-carboxylate;
Methyl 5'-(4-(dimethylamino)butanamido)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(2-(diethylamino)acetamido)-[2,2'-bipyridine]-4-carboxylate;
Methyl 5'-(3-(piperidin-1-yl)propanamido)-[2,2'-bipyridineH-carboxylate;
5'-(([1 , 1 '-Biphenyi]-4-ylmethyl)amino)-[2,2'-bipyridine3-4-caitioxyiic acid;
5'-((3-Aminopropyl)amino)-[2,2'-bipyridine3-4-carboxylic acid; 2-(5-(2-Phenylacetamido)pyrazin-2-y!)isonicotinic acid ,
Methyl 5'-(3-(pyrrolidin-1-yl) propanamido)-2, 2'-bipyridine-4-carboxylate;
Methyl 5'-(3-{cyclopentylamino)propanamido)-[2,2'-bipyridine]-4-carboxylate; Methyl 5X3-(cyclopentyl(ethyl)amino)piOpanamido)-[2,2'-bipyridine]4-carboxylate; Methyl 5'-(2-(4-(aminomethyl)phenyl)acetamido)-[2!2'-bipyridine]-4-carboxylate; 5'-(2-(4-(Aminomethyl)phenyl)acetamido)-[2,2'-bipyridine]-4-carboxyiic acid; Methyl 5'-(3-{diethylamino)prop-1-ynyl)-2,2'-bipyridine4-carboxylate:
Methyl 5'-(3-(diethylamino)propyl)-2,2'-bipyridine-4-carboxylate;
5'-{2-([1 , 1 '-Biphenyl]-4-yl)acetamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-Phenylpropoxy)-[2,2'-bipyridine]-4-carboxyiic acid;
5,-{4-(Dimethylamino)butanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(2-(Diethylamino)acetamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-(Piperidin-1-yl)propanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-Methoxypropanamido)-[2,2'-bipyridineH-carboxylic acid;
5'-(2-Cyclobutylacetamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(5-(Benzylamino)-1 ,3,4-oxadiazol-2-yl}-[2,2'-bipyridine]-4-carboxylic acid;
5'-(5-(Phenethy!amino)-1 ,3,4-oxadiazol-2-yl)-[2,2'-bipyridine]-4-carboxylic acid; 5XPhenylamino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-Phenylpropanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((3-(1-Methyl-1 H-pyrazol-4-yl) propyl)amino)-[2,2'-bipyridine]-4-carboxylic acid; 5'-((3-(4-Fluorophenyl) propyl)amino)-[2,2'-bipyridine]4-carboxylic acid;
5'-((3-(4-Chlorophenyl) propyl)amino)-[2,2'-bipyridine]-4-cart)oxylic acid;
5,-(3-(Diethylamino)propanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(2-Phenylacetamido}-[2,2'-bipyridine]-4-carboxyiic acid;
5'-(4-Phenylbutanamido)-[2,2'-bipyridine]-4-carboxylic acid;
2-(5-((3-Phenylpropyl)amino)pyrazin-2-yl)isonicotinic acid;
5,-(3-(Pyrrolidin-1-yl)propanamido)-[2,2'-bipyridine]4-carboxylic acid;
5'-(3-(Cyclopenty!amino)propanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-(Cyclopentyl(ethyi)amino)propanamido)-[2,2'-bipyridine]4-carboxylic acid; 2-(5-(3-(Diethylamino)propoxy)pyrazin-2-yl)isonicotinic acid;
2-(5-{2-(Diethylamino)ethoxy)pyrazin-2-yl)isonicotinic acid;
5'-((3-{Diethylamino)propoxy)methyl)-[2,2'-bipyridine]4-carboxylic acid ;
5'-(2-Morpholinoethoxy)-[2,2'-bipyridine]4-carboxylic acid;
5'-(3-{Diethylamino)propoxy)-[2,2'-bipyridine]4-carboxylic acid;
5'-(4-{2-(Diethylamino)ethyl)4 H-pyrazol-1-yl)-[2,2'-bipyridine]4-carboxylic acid; 5'-(3-(Ethyl(phenethyl)amino)propanamido)-[2,2'-bipyridine]4-carboxylic acid; 5'-(3-(Diethylamino)propyl)-2,2'-bipyridine-4-cartx)xylic acid;
5'-((3-(1 H-Pyrazo!-1-yi)propyi)(methyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(4-(Diethylamino)butyl)-[212l-bipyridine]-4-carboxylic acid;
5'-(2-(Pyridin-2-yl)ethylamino)-[2!2'-bipyridine]4-carboxylic acid;
5'-{(2-(DiethyIamsno)ethoxy)methyl)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(4-(4,4-Difluoropiperidin-1-yl}butyl)-[2>2'-bipyridine]-4-carboxylic acid;
5'-(4-(1 H-Pyrazol-1-yl)butyi)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(Phenethoxymethyl)-[2,2'-bipyridine]-4-carboxyiic acid;
5l-((Cyciohexylmeihoxy)meihy!)-[2J2'-bipyridine]-4-carboxylic acid;
5'-((Cyclopentylmethoxy)methyl)-2,2'-bipyridine4-carboxylic acid;
5'-(Benzyloxy)-[2,2'-bipyridine]-4-carboxylic acid;
5'-Phenethoxy-[2,2'-bipyridine]-4-carboxy!ic acid;
5'-(3-Phenylpropoxy)-[2,2'-bipyridine]-4-carboxylic acid;
5'-Butoxy-[2,2'-bipyridine]-4-carboxylic acid;
5'-(Butyl(methyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-{([1 ,1'-Biphenyl]-4-y!methyi)(butyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(N-Butyl-3-phenylpropanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(Butyi(3-phenylpropyi)amino)-[2,2'-bipyridine]-4-carboxy!ic acid;
^-(N-Butyl-l-methylcyclobutane-l-carboxamidoJ-p^'-bipyridineH-carboxylic acid; 5'-(N-Butyi-2-cyciobutylacetamido)-[2,2'-bipyridine]-4-carboxy!ic acid;
5'-(N-Butyl-3-methoxypropanamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-(4,4-Difluoropiperidin-1-yl) propyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((3-(44-Difluoropiperidin-1-yi}propyl)(methyl}amino)42>2'-bipyridine]-4-carboxylic acid; 2-(5-(4-(Diethyiamino)butyi)pyrazin-2-yl)isonicotinic acid;
5'-{Butyi{3-(4,4-difluoropipendin-1-yl)propyl)amino)-[2,2'-bipyridine]-4-carboxy!ic acid; 5'-(3-(44-Difluoropiperidin-1-yl)propoxy)-[2,2,-bipyridine]-4-carboxylic acid;
5'-((Cyciopropyimethyl)(methyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((2-Cyclopropylethyl)(methyl)amino)-[2,2'-bipyridine]-4-caitoxylic acid;
5'-(3-(Benzyloxy)propoxy)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-{Ethyl(phenethyl)amino)propoxy)-[2,2'-b!pyridine]4-carboxylic acid;
2-(5-(([1 ,1 '-Biphenyl]-4-yimethyl)amino)pyrazin-2-yl)isonicotinic acid;
5'-{(2-(4,4-Difluoropiperidin-1-yi)ethoxy)methyl)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(Methyl(10J0,10-trifluorodecyl)amino)-[2,2'-bipyridine]4-cartx)xylic acid;
5'-(([1 ,1 '-Biphenyl]-4-ylmethyl)(methyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((3-(4-Chlorophenyl)propy!)(methyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((3-Phenyipropoxy)methyl)-[2,2'-bipyridine]-4-carboxylic acid; 5'-{2-([1 J'-Biphenyl]-4-yl)-N-butylacetamido)-[2,2'-bipyridineH-carboxylic acid;
5'-(3-Methyloxetane-3-ca!toxamido)-2,2'-bipyridine-4-carboxyiic acid;
5'-({3-(1 H-Pyrazol-1-yl)propyl)amino)-3-fluoro-[2,2'-bipyridine]-4-carboxyiic acid;
5'-Pentyl-[2,2'-bipyridine]-4-carboxylic acid;
5'-((3-(1 H-Pyrazoi-1-yi)propyl)amino)-5-fiuoro-[2, 2'-bipyridine]-4-carboxylic acid;
Methyl 5'-(hydroxymethyl)-[2,2'-bipyridine]-4-carboxylate;
5'-(Benzyloxymethyl)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((Cyclopropylmethoxy)rnethyl)-[2,2'-bipyridine]-4-carboxylic acid;
or a salt thereof.
The compound of claim 3, wherein the compound is selected from:
5'-((3-(4-chlorophenyl) propyl)amino)-[2,2'-bipyridinej-4-carboxylic acid,
5'-(benzyloxy}-[2,2'-bipyridine]-4-carboxylic acid;
S'-iphenethoxymethyO-^^'-bipyridineH-carboxylic acid;
5'-(4-(4,4-difluoropiperidin-1-yl)butyl}-[2!2'-bipyridine]-4-carboxyiic acid;
5'-(3-(4,4-difluoropiperidin-1-yl)propoxy)-[2,2'-bipyridine]-4-carboxylic acid;
5,-((3-(4,4-difluoropiperidin-1-yl)propyl)(methyl)amino)-[2,2'-bipyridine]4-carboxylic acid; 5,-(butyl(3-(4,4-difluoropiperidin-1-yl)propyl)amino)-[2,2'-bipyridine]-4-carboxyiic acid; 5'-((cyclopropylmethoxy)methyl)-[2,2'-bipyridine]-4-cartx)xylic acid;
5'-{(cyclopropylmethyl)(methyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((2-cyctopropylethyl)(methyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-pentyl-[2,2'-bipyridine]-4-carboxylic acid;
5'-(butylamino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-{/V-Butyl-1 -methylcyclobutane-1 -carboxamido)-[2,2'-bipyridine]-4-carboxylic acid;
5'-((3-(1 H-Pyrazol-1-yl)propyl)amino)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(4-(2-(Diethy!amino)ethyl)-1H-pyrazol-1-yl)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(2-([1ir-Biphenyl]-4-yl)-W-butylacetamido)-{2,2'-bipyridine]-4-carboxy!ic acid;
5'-(2-([1 , 1 '-Biphenyl]-4-yl)acetamido)-[2,2'-bipyridine]-4-carboxylic acid;
5l-((2-(4,4-difluoropiperidin-1-yl)ethoxy)methyl)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-(Ethyl(phenethyl)amino)propoxy)-[2,2'-bipyridine]-4-carboxylic acid;
5'-(3-(Ethyl(phenethyl)amino)propanamido)-[2,2'-bipyridine]-4-carboxy!ic acid;
5'-(3-(Diethylamino)propoxy)-[2,2'-bipyridine]-4-carboxylic acid;
or a salt thereof.
A pharmaceutical composition which comprises a compound of any one of claims 1 to 48 or laceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
50. A compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, for use as a medicament.
51. A compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 49, for use in the treatment of a disease associated with a JmjC-KDM,
52. A compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 49, for use in the treatment of cancer.
53. A compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 49, for use in the treatment of a viral infection.
54. 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 48, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
55. A method for treating cancer, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
56. A method for treating a viral infection, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
57. Use of a compound of any one of claims 1 to 48, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease associated with a JmjC-KDM.
58. Use of a compound of any one of claims 1 to 48, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.
59. Use of a compound of any one of claims 1 to 48, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a viral infection.
60. In vitro use of a compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, as a JmjC-KDM inhibitor.
PCT/EP2017/063585 2016-06-03 2017-06-02 Heteroaryl-carboxylic acids as histone demethylase inhibitors WO2017207813A1 (en)

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